Genetic Determinants of Clinical Phenotype in Hypertrophic Cardiomyopathy

Genetic Determinants of Clinical Phenotype in Hypertrophic Cardiomyopathy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research article Genetic Determinants of Clinical Phenotype in Hypertrophic Cardiomyopathy Lazar Velicki, Djordje G Jakovljevic, Andrej Preveden, Miodrag Golubovic, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-36810/v5 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 09 Dec, 2020 Read the published version in BMC Cardiovascular Disorders → Version 5 posted 4 You are reading this latest preprint version Show more versions Abstract Background: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease that affects approximately one in 500 people. HCM is a recognized genetic disorder most often caused by mutations involving myosin-binding protein C (MYBPC3) and β-myosin heavy chain (MYH7) which are responsible for approximately three-quarters of the identified mutations. Methods: As a part of the international multidisciplinary SILICOFCM project ( www.silicofcm.eu ) the present study evaluated the association between underlying genetic mutations and clinical phenotype in patients with HCM. Only patients with confirmed single pathogenic mutations in either MYBPC3 or MYH7 genes were included in the study and divided into two groups accordingly. The MYBPC3 group was comprised of 48 patients (76%), while the MYH7 group included 15 patients (24%). Each patient underwent clinical examination and echocardiography. Results: The most prevalent symptom in patients with MYBPC3 was dyspnea (44%), whereas in patients with MYH7 it was palpitations (33%). The MYBPC3 group had a significantly higher number of patients with a positive family history of HCM (46% vs. 7%; p=0.014). There was a numerically higher prevalence of atrial fibrillation in the MYH7 group (60% vs. 35%, p=0.085). Laboratory analyses revealed normal levels of creatinine (85.5±18.3 vs. 81.3±16.4 µmol/l; p=0.487) and blood urea nitrogen (10.2±15.6 vs. 6.9±3.9 mmol/l; p=0.472) which were similar in both groups. The systolic anterior motion presence was significantly more frequent in patients carrying MYH7 mutation (33% vs. 10%; p=0.025), as well as mitral leaflet abnormalities (40% vs. 19%; p=0.039). Calcifications of mitral annulus were registered only in MYH7 patients (20% vs. 0%; p=0.001). The difference in diastolic function, i.e. E/e’ ratio between the two groups was also noted (MYBPC3 8.8±3.3, MYH7 13.9±6.9, p=0.079). Conclusions: Major findings of the present study corroborate the notion that MYH7 gene mutation patients are presented with more pronounced disease severity than those with MYBPC3. Cardiac & Cardiovascular Systems Hypertrophic Cardiomyopathy Clinical Phenotype Figures Figure 1 Background Hypertrophic cardiomyopathy (HCM) is the most frequent inherited disease of the myocardium, with a prevalence of approximately 0.2% [1, 2]. Despite the significant developments in diagnostic tools and genetic tests, the diagnosis of HCM is often delayed [2]. HCM is characterized by left ventricular (LV) hypertrophy without dilatation, in the absence of any other cardiac, systemic, metabolic, or syndromic disease that could explain myocardial hypertrophy [2-5]. Clinical presentation of HCM varies from completely asymptomatic with normal life expectancy, to typical symptoms like chest pain, shortness of breath, heart failure, palpitations, syncope, and in the worst case even sudden cardiac death [2, 6]. Complications of non-obstructive HCM include advanced myocardial fibrosis, microvascular ischemia, and deterioration of cardiac function [7]. HCM is a recognized genetic disorder transmitted in an autosomal dominant fashion, caused by a single mutation in one of the sarcomeric protein genes, which can be present in either thick- or thin-filament genes [8, 9]. The two most common mutations involving thick filament are myosin-binding protein C (MYBPC3) and β-myosin heavy chain (MYH7) gene mutations, which are responsible for approximately three-quarters of the identified mutations in HCM patients [9, 10]. Aside from these two, a few other less frequent gene mutations (e.g. troponin I type 3 [TNNI3], troponin T type 2 [TNNT2], α-tropomyosin [TPM1], α-actin [ACTC]) are possible causes of HCM as well and are therefore also included in the routine HCM genetic testing [11]. Technological progress has made it possible to identify new genes associated with HCM - numerous other genes that do not encode sarcomere proteins but rather genes encoding the synthesis of Z-disk proteins and proteins involved in the calcium signaling pathway. With the introduction and implementation of the next-generation sequencing solutions, the identification of nearly 50 gene mutations associated with some form of HCM throughout literature has become possible [12]. Regardless of the mutation type, the same pathophysiology mechanisms are responsible for the development of typical HCM phenotype and disease progression. Disrupted sarcomere properties due to the mutations cause impaired relaxation and lead to diastolic dysfunction, which is followed by hyperdynamic contractility and hypertrophy of the LV in the later course [9, 11]. Due to variable penetrance and expressivity, the phenotypic characteristics of HCM are multifaceted and may be influenced by other factors beyond single pathogenic mutations [13]. In addition to LV hypertrophy, phenotypic HCM expression also includes myocardial hypercontractivity, myofibril disorganization, fibrosis, as well as the presence of mild myocardial inflammation. Although the clinical phenotype can partially differ depending on the affected gene, no distinctive correlation between disease severity and specific genes has been established. Moreover, clinical features such as disease penetration, hypertrophy severity, and patient prognosis are known to vary depending on different mutations within the same gene [11]. The precise link between determined underlying gene mutation and the clinical course remains elusive in this heterogeneous condition. The motivation to compile this HCM patient registry was to try to define what patient features are more prevalent with specific gene mutations and to establish whether the level of disease expression might be linked to one of the two most common mutations responsible for HCM. The goal was to reveal and distinguish subtle differences that may exist in clinical presentation and, more importantly, in heart structure and function recorded by cardiac imaging (i.e. echocardiography) between different gene mutations, thus providing essential information for the computational model development. Moreover, data from this study will also complement the clinical trial (NCT03832660 at clinicaltrials.gov ) evaluating the effects of pharmacological (sacubitril/valsartan) versus lifestyle intervention in HCM patients [14], also a fundamental part of the SILICOFCM project. Methods As a part of the international multidisciplinary SILICOFCM project ( www.silicofcm.eu ) developing a computational platform for in silico clinical trials of familial cardiomyopathies, the present study evaluated the association between genetic mutations and clinical phenotype in patients with HCM. The study protocol was approved by the UK National Health Service Health Research Authority North East – Tyne & Wear South Research Ethics Committee with the reference number 18/NE/0318 and was adopted by the Institutional Review Board of each participating center. All patients provided written informed consent and all procedures were conducted following the Declaration of Helsinki. Study design Participating centers included patients with diagnoses of HCM who were identified in the period from June 2018 to February 2019. The diagnosis of HCM was defined according to the European Society of Cardiology guidelines i.e. maximal LV wall thickness of ≥15 mm on echocardiography, in the absence of any other cardiac or systemic disease that would be capable of producing myocardial hypertrophy, such as afterload abnormalities like aortic valve stenosis or arterial hypertension [5]. Of the total of 74 HCM patients, 11 were excluded because of the relatively small number of other gene mutations (TNNI3 – 5 patients, TNNT2 – 2 patients, TPM1 – 1 patient, myosin heavy chain 6 – 1 patient, myosin light chain 2 – 1 patient, lamin A/C – 1 patient) might have biased the overall study analysis. In the final analysis, the study included a total of 63 adult patients with a confirmed diagnosis of HCM. We excluded patients with significant atherosclerotic coronary artery disease (>50% stenosis in a major artery), patients with prior cardiac surgery (including septal myectomy), alcohol septal ablation, major LV outflow obstruction with pressure gradient >50 mmHg, and chronic renal failure (<30 ml/min/1.73 m 2 ). Genetic testing Genetic testing was performed from peripheral blood samples acquired by phlebotomy with the utilization of the QIAamp DNA Blood BioRobot MDx kit (QIAGEN GmbH, Hilden, Germany). Polymerase chain reaction with primers was used for the amplification of candidate exons. Blood samples were analyzed for the presence of the 8 most common mutations, which represent the basis of the commonly available genetic tests for HCM. These mutations include the protein-coding exons responsible for encoding myosin-binding protein C (MYBPC3), thick-filament proteins (β-myosin heavy chain [MYH7] and the regulatory and essential light chains [MYL2 and MYL3]), and thin-filament proteins (troponin T type 2 [TNNT2], troponin I type 3 [TNNI3], α-tropomyosin [TPM1], and α-actin [ACTC]). Only patients with confirmed single pathogenic mutations in either MYBPC3 or MYH7 genes were included in the study. Based on the identified gene mutation the patients were divided into two groups. The MYBPC3 group was comprised of 48 patients (76%), while the MYH7 group included 15 patients (24%). Electrocardiogram and ECG Holter monitoring The ECG was performed using a standard 12-lead­electrocardiogram in a supine position. To identify sporadic arrhythmia, all participants were asked to wear an ECG-Holter monitor for 24 hours and to keep a diary of activities and symptoms. Echocardiography Transthoracic echocardiography was performed in all patients. Images were obtained using regular parasternal and apical views. All the parameters were calculated and indexed for body surface area (BSA). LV wall thickness and chamber dimensions were measured using the parasternal long-axis view [14, 15]. The Devereux formula [16] was used to calculate LV myocardial mass. LV geometry was assessed by the relative wall thickness which is calculated as two times the LV posterior wall thickness divided by LV end-diastolic diameter. LV systolic and diastolic volumes were measured with Simpson’s modified biplane method using apical 4-chamber and 2-chamber views, and LV systolic function was expressed through the ejection fraction [15]. For diastolic function assessment, an apical 4-chamber view was used [17]. Blood flow through the mitral valve was measured by pulsed-wave Doppler between the tips of mitral leaflets and the peak modal velocity in early diastole (E) was determined. Velocities of basal regions at lateral and septal mitral annulus were recorded using tissue Doppler imaging and then their average ratio (e’) was computed. The filling pressure of the LV was expressed through the E/e’ ratio, which is the most accurate indicator of diastolic function according to the literature [18]. Statistical analysis Continuous variables are expressed as mean values ± standard deviation and categorical variables are presented as absolute numbers and percentages. Quantitative data distribution was assessed using the Kolmogorov–Smirnov test. Mean values of continuous variables were compared using the independent samples t-test or Mann-Whitney U test, whereas categorical variables were compared using the chi-square test. Statistical significance for all tests was set at the p-value of <0.05. All the analyses were done in SPSS version 20.0. Results The mean age of HCM patients regardless of genetic mutation was 51.1±14.2 years and most of them were male 48 (76%). They were slightly overweight according to their mean BMI of 26.4±4.4 kg/m 2 . One-third of patients (36%) had a positive family history for HCM. Differences in terms of patient profile depending on genetic mutation are shown in Table 1. There was no significant difference between patients carrying the MYBPC3 and MYH7 mutations regarding age (49.8±14.3 vs. 55.1±13.3 years, p=0.211) and gender distribution (21% vs. 33% females, p=0.321). The most prevalent symptom in patients with MYBPC3 was dyspnea (44%), whereas in patients with MYH7 it was palpitations (33%). Other less frequently reported symptoms included fatigue, chest pain, and syncope, with similar distribution among the groups. Interestingly, the MYBPC3 group had a significantly higher number of patients with a positive family history of HCM (46% vs. 7%; p=0.014). Table 1 General characteristics of patients with MYBPC3 and MYH7 gene mutation Overall MYBPC3 MYH7 p-value Age (years) 51.1±14.2 49.8±14.3 55.1±13.3 0.211 Females, n (%) 15 (23.8%) 10 (20.8%) 5 (33.3%) 0.321 BMI (kg/m 2 ) 26.4±4.4 26.1±4.6 27.8±3.1 0.260 Fatigue, n (%) 9 (14.3%) 7 (14.6%) 2 (13.3%) 0.881 Dyspnea, n (%) 25 (39.7%) 21 (43.7%) 4 (26.7%) 0.238 Chest pain, n (%) 6 (9.5%) 4 (8.3%) 2 (13.3%) 0.565 Palpitations, n (%) 13 (20.6%) 8 (16.7%) 5 (33.3%) 0.177 Syncope, n (%) 10 (15.9%) 9 (18.7%) 1 (6.6%) 0.264 Family history of HCM, n (%) 23 (36.5%) 22 (45.8%) 1 (6.6%) 0.014* Comorbidities Diabetes mellitus, n (%) 3 (4.8%) 3 (6.2%) - - Chronic obstructive pulmonary disease, n (%) 2 (3.2%) 2 (4.2%) - - Thyroid dysfunction, n (%) 8 (12.7%) 7 (14.6%) 1 (6.7%) 0.422 Anemia, n (%) 1 (1.6%) 1 (2.1%) - - Laboratory analyses Glucose (mmol/l) 5.6±1.2 5.8±1.3 5.0±0.6 0.071 Creatinine (µmol/l) 84.4±17.7 85.5±18.3 81.3±16.4 0.487 Blood urea nitrogen (mmol/l) 9.0±12.7 10.2±15.6 6.9±3.9 0.472 ALT (U/l) 30.1±15.7 31.8±17.0 25.0±10.4 0.268 Total protein (g/l) 69.1±8.4 69.3±7.2 68.6±11.1 0.853 Albumin (g/l) 44.0±6.8 44.1±6.4 43.9±8.0 0.948 Sodium (mmol/l) 140.3±2.1 140.4±2.1 140.2±2.3 0.868 Potassium (mmol/l) 4.5±0.4 4.5±0.3 4.6±0.5 0.531 Calcium (mmol/l) 2.3±0.1 2.3±0.1 2.3±0.2 0.689 NT-proBNP (ng/l) 1328.3±1420.2 1304.5±1457.5 1757.2±1335.2 0.766 Abbreviations: ALT alanine transaminase; BMI body mass index, HCM hypertrophic cardiomyopathy; NT-proBNP N-terminal pro-brain natriuretic peptide The most frequently found comorbidity was thyroid gland dysfunction, which was present in 8 patients (13%) in total, without significant difference between MYBPC3 and MYH7 groups (15% vs. 7%; p=0.422). No significant difference between the MYBPC3 and MYH7 patients was observed in other comorbidities as well: diabetes mellitus (6% vs. 0%; p=0.321), chronic obstructive pulmonary disease (4% vs. 0%; p=0.422), anemia (2% vs. 0%; p=0.573). The mean heart rate was similar between MYBPC3 and MYH7 patients (64.6±11.8 vs. 67.8±20.4 bpm; p=0.546). However, there was a numerically higher prevalence of atrial fibrillation in the MYH7 group (60% vs. 35%, p=0.085). Blood laboratory analyses indicating renal and liver function, as well as blood glucose and electrolytes, showed levels within the reference range, without differences between MYBPC3 and MYH7 patients (Table 1). Levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) were elevated in all patients, but without difference among groups. Echocardiography findings are presented in Table 2 and Figure 1. There was no difference in the posterolateral wall (10.6±2.1 vs. 10.8±1.7 mm, p=0.776) and interventricular septum (21.5±7.0 vs. 21.6±7.9 mm, p=0.982) thickness between MYBPC3 and MYH7 patients. Left atrial volume was 14% lower (p=0.518) and left ventricular end-diastolic volume was 19% higher (p=0.560) in MYBPC3. Left ventricular end-systolic volume was similar between MYBPC3 and MYH7 (52.6±37.4 vs. 44.0±19.0 ml; p=0.700) as was left ventricular ejection fraction (55.6±8.2 vs. 54.1±6.3, p=0.594) and tricuspid annular plane systolic excursion (TAPSE) (21.0±4.4 vs. 22.5±6.0 mm, p=0.363). Importantly, the systolic anterior motion was significantly higher in patients carrying MYH7 mutation (33% vs. 10%; p=0.025), as well as mitral leaflet abnormalities (40% vs. 19%; p=0.039). Calcifications of mitral annulus were registered only in MYH7 patients (20% vs. 0%; p=0.001). An interesting finding is the difference of E/e’ ratio – a marker of LV filling pressure – between the groups (MYBPC3 8.8±3.3, MYH7 13.9±6.9, p=0.079). Although the level of significance is slightly beyond the threshold, the difference is indicative. Table 2 Echocardiography findings in patients with MYBPC3 and MYH7 gene mutation Overall MYBPC3 MYH7 p-value PLW thickness (mm) 10.6±2.0 10.6±2.1 10.8±1.7 0.776 IVS thickness (mm) 21.5±7.1 21.5±7.0 21.6±7.9 0.982 LA volume (ml) 115.6±56 111.7±83.9 130.3±87.2 0.518 LV end-diastolic volume (ml) 108.9±49.7 110.8±52.2 92.7±7.0 0.560 LV end-systolic volume (ml) 51.6±35.6 52.6±37.4 44.0±19.0 0.700 LV ejection fraction (%) 55.3±7.8 55.6±8.2 54.1±6.3 0.594 LV mass (g) 301.4±114.0 306.0±115.2 261.0±115.4 0.527 LV mass index (g/m 2 ) 155.9±52.3 159.0±53.1 129.5±43.1 0.364 Relative wall thickness 0.43±0.10 0.44±0.10 0.34±0.02 0.103 LV outflow pressure gradient (mmHg) 8.2±11.1 6.0±2.5 16.1±22.7 0.252 E/e’ ratio 9.7±4.5 8.8±3.3 13.9±6.9 0.079* TAPSE (mm) 21.4±4.8 21.0±4.4 22.5±6.0 0.363 Systolic anterior motion, n (%) 10 (15.9%) 5 (10.4%) 5 (33.3%) 0.025* Papillary muscle abnormalities, n (%) 4 (6.3%) 4 (8.3%) - 0.261 Mitral leaflet abnormalities, n (%) 15 (23.8%) 9 (18.8%) 6 (40.0%) 0.039* Calcification of mitral annulus, n (%) 3 (4.8%) - 3 (20.0%) 0.001* Abbreviations : PLW posterolateral wall, IVS interventricular septum, LA left atrium, LV left ventricle, E/e’ LV filling pressure, TAPSE tricuspid annular plane systolic excursion Discussion The genetic basis of HCM is more complex than previously thought: known genetic mutations are responsible for about half of the cases, while the remaining causes are unknown. Since variants have not been found to explain the presence of the disease in many patients, there are certainly other, yet unidentified genes. There is an emphasized need to discover additional genetic, epigenetic, and environmental causes that would explain the high proportion of cases of unknown etiology. For many newly reported genes, the lack of strong evidence to support a causal role in HCM creates uncertainty in the interpretation of the results. One of the major roles of genetic testing for HCM patients is better clinical surveillance of asymptomatic family members. This study analyzed the genetic determinacy of various clinical phenotype parameters among patients with HCM. Only carriers of a single gene mutation, either MYBPC3 or MYH7 were included. Studies that performed genetic screening in large cohorts of patients with a confirmed clinical diagnosis of HCM managed to detect a pathogenic mutation in about 40-50% of patients [13, 15], suggesting that as much as half of the HCM diagnosed patients do not have known sarcomeric gene mutations. The MYBPC3 and MYH7 mutations are the two most common mutations among HCM patients with identified sarcomeric gene mutations. A recent meta-analysis on 7675 HCM patients including a total of 51 studies performed by Sedaghat-Hamedani et al. [16] found that the prevalence of MYBPC3 and MYH7 gene mutations were 20% and 14%, respectively, while all the other mutations had a prevalence below 2%. HCM is a disease of a younger age, as it is often first diagnosed before the age of 40 [15, 17]. In our study, patients’ mean age was 50 for MYBPC3 and 55 for MYH7 mutations, with no significant difference among groups. This contrasts with previous findings, which suggest earlier onset and diagnosis of the disease for MYH7 mutation [16, 18]. Patients in our study were predominantly male, which is consistent with gender distribution across literature, where about two-thirds of HCM patients are male [13, 19, 20]. Olivotto et al. [21] in their multicenter study from 2005, examined differences in HCM presentation among genders in a population of 969 patients. Although most patients were male (59%), mortality rates did not differ among genders. The authors also pointed out that female patients with HCM although more symptomatic, were under-represented and older. Females were more susceptible to advanced heart failure development, mostly due to LV outflow obstruction. Results from a more recent study from Jang et al. [22] conducted on 202 HCM patients without LV outflow obstruction are in-line with previously mentioned. Jang et al. concluded that females had a higher incidence of heart failure, as well as a greater risk of hospitalization and cardiovascular-related mortality. A higher risk of heart failure in female patients was attributed to the differences in LA and LV morphology and diastolic function between the genders. Patients with MYBPC3 mutation in our study had a notable number (46%) of relatives with a confirmed HCM diagnosis. Across the literature, various rates of positive family history ranging from 25-70% have been reported [18, 19]. However, the reliability of these numbers should be taken with reserve, because family screening in patients with HCM has still not been fully implemented, despite the clear recommendations for a detailed follow-up of all adult first-degree relatives [5, 23]. New evidence suggests that screening should be performed even earlier in child age, especially in families with MYBPC3 and MYH7 mutations [24]. Moreover, the diagnosis in relatives is often established solely on phenotypic expression (i.e. imaging methods like echocardiography and cardiac magnetic resonance), without proper genetic testing. Even in the case of performed genetic analysis, currently available methods still fail to identify more than half of patients with HCM [25]. Several studies have attempted to differentiate between disease severity, progression, and phenotype-based on specific mutation subclasses, but there is currently no consensus as to whether a specific phenotype or prognosis can be predicted from an MYBPC3 mutation [26]. Mutation of the MYH7 gene is associated with an earlier onset of symptoms, more pronounced hypertrophy, and poor prognosis [27]. The Arg453Cys mutation of MYH7 is associated with a high incidence of terminal heart failure and premature death [28]. Several studies have found a correlation between five mutations (four in the MYH7 gene and one in the gene encoding cardiac troponin T) and high incidences of advanced cardiac death, however, these associations were not consistent with the results of other studies [29]. The study by Olivotto et al. [30] assessed the occurrence of atrial fibrillation and outcome in 480 consecutive HCM patients (age at diagnosis, 45±20 years; 61% male) during a follow-up period of 9.1±6.4 years. In their cohort, atrial fibrillation was documented in 107 patients, with a prevalence of 22%. The authors concluded that atrial fibrillation is associated with substantial risk for heart failure-related mortality, stroke, and severe functional disability, particularly in patients with outflow obstruction, those ≤50 years of age, or those developing chronic atrial fibrillation. Atrial fibrillation tended to be more prevalent in the MYH7 group in our study. This finding is consistent with previous studies [17, 31], which reported a higher incidence of atrial fibrillation in patients with MYH7 mutation in comparison to other HCM patients. Since the development of atrial fibrillation was associated with risk factors such as LA enlargement, LV wall thickness, and LV outflow tract obstruction, these results suggest that patients with MYH7 mutation present with a more severe clinical phenotype. However, a prospective study on 237 HCM patients with a mean follow-up period of 14±10 years found no statistically significant difference in atrial fibrillation between patients with MYBPC3 and MYH7 mutations, with an incidence of 31% and 37%, respectively [32]. Detailed analysis of echocardiography parameters between the MYBPC3 and MYH7 groups in the present study revealed a somewhat similar phenotype expression with minor differences between the groups, although with slightly more severe disease presentation in the MYH7 group. Most importantly, LV wall hypertrophy was equally expressed in both groups at the posterolateral wall and interventricular septum. Previous studies on larger groups of HCM patients that analyzed myocardial wall thickness measured by both echocardiography [16-18, 33] and cardiac magnetic resonance [20] also discovered no significant differences regarding LV wall thickness between MYBPC3 and MYH7 patients. The somewhat counterintuitive finding came from the Florence group [34], stating that LV mass index was normal in about 20% of patients with definite HCM phenotype and that increased LV mass alone should not be the parameter for establishing the clinical diagnosis of HCM. The LV mass correlated weakly with maximal wall thickness and proved more sensitive in predicting outcomes. Heart systolic function measured through ejection fraction for LV and TAPSE for right ventricle were preserved in all study patients, with no differences between the groups. This is consistent with previous findings and the current standpoint that HCM generally does not lead to systolic function deterioration. The symptoms and clinical severity are dominantly determined by the combination of diastolic dysfunction, mitral apparatus abnormalities, and LV outflow tract obstruction [35, 36]. A recent study by Miller et al. [37] established that patients with pathogenic, likely pathogenic or rare MYH7 variants had higher LV ejection fraction than those with MYBPC3 variants (68.8 vs. 59.1, p<0.001) and higher right ventricle ejection fraction (67.3 vs. 60.8, p = 0.018). Additionally, patients with MYBPC3 variants were more likely to have LV ejection fraction <55% (29.7% vs. 4.9%, p = 0.005). A very interesting paper from Maron et al. [38] explored mitral valve abnormalities in HCM patients using cardiovascular magnetic resonance imaging. Mitral valve morphology was observed and compared between 172 patients with HCM and 172 controls without evidence of cardiovascular disease. After careful characterization, they concluded that mitral valve abnormalities (i.e. leaflet elongation) independently contribute to the severity of HCM presentation, thus expanding the area undesirable effects of HCM genes from solely sarcomere mutations to valvular structures as well. We wanted to further classify mitral valve abnormalities depending on the genetic basis. In this regard, the MYH7 group in our study had a significantly higher number of mitral leaflet abnormalities, mitral annulus calcifications, and the most important higher number of systolic anterior motion, contributing to the worse phenotype expression of MYH7 versus MYBPC3 gene mutations. The study of Groarke et al. [39] observed an increased number of mitral valve abnormalities in patients with sarcomeric gene mutations, however, they did not analyze the difference among the particular gene mutations. Waldmuller et al. [15] on the other hand, reported a more severe level of mitral regurgitation in patients with MYH7 mutation than in patients with MYBPC3 mutation. Diagnosis of hereditary cardiac disorders based on genetic information is particularly challenging because of the high genetic heterogeneity and overlapping and variable nature of these clinical presentations. The clinical presentation of HCM is influenced by age, lifestyle, and presence of hypertension, among other factors. Although there is still no consensus on the exact impact of gender on HCM presentation and progression, gender influence is thought to exist and that differences in gene expression and hormonal differences affect the symptoms and clinical outcomes of HCM. Our study was able to demonstrate the subtle but clinically important difference between patients with different genetic profiles. The clinical implications that may arise from these findings point to the fact that structural abnormalities are more prevalent in MYH7 gene mutation. Patients with MYH7 mutation would probably benefit from more intense imaging surveillance that should start at a younger age as they are likely to develop mitral valve dysfunction and LVOT obstruction. Concerning diastolic dysfunction, it is reasonable to assume that patients with MYH7 gene mutation would benefit from earlier commencement and more aggressive medical treatment. Given the clinical profile, MYH7 mutation patients would be ideal candidates for cardiac myosin inhibitors such as mavacamten. Strenuous exercise should be routinely discouraged, especially in patients with the MYH7 gene mutation. Our data also suggest and confirm already established management paradigms – an individualized approach concerning specific underlying clinical conditions and pathways (sudden cardiac death risk, heart failure, and atrial fibrillation). Such an approach has been proven to provide the opportunity to aggressively alter the progression of the disease, prevent mortality, and provide normal or extended life expectancy associated with improved quality of life. Study limitations We acknowledge that the large number of operators involved in echocardiographic measurements in this multicenter study represents an unavoidable limitation. However, care was taken to standardize measurements of cardiac dimension and function by prospectively providing detailed technical instructions to all participating centers. Finally, although the number of included patients in the study is modest, we believe that patient heterogenicity (multicenter study) confers substantial power to our data. Nevertheless, the modest size is one reason to exercise caution in extrapolating these results to the broad spectrum of hypertrophic cardiomyopathy. A cross-sectional study design does not allow monitoring of disease progression. However, disease progression and response to pharmacological and lifestyle intervention in HCM is subject to our separate ongoing longitudinal SILICOFCM study [14, 40]. Conclusions Up to this point, numerous mutations leading to HCM have been identified and various clinical manifestations and phenotypic expressions of HCM have been described (from a completely asymptomatic condition, through outflow tract obstruction, diastolic dysfunction, to progressive heart failure and sudden cardiac death). However, no consistent association between the HCM genotype and phenotype have been identified. In those terms, our study is no exception. Although we focused our attention on the two most common sarcomeric gene mutations responsible for HCM – MYBPC3 and MYH7 gene mutations – we were not able to demonstrate any substantial differences regarding clinical and echocardiography findings. More frequent systolic anterior motion and other mitral valve abnormalities as well as increased left ventricle filling pressure in MYH7 gene mutation suggests that MYH7 gene mutation does present with a more severe disease phenotype. Correlation between the genetic and clinical status of HCM patients remains elusive in most of the cases - limitation with a major impact on the development of personalized medicine approaches. Our study might subtly add to the overall understanding of such complex relations and might push genetic testing results from strictly diagnostic to prognostic fashion. Abbreviations ACTC: α-actin; BMI: body mass index; BSA: body surface area; CO: cardiac output; E/e’: left ventricle filling pressure; HCM: hypertrophic cardiomyopathy; HR: heart rate; IVS: interventricular septum; LA: left atrium; LV: left ventricle; LVEDV: left ventricular end-diastolic volume; LVESV: left ventricle end-systolic volume; LVmass: left ventricle myocardial mass; MYBPC3: myosin-binding protein C; MYH7: β-myosin heavy chain; PLW: posterolateral wall; RWT: relative wall thickness; SV: stroke volume; TAPSE: tricuspid annular plane systolic excursion; TNNI3: troponin I type 3; TNNT2: troponin T type 2; TPM1: α-tropomyosin. Declarations Ethics approval and consent to participate The study was approved by the UK National Health Service Health Research Authority North East – Tyne & Wear South Research Ethics Committee with reference number 18/NE/0318 and adopted by the Institutional Review Board of each participating institution with study participants providing written informed consent. Consent for publication Not applicable. Availability of data and materials The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding This work has been conducted as part of the SILICOFCM project which received funding from the European Union’s Horizon 2020 Research and Innovation Programme under Grant Agreement No 777204. The funder did not influence the design of the study and data collection, analysis, and interpretation of data, nor writing the manuscript. Authors' contributions LV, DGJ, LM, and IO conceptualized and designed the study. LV and AP analyzed and interpreted the data, and wrote the manuscript. LV, DGJ, AR, GAM, LM, and IO revised the manuscript. AP, MG, MB, AI, SS, FB, MT, NO, MT, PB, NF, and DP participated in data acquisition and database creation. All authors approved the final version of the manuscript. Acknowledgments Part of this investigation was presented in the form of a poster presentation at the EuroHeartCare ACNAP Congress 2020. References Maron BJ, Maron MS. Hypertrophic cardiomyopathy. Lancet. 2013;381(9862):242-55. Maron BJ. Clinical Course and Management of Hypertrophic Cardiomyopathy. The New England journal of medicine. 2018;379(20):1977. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011;124(24):2761-96. Maron BJ, Ommen SR, Semsarian C, Spirito P, Olivotto I, Maron MS. Hypertrophic cardiomyopathy: present and future, with translation into contemporary cardiovascular medicine. Journal of the American College of Cardiology. 2014;64(1):83-99. Authors/Task Force m, Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). European heart journal. 2014;35(39):2733-79. Force T, Bonow RO, Houser SR, Solaro RJ, Hershberger RE, Adhikari B, et al. Research priorities in hypertrophic cardiomyopathy: report of a Working Group of the National Heart, Lung, and Blood Institute. Circulation. 2010;122(11):1130-3. Lu DY, Pozios I, Haileselassie B, Ventoulis I, Liu H, Sorensen LL, et al. Clinical Outcomes in Patients With Nonobstructive, Labile, and Obstructive Hypertrophic Cardiomyopathy. Journal of the American Heart Association. 2018;7(5). Lopes LR, Rahman MS, Elliott PM. A systematic review and meta-analysis of genotype-phenotype associations in patients with hypertrophic cardiomyopathy caused by sarcomeric protein mutations. Heart. 2013;99(24):1800-11. Garfinkel AC, Seidman JG, Seidman CE. Genetic Pathogenesis of Hypertrophic and Dilated Cardiomyopathy. Heart failure clinics. 2018;14(2):139-46. Olivotto I, Girolami F, Ackerman MJ, Nistri S, Bos JM, Zachara E, et al. Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy. Mayo Clinic proceedings. 2008;83(6):630-8. Keren A, Syrris P, McKenna WJ. Hypertrophic cardiomyopathy: the genetic determinants of clinical disease expression. Nature clinical practice Cardiovascular medicine. 2008;5(3):158-68. Mazzarotto F, Girolami F, Boschi B, Barlocco F, Tomberli A, Baldini K, et al. Defining the diagnostic effectiveness of genes for inclusion in panels: the experience of two decades of genetic testing for hypertrophic cardiomyopathy at a single center. Genetics in medicine : official journal of the American College of Medical Genetics. 2019;21(2):284-92. Millat G, Bouvagnet P, Chevalier P, Dauphin C, Jouk PS, Da Costa A, et al. Prevalence and spectrum of mutations in a cohort of 192 unrelated patients with hypertrophic cardiomyopathy. European journal of medical genetics. 2010;53(5):261-7. Tafelmeier M, Baessler A, Wagner S, Unsoeld B, Preveden A, Barlocco F, et al. Design of the SILICOFCM study: Effect of sacubitril/valsartan vs lifestyle intervention on functional capacity in patients with hypertrophic cardiomyopathy. Clinical cardiology. 2020. Waldmuller S, Erdmann J, Binner P, Gelbrich G, Pankuweit S, Geier C, et al. Novel correlations between the genotype and the phenotype of hypertrophic and dilated cardiomyopathy: results from the German Competence Network Heart Failure. European journal of heart failure. 2011;13(11):1185-92. Sedaghat-Hamedani F, Kayvanpour E, Tugrul OF, Lai A, Amr A, Haas J, et al. Clinical outcomes associated with sarcomere mutations in hypertrophic cardiomyopathy: a meta-analysis on 7675 individuals. Clinical research in cardiology: official journal of the German Cardiac Society. 2018;107(1):30-41. Marsiglia JD, Credidio FL, de Oliveira TG, Reis RF, Antunes Mde O, de Araujo AQ, et al. Screening of MYH7, MYBPC3, and TNNT2 genes in Brazilian patients with hypertrophic cardiomyopathy. American heart journal. 2013;166(4):775-82. Garcia-Castro M, Coto E, Reguero JR, Berrazueta JR, Alvarez V, Alonso B, et al. [Mutations in sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in patients with hypertrophic cardiomyopathy]. Rev Esp Cardiol. 2009;62(1):48-56. Liu X, Jiang T, Piao C, Li X, Guo J, Zheng S, et al. Screening Mutations of MYBPC3 in 114 Unrelated Patients with Hypertrophic Cardiomyopathy by Targeted Capture and Next-generation Sequencing. Scientific reports. 2015;5:11411. Weissler-Snir A, Hindieh W, Gruner C, Fourey D, Appelbaum E, Rowin E, et al. Lack of Phenotypic Differences by Cardiovascular Magnetic Resonance Imaging in MYH7 (beta-Myosin Heavy Chain)- Versus MYBPC3 (Myosin-Binding Protein C)-Related Hypertrophic Cardiomyopathy. Circulation Cardiovascular imaging. 2017;10(2). Olivotto I, Maron MS, Adabag AS, Casey SA, Vargiu D, Link MS, et al. Gender-related differences in the clinical presentation and outcome of hypertrophic cardiomyopathy. Journal of the American College of Cardiology. 2005;46(3):480-7. Jang JH, Shin SH, Beak YS, Ko KY, Kwon SW, Park SD, et al. Impact of gender on heart failure presentation in non-obstructive hypertrophic cardiomyopathy. Heart and vessels. 2020;35(2):214-22. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011;124(24):e783-831. Semsarian C, Ho CY. Screening children at risk for hypertrophic cardiomyopathy: balancing benefits and harms. European heart journal. 2019;40(45):3682-4. Marian AJ, Braunwald E. Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy. Circulation research. 2017;121(7):749-70. Kraft T, Montag J, Radocaj A, Brenner B. Hypertrophic Cardiomyopathy: Cell-to-Cell Imbalance in Gene Expression and Contraction Force as Trigger for Disease Phenotype Development. Circulation research. 2016;119(9):992-5. Hallioglu Kilinc O, Giray D, Bisgin A, Tug Bozdogan S, Karpuz D. Familial hypertrophic cardiomyopathy: A case with a new mutation in the MYBPC3 gene. Turk Kardiyoloji Dernegi arsivi : Turk Kardiyoloji Derneginin yayin organidir. 2017;45(5):450-3. Tower-Rader A, Desai MY. Phenotype-Genotype Correlation in Hypertrophic Cardiomyopathy: Less Signal, More Noise? Circulation Cardiovascular imaging. 2017;10(2). Weissler-Snir A, Adler A, Williams L, Gruner C, Rakowski H. Prevention of sudden death in hypertrophic cardiomyopathy: bridging the gaps in knowledge. European heart journal. 2017;38(22):1728-37. Olivotto I, Cecchi F, Casey SA, Dolara A, Traverse JH, Maron BJ. Impact of atrial fibrillation on the clinical course of hypertrophic cardiomyopathy. Circulation. 2001;104(21):2517-24. Lee SP, Ashley EA, Homburger J, Caleshu C, Green EM, Jacoby D, et al. Incident Atrial Fibrillation Is Associated With MYH7 Sarcomeric Gene Variation in Hypertrophic Cardiomyopathy. Circulation Heart failure. 2018;11(9):e005191. Bongini C, Ferrantini C, Girolami F, Coppini R, Arretini A, Targetti M, et al. Impact of Genotype on the Occurrence of Atrial Fibrillation in Patients With Hypertrophic Cardiomyopathy. The American journal of cardiology. 2016;117(7):1151-9. Viswanathan SK, Sanders HK, McNamara JW, Jagadeesan A, Jahangir A, Tajik AJ, et al. Hypertrophic cardiomyopathy clinical phenotype is independent of gene mutation and mutation dosage. PloS one. 2017;12(11):e0187948. Olivotto I, Maron MS, Autore C, Lesser JR, Rega L, Casolo G, et al. Assessment and significance of left ventricular mass by cardiovascular magnetic resonance in hypertrophic cardiomyopathy. Journal of the American College of Cardiology. 2008;52(7):559-66. Olivotto I, Cecchi F, Poggesi C, Yacoub MH. Patterns of disease progression in hypertrophic cardiomyopathy: an individualized approach to clinical staging. Circulation Heart failure. 2012;5(4):535-46. Ommen SR, Shah PM, Tajik AJ. Left ventricular outflow tract obstruction in hypertrophic cardiomyopathy: past, present and future. Heart. 2008;94(10):1276-81. Miller RJH, Heidary S, Pavlovic A, Schlachter A, Dash R, Fleischmann D, et al. Defining genotype-phenotype relationships in patients with hypertrophic cardiomyopathy using cardiovascular magnetic resonance imaging. PloS one. 2019;14(6):e0217612. Maron MS, Olivotto I, Harrigan C, Appelbaum E, Gibson CM, Lesser JR, et al. Mitral valve abnormalities identified by cardiovascular magnetic resonance represent a primary phenotypic expression of hypertrophic cardiomyopathy. Circulation. 2011;124(1):40-7. Groarke JD, Galazka PZ, Cirino AL, Lakdawala NK, Thune JJ, Bundgaard H, et al. Intrinsic mitral valve alterations in hypertrophic cardiomyopathy sarcomere mutation carriers. European heart journal cardiovascular Imaging. 2018;19(10):1109-16. Velicki L, Preveden A, Tafelmeier M, Olivotto I, Barlocco F, Popovic D, et al. Genetic determinants of clinical phenotype in hypertrophic cardiomyopathy. European journal of cardiovascular nursing. 2020;19(1_suppl):S43-S44. Cite Share Download PDF Status: Published Journal Publication published 09 Dec, 2020 Read the published version in BMC Cardiovascular Disorders → Version 5 posted Submission checks completed at journal 02 Dec, 2020 Editorial decision: Accept 30 Nov, 2020 Editor assigned by journal 29 Nov, 2020 Editor invited by journal 29 Nov, 2020 You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Despite the significant developments in diagnostic tools and genetic tests, the diagnosis of HCM is often delayed [2].\u003c/p\u003e\n\u003cp\u003eHCM is characterized by left ventricular (LV) hypertrophy without dilatation, in the absence of any other cardiac, systemic, metabolic, or syndromic disease that could explain myocardial hypertrophy [2-5]. Clinical presentation of HCM varies from completely asymptomatic with normal life expectancy, to typical symptoms like chest pain, shortness of breath, heart failure, palpitations, syncope, and in the worst case even sudden cardiac death [2, 6]. Complications of non-obstructive HCM include advanced myocardial fibrosis, microvascular ischemia, and deterioration of cardiac function [7].\u003c/p\u003e\n\u003cp\u003eHCM is a recognized genetic disorder transmitted in an autosomal dominant fashion, caused by a single mutation in one of the sarcomeric protein genes, which can be present in either thick- or thin-filament genes [8, 9]. The two most common mutations involving thick filament are myosin-binding protein C (MYBPC3) and \u0026beta;-myosin heavy chain (MYH7) gene mutations, which are responsible for approximately three-quarters of the identified mutations in HCM patients [9, 10]. Aside from these two, a few other less frequent gene mutations (e.g. troponin I type 3 [TNNI3], troponin T type 2 [TNNT2], \u0026alpha;-tropomyosin [TPM1], \u0026alpha;-actin [ACTC]) are possible causes of HCM as well and are therefore also included in the routine HCM genetic testing [11]. Technological progress has made it possible to identify new genes associated with HCM - numerous other genes that do not encode sarcomere proteins but rather genes encoding the synthesis of Z-disk proteins and proteins involved in the calcium signaling pathway. With the introduction and implementation of the next-generation sequencing solutions, the identification of nearly 50 gene mutations associated with some form of HCM throughout literature has become possible [12].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRegardless of the mutation type, the same pathophysiology mechanisms are responsible for the development of typical HCM phenotype and disease progression. Disrupted sarcomere properties due to the mutations cause impaired relaxation and lead to diastolic dysfunction, which is followed by hyperdynamic contractility and hypertrophy of the LV in the later course [9, 11].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDue to variable penetrance and expressivity, the phenotypic characteristics of HCM are multifaceted and may be influenced by other factors beyond single pathogenic mutations [13]. \u0026nbsp;In addition to LV hypertrophy, phenotypic HCM expression also includes myocardial hypercontractivity, myofibril disorganization, fibrosis, as well as the presence of mild myocardial inflammation. Although the clinical phenotype can partially differ depending on the affected gene, no distinctive correlation between disease severity and specific genes has been established. Moreover, clinical features such as disease penetration, hypertrophy severity, and patient prognosis are known to vary depending on different mutations within the same gene [11].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe precise link between determined underlying gene mutation and the clinical course remains elusive in this heterogeneous condition. The motivation to compile this HCM patient registry was to try to define what patient features are more prevalent with specific gene mutations and to establish whether the level of disease expression might be linked to one of the two most common mutations responsible for HCM. The goal was to reveal and distinguish subtle differences that may exist in clinical presentation and, more importantly, in heart structure and function recorded by cardiac imaging (i.e. echocardiography) between different gene mutations, thus providing essential information for the computational model development. Moreover, data from this study will also complement the clinical trial (NCT03832660 at \u003cem\u003eclinicaltrials.gov\u003c/em\u003e) evaluating the effects of pharmacological (sacubitril/valsartan) versus lifestyle intervention in HCM patients [14], also a fundamental part of the SILICOFCM project.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eAs a part of the international multidisciplinary SILICOFCM project (\u003cem\u003ewww.silicofcm.eu\u003c/em\u003e) developing a computational platform for \u003cem\u003ein silico\u003c/em\u003e clinical trials of familial cardiomyopathies, the present study evaluated the association between genetic mutations and clinical phenotype in patients with HCM. The study protocol was approved by the UK National Health Service Health Research Authority North East \u0026ndash; Tyne \u0026amp; Wear South Research Ethics Committee with the reference number 18/NE/0318 and was adopted by the Institutional Review Board of each participating center. All patients provided written informed consent and all procedures were conducted following the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStudy design\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipating centers included patients with diagnoses of HCM who were identified in the period from June 2018 to February 2019.\u003c/p\u003e\n\u003cp\u003eThe diagnosis of HCM was defined according to the European Society of Cardiology guidelines i.e. maximal LV wall thickness of \u0026ge;15 mm on echocardiography, in the absence of any other cardiac or systemic disease that would be capable of producing myocardial hypertrophy, such as afterload abnormalities like aortic valve stenosis or arterial hypertension [5]. Of the total of 74 HCM patients, 11 were excluded because of the relatively small number of other gene mutations (TNNI3 \u0026ndash; 5 patients, TNNT2 \u0026ndash; 2 patients, TPM1 \u0026ndash; 1 patient, myosin heavy chain 6 \u0026ndash; 1 patient, myosin light chain 2 \u0026ndash; 1 patient, lamin A/C \u0026ndash; 1 patient) might have biased the overall study analysis. In the final analysis, the study included a total of 63 adult patients with a confirmed diagnosis of HCM.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe excluded patients with significant atherosclerotic coronary artery disease (\u0026gt;50% stenosis in a major artery), patients with prior cardiac surgery (including septal myectomy), alcohol septal ablation, major LV outflow obstruction with pressure gradient \u0026gt;50 mmHg, and chronic renal failure (\u0026lt;30 ml/min/1.73 m\u003csup\u003e2\u003c/sup\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eGenetic testing\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGenetic testing was performed from peripheral blood samples acquired by phlebotomy with the utilization of the QIAamp DNA Blood BioRobot MDx kit (QIAGEN GmbH, Hilden, Germany). Polymerase chain reaction with primers was used for the amplification of candidate exons.\u003c/p\u003e\n\u003cp\u003eBlood samples were analyzed for the presence of the 8 most common mutations, which represent the basis of the commonly available genetic tests for HCM. These mutations include the protein-coding exons responsible for encoding myosin-binding protein C (MYBPC3), thick-filament proteins (\u0026beta;-myosin heavy chain [MYH7] and the regulatory and essential light chains [MYL2 and MYL3]), and thin-filament proteins (troponin T type 2 [TNNT2], troponin I type 3 [TNNI3], \u0026alpha;-tropomyosin [TPM1], and \u0026alpha;-actin [ACTC]).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOnly patients with confirmed single pathogenic mutations in either MYBPC3 or MYH7 genes were included in the study. Based on the identified gene mutation the patients were divided into two groups. The MYBPC3 group was comprised of 48 patients (76%), while the MYH7 group included 15 patients (24%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eElectrocardiogram and ECG Holter monitoring\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe ECG was performed using a standard 12-lead\u0026shy;electrocardiogram in a supine position. To identify sporadic arrhythmia, all participants were asked to wear an ECG-Holter monitor for 24 hours and to keep a diary of activities and symptoms.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEchocardiography\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTransthoracic echocardiography was performed in all patients. Images were obtained using regular parasternal and apical views. All the parameters were calculated and indexed for body surface area (BSA).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLV wall thickness and chamber dimensions were measured using the parasternal long-axis view [14, 15]. The Devereux formula [16] was used to calculate LV myocardial mass.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eLV geometry was assessed by the relative wall thickness which is calculated as two times the LV posterior wall thickness divided by LV end-diastolic diameter.\u003c/p\u003e\n\u003cp\u003eLV systolic and diastolic volumes were measured with Simpson\u0026rsquo;s modified biplane method using apical 4-chamber and 2-chamber views, and LV systolic function was expressed through the ejection fraction [15].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFor diastolic function assessment, an apical 4-chamber view was used [17]. Blood flow through the mitral valve was measured by pulsed-wave Doppler between the tips of mitral leaflets and the peak modal velocity in early diastole (E) was determined. Velocities of basal regions at lateral and septal mitral annulus were recorded using tissue Doppler imaging and then their average ratio (e\u0026rsquo;) was computed.\u003c/p\u003e\n\u003cp\u003eThe filling pressure of the LV was expressed through the E/e\u0026rsquo; ratio, which is the most accurate indicator of diastolic function according to the literature [18].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStatistical analysis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eContinuous variables are expressed as mean values \u0026plusmn; standard deviation and categorical variables are presented as absolute numbers and percentages. Quantitative data distribution was assessed using the Kolmogorov\u0026ndash;Smirnov test. Mean values of continuous variables were compared using the independent samples t-test or Mann-Whitney U test, whereas categorical variables were compared using the chi-square test. Statistical significance for all tests was set at the p-value of \u0026lt;0.05. All the analyses were done in SPSS version 20.0.\u0026nbsp;\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe mean age of HCM patients regardless of genetic mutation was 51.1\u0026plusmn;14.2 years and most of them were male 48 (76%). They were slightly overweight according to their mean BMI of 26.4\u0026plusmn;4.4 kg/m\u003csup\u003e2\u003c/sup\u003e. One-third of patients (36%) had a positive family history for HCM.\u003c/p\u003e\n\u003cp\u003eDifferences in terms of patient profile depending on genetic mutation are shown in Table 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThere was no significant difference between patients carrying the MYBPC3 and MYH7 mutations regarding age (49.8\u0026plusmn;14.3 vs. 55.1\u0026plusmn;13.3 years, p=0.211) and gender distribution (21% vs. 33% females, p=0.321).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe most prevalent symptom in patients with MYBPC3 was dyspnea (44%), whereas in patients with MYH7 it was palpitations (33%). Other less frequently reported symptoms included fatigue, chest pain, and syncope, with similar distribution among the groups.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eInterestingly, the MYBPC3 group had a significantly higher number of patients with a positive family history of HCM (46% vs. 7%; p=0.014).\u003c/p\u003e\n\u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eTable 1\u003c/span\u003e\u003c/strong\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e\u0026nbsp;General characteristics of patients with MYBPC3 and MYH7 gene mutation\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cdiv align=\"center\" style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;line-height:107%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\n \u003ctable style=\"border-collapse:collapse;border:none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:68.5pt;border:solid windowtext 1.0pt;border-left: none;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eOverall\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:68.5pt;border:solid windowtext 1.0pt;border-left: none;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eMYBPC3\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:61.45pt;border:solid windowtext 1.0pt;border-left: none;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eMYH7\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:53.05pt;border:solid windowtext 1.0pt;border-left: none;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003ep-value\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eAge (years)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e51.1\u0026plusmn;14.2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:68.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e49.8\u0026plusmn;14.3\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:61.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e55.1\u0026plusmn;13.3\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:53.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.211\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eFemales, \u003cem\u003en (%)\u003c/em\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e15 (23.8%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:68.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e10 (20.8%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:61.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e5 (33.3%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:53.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.321\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e26.4\u0026plusmn;4.4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:68.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e26.1\u0026plusmn;4.6\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:61.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e27.8\u0026plusmn;3.1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:53.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.260\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eFatigue, \u003cem\u003en (%)\u003c/em\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e9 (14.3%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:68.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e7 (14.6%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:61.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e2 (13.3%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:53.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.881\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eDyspnea, \u003cem\u003en (%)\u003c/em\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e25 (39.7%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:68.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e21 (43.7%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:61.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e4 (26.7%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:53.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.238\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eChest pain, \u003cem\u003en (%)\u003c/em\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e6 (9.5%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:68.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e4 (8.3%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:61.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e2 (13.3%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:53.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.565\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003ePalpitations, \u003cem\u003en (%)\u003c/em\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e13 (20.6%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:68.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e8 (16.7%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:61.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e5 (33.3%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:53.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.177\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eSyncope, \u003cem\u003en (%)\u003c/em\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e10 (15.9%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:68.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e9 (18.7%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:61.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e1 (6.6%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:53.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.264\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eFamily history of HCM, \u003cem\u003en (%)\u003c/em\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e23 (36.5%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:68.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e22 (45.8%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:61.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height: 200%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e1 (6.6%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:53.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height: 200%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.014*\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" style=\"width: 421.35pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eComorbidities\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;margin-left:15.65pt;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eDiabetes mellitus, \u003cem\u003en (%)\u003c/em\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e3 (4.8%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:68.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e3 (6.2%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:61.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height: 200%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e-\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:53.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e-\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;margin-left:15.65pt;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eChronic obstructive pulmonary disease, \u003cem\u003en (%)\u003c/em\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e2 (3.2%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e2 (4.2%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 61.45pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:200%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e-\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:53.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e-\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;margin-left:15.65pt;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eThyroid dysfunction, \u003cem\u003en (%)\u003c/em\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e8 (12.7%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:68.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e7 (14.6%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:61.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height: 200%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e1 (6.7%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:53.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e0.422\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;margin-left:15.65pt;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eAnemia, \u003cem\u003en (%)\u003c/em\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e1 (1.6%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:68.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e1 (2.1%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:61.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height: 200%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e-\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:53.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e-\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" style=\"width: 421.35pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eLaboratory analyses\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;margin-left:15.65pt;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eGlucose (mmol/l)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e5.6\u0026plusmn;1.2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:68.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e5.8\u0026plusmn;1.3\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:61.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height: 200%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e5.0\u0026plusmn;0.6\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:53.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e0.071\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;margin-left:15.65pt;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eCreatinine (\u0026micro;mol/l)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e84.4\u0026plusmn;17.7\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:68.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e85.5\u0026plusmn;18.3\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:61.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height: 200%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e81.3\u0026plusmn;16.4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:53.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e0.487\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;margin-left:15.65pt;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eBlood urea nitrogen (mmol/l)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e9.0\u0026plusmn;12.7\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:68.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e10.2\u0026plusmn;15.6\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:61.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height: 200%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e6.9\u0026plusmn;3.9\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:53.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e0.472\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;margin-left:15.65pt;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eALT (U/l)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e30.1\u0026plusmn;15.7\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:68.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e31.8\u0026plusmn;17.0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:61.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height: 200%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e25.0\u0026plusmn;10.4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:53.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e0.268\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;margin-left:15.65pt;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eTotal protein (g/l)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e69.1\u0026plusmn;8.4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:68.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e69.3\u0026plusmn;7.2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:61.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height: 200%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e68.6\u0026plusmn;11.1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:53.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e0.853\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;margin-left:15.65pt;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003eAlbumin (g/l)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e44.0\u0026plusmn;6.8\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:68.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e44.1\u0026plusmn;6.4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:61.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height: 200%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e43.9\u0026plusmn;8.0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:53.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e0.948\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;margin-left:15.65pt;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eSodium (mmol/l)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e140.3\u0026plusmn;2.1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:68.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e140.4\u0026plusmn;2.1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:61.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height: 200%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e140.2\u0026plusmn;2.3\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:53.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e0.868\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;margin-left:15.65pt;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003ePotassium (mmol/l)\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e4.5\u0026plusmn;0.4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:68.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e4.5\u0026plusmn;0.3\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:61.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height: 200%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e4.6\u0026plusmn;0.5\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:53.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e0.531\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;margin-left:15.65pt;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eCalcium (mmol/l)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e2.3\u0026plusmn;0.1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:68.5pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e2.3\u0026plusmn;0.1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:61.45pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height: 200%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e2.3\u0026plusmn;0.2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:53.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;'\u003e0.689\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;margin-left:15.65pt;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family: \"Times New Roman\",serif;'\u003eNT-proBNP (ng/l)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='line-height:200%;font-family:\"Times New Roman\",serif;'\u003e1328.3\u0026plusmn;1420.2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68.5pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='line-height:200%;font-family:\"Times New Roman\",serif;'\u003e1304.5\u0026plusmn;1457.5\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 61.45pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:200%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u003cspan style='line-height:200%;font-family:\"Times New Roman\",serif;'\u003e1757.2\u0026plusmn;1335.2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:53.05pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='line-height:200%;font-family:\"Times New Roman\",serif;'\u003e0.766\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" style=\"width: 421.35pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 12.55pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cem\u003e\u003cspan style='font-size:16px;line-height: 200%;font-family:\"Times New Roman\",serif;color:black;'\u003eAbbreviations: ALT\u0026nbsp;\u003c/span\u003e\u003c/em\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003ealanine transaminase;\u003cem\u003e\u0026nbsp;BMI\u003c/em\u003e body mass index, \u003cem\u003eHCM\u003c/em\u003e hypertrophic cardiomyopathy; \u003cem\u003eNT-proBNP\u0026nbsp;\u003c/em\u003eN-terminal pro-brain natriuretic peptide\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003eThe most frequently found comorbidity was thyroid gland dysfunction, which was present in 8 patients (13%) in total, without significant difference between MYBPC3 and MYH7 groups (15% vs. 7%; p=0.422). No significant difference between the MYBPC3 and MYH7 patients was observed in other comorbidities as well: diabetes mellitus (6% vs. 0%; p=0.321), chronic obstructive pulmonary disease (4% vs. 0%; p=0.422), anemia (2% vs. 0%; p=0.573).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe mean heart rate was similar between MYBPC3 and MYH7 patients (64.6\u0026plusmn;11.8 vs. 67.8\u0026plusmn;20.4 bpm; p=0.546). However, there was a numerically higher prevalence of atrial fibrillation in the MYH7 group (60% vs. 35%, p=0.085).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBlood laboratory analyses indicating renal and liver function, as well as blood glucose and electrolytes, showed levels within the reference range, without differences between MYBPC3 and MYH7 patients (Table 1). Levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) were elevated in all patients, but without difference among groups.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEchocardiography findings are presented in Table 2 and Figure 1. There was no difference in the posterolateral wall (10.6\u0026plusmn;2.1 vs. 10.8\u0026plusmn;1.7 mm, p=0.776) and interventricular septum (21.5\u0026plusmn;7.0 vs. 21.6\u0026plusmn;7.9 mm, p=0.982) thickness between MYBPC3 and MYH7 patients. Left atrial volume was 14% lower (p=0.518) and left ventricular end-diastolic volume was 19% higher (p=0.560) in MYBPC3. Left ventricular end-systolic volume was similar between MYBPC3 and MYH7 (52.6\u0026plusmn;37.4 vs. 44.0\u0026plusmn;19.0 ml; p=0.700) as was left ventricular ejection fraction (55.6\u0026plusmn;8.2 vs. 54.1\u0026plusmn;6.3, p=0.594) and tricuspid annular plane systolic excursion (TAPSE) (21.0\u0026plusmn;4.4 vs. 22.5\u0026plusmn;6.0 mm, p=0.363).\u003c/p\u003e\n\u003cp\u003eImportantly, the systolic anterior motion was significantly higher in patients carrying MYH7 mutation (33% vs. 10%; p=0.025), as well as mitral leaflet abnormalities (40% vs. 19%; p=0.039). Calcifications of mitral annulus were registered only in MYH7 patients (20% vs. 0%; p=0.001).\u003c/p\u003e\n\u003cp\u003eAn interesting finding is the difference of E/e\u0026rsquo; ratio \u0026ndash; a marker of LV filling pressure \u0026ndash; between the groups (MYBPC3 8.8\u0026plusmn;3.3, MYH7 13.9\u0026plusmn;6.9, p=0.079). Although the level of significance is slightly beyond the threshold, the difference is indicative.\u003c/p\u003e\n\u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eTable 2\u003c/span\u003e\u003c/strong\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e\u0026nbsp;Echocardiography findings in patients with MYBPC3 and MYH7 gene mutation\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cdiv align=\"center\" style='margin-top:0in;margin-right:0in;margin-bottom:8.0pt;margin-left:0in;line-height:107%;font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\n \u003ctable style=\"border-collapse:collapse;border:none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:71.4pt;border:solid windowtext 1.0pt;border-left: none;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eOverall\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:71.4pt;border:solid windowtext 1.0pt;border-left: none;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eMYBPC3\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:62.75pt;border:solid windowtext 1.0pt;border-left: none;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eMYH7\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:54.6pt;border:solid windowtext 1.0pt;border-left: none;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:center;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003ep-value\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003ePLW thickness (mm)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e10.6\u0026plusmn;2.0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:71.4pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e10.6\u0026plusmn;2.1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:62.75pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e10.8\u0026plusmn;1.7\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:54.6pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.776\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eIVS thickness (mm)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e21.5\u0026plusmn;7.1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:71.4pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e21.5\u0026plusmn;7.0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:62.75pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e21.6\u0026plusmn;7.9\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:54.6pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.982\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eLA volume (ml)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e115.6\u0026plusmn;56\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:71.4pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e111.7\u0026plusmn;83.9\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:62.75pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e130.3\u0026plusmn;87.2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:54.6pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.518\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eLV end-diastolic volume (ml)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:71.4pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e108.9\u0026plusmn;49.7\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:71.4pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e110.8\u0026plusmn;52.2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:62.75pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e92.7\u0026plusmn;7.0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:54.6pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.560\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eLV end-systolic volume (ml)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:71.4pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e51.6\u0026plusmn;35.6\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:71.4pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e52.6\u0026plusmn;37.4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:62.75pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e44.0\u0026plusmn;19.0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:54.6pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.700\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eLV ejection fraction (%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:71.4pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e55.3\u0026plusmn;7.8\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:71.4pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e55.6\u0026plusmn;8.2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:62.75pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e54.1\u0026plusmn;6.3\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:54.6pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.594\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eLV mass (g)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e301.4\u0026plusmn;114.0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:71.4pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e306.0\u0026plusmn;115.2\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:62.75pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e261.0\u0026plusmn;115.4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:54.6pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.527\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eLV mass index (g/m\u003csup\u003e2\u003c/sup\u003e)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e155.9\u0026plusmn;52.3\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:71.4pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e159.0\u0026plusmn;53.1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:62.75pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e129.5\u0026plusmn;43.1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:54.6pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.364\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eRelative wall thickness\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.4pt;border-top: none;border-left: none;border-bottom: 1pt solid windowtext;border-right: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.43\u0026plusmn;0.10\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:71.4pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.44\u0026plusmn;0.10\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:62.75pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.34\u0026plusmn;0.02\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:54.6pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.103\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eLV outflow pressure gradient (mmHg)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:71.4pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e8.2\u0026plusmn;11.1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:71.4pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e6.0\u0026plusmn;2.5\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:62.75pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e16.1\u0026plusmn;22.7\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:54.6pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.252\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eE/e\u0026rsquo; ratio\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:71.4pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e9.7\u0026plusmn;4.5\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:71.4pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e8.8\u0026plusmn;3.3\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:62.75pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e13.9\u0026plusmn;6.9\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:54.6pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cem\u003e\u003cspan style='font-size:16px;line-height: 200%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.079*\u003c/span\u003e\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eTAPSE (mm)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:71.4pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e21.4\u0026plusmn;4.8\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:71.4pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e21.0\u0026plusmn;4.4\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:62.75pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e22.5\u0026plusmn;6.0\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:54.6pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.363\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eSystolic anterior motion, \u003cem\u003en (%)\u003c/em\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:71.4pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e10 (15.9%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:71.4pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e5 (10.4%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:62.75pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height: 200%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e5 (33.3%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:54.6pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height: 200%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.025*\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003ePapillary muscle abnormalities, \u003cem\u003en (%)\u003c/em\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:71.4pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e4 (6.3%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:71.4pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e4 (8.3%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:62.75pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height: 200%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e-\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:54.6pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.261\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eMitral leaflet abnormalities, \u003cem\u003en (%)\u003c/em\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:71.4pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e15 (23.8%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:71.4pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e9 (18.8%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:62.75pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height: 200%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e6 (40.0%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:54.6pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height: 200%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.039*\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 169.85pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003eCalcification of mitral annulus, \u003cem\u003en (%)\u003c/em\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:71.4pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e3 (4.8%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:71.4pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e-\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:62.75pt;border-top:none;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height: 200%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;'\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e3 (20.0%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:54.6pt;border-top:none;border-left:none;border-bottom: solid windowtext 1.0pt;border-right:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height: 200%;font-family:\"Times New Roman\",serif;color:black;'\u003e0.001*\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" style=\"width: 430pt;border-right: 1pt solid windowtext;border-bottom: 1pt solid windowtext;border-left: 1pt solid windowtext;border-image: initial;border-top: none;padding: 0in 5.4pt;height: 19.95pt;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;line-height:200%;'\u003e\u003cem\u003e\u003cspan style='font-size:16px;line-height: 200%;font-family:\"Times New Roman\",serif;color:black;'\u003eAbbreviations\u003c/span\u003e\u003c/em\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e: \u003cem\u003ePLW\u003c/em\u003e posterolateral wall, \u003cem\u003eIVS\u003c/em\u003e interventricular septum, \u003cem\u003eLA\u003c/em\u003e left atrium, \u003cem\u003eLV\u003c/em\u003e left ventricle, \u003cem\u003eE/e\u0026rsquo;\u003c/em\u003e LV filling pressure, \u003cem\u003eTAPSE\u003c/em\u003e tricuspid annular plane systolic excursion\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp style='margin-top:0in;margin-right:0in;margin-bottom:0in;margin-left:0in;line-height:200%;font-size:15px;font-family:\"Calibri\",sans-serif;text-align:justify;'\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;line-height:200%;font-family:\"Times New Roman\",serif;color:black;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe genetic basis of HCM is more complex than previously thought: known genetic mutations are responsible for about half of the cases, while the remaining causes are unknown. Since variants have not been found to explain the presence of the disease in many patients, there are certainly other, yet unidentified genes. There is an emphasized need to discover additional genetic, epigenetic, and environmental causes that would explain the high proportion of cases of unknown etiology. For many newly reported genes, the lack of strong evidence to support a causal role in HCM creates uncertainty in the interpretation of the results. One of the major roles of genetic testing for HCM patients is better clinical surveillance of asymptomatic family members.\u003c/p\u003e\n\u003cp\u003eThis study analyzed the genetic determinacy of various clinical phenotype parameters among patients with HCM. Only carriers of a single gene mutation, either MYBPC3 or MYH7 were included. Studies that performed genetic screening in large cohorts of patients with a confirmed clinical diagnosis of HCM managed to detect a pathogenic mutation in about 40-50% of patients [13, 15], suggesting that as much as half of the HCM diagnosed patients do not have known sarcomeric gene mutations.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe MYBPC3 and MYH7 mutations are the two most common mutations among HCM patients with identified sarcomeric gene mutations. A recent meta-analysis on 7675 HCM patients including a total of 51 studies performed by Sedaghat-Hamedani et al. [16] found that the prevalence of MYBPC3 and MYH7 gene mutations were 20% and 14%, respectively, while all the other mutations had a prevalence below 2%.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHCM is a disease of a younger age, as it is often first diagnosed before the age of 40 [15, 17]. In our study, patients\u0026rsquo; mean age was 50 for MYBPC3 and 55 for MYH7 mutations, with no significant difference among groups. This contrasts with previous findings, which suggest earlier onset and diagnosis of the disease for MYH7 mutation [16, 18]. Patients in our study were predominantly male, which is consistent with gender distribution across literature, where about two-thirds of HCM patients are male [13, 19, 20].\u003c/p\u003e\n\u003cp\u003eOlivotto et al. [21] in their multicenter study from 2005, examined differences in HCM presentation among genders in a population of 969 patients. Although most patients were male (59%), mortality rates did not differ among genders. The authors also pointed out that female patients with HCM although more symptomatic, were under-represented and older. Females were more susceptible to advanced heart failure development, mostly due to LV outflow obstruction. Results from a more recent study from Jang et al. [22] conducted on 202 HCM patients without LV outflow obstruction are in-line with previously mentioned. Jang et al. concluded that females had a higher incidence of heart failure, as well as a greater risk of hospitalization and cardiovascular-related mortality. A higher risk of heart failure in female patients was attributed to the differences in LA and LV morphology and diastolic function between the genders.\u003c/p\u003e\n\u003cp\u003ePatients with MYBPC3 mutation in our study had a notable number (46%) of relatives with a confirmed HCM diagnosis. Across the literature, various rates of positive family history ranging from 25-70% have been reported [18, 19]. However, the reliability of these numbers should be taken with reserve, because family screening in patients with HCM has still not been fully implemented, despite the clear recommendations for a detailed follow-up of all adult first-degree relatives [5, 23]. New evidence suggests that screening should be performed even earlier in child age, especially in families with MYBPC3 and MYH7 mutations [24]. Moreover, the diagnosis in relatives is often established solely on phenotypic expression (i.e. imaging methods like echocardiography and cardiac magnetic resonance), without proper genetic testing. Even in the case of performed genetic analysis, currently available methods still fail to identify more than half of patients with HCM [25].\u003c/p\u003e\n\u003cp\u003eSeveral studies have attempted to differentiate between disease severity, progression, and phenotype-based on specific mutation subclasses, but there is currently no consensus as to whether a specific phenotype or prognosis can be predicted from an MYBPC3 mutation [26]. Mutation of the MYH7 gene is associated with an earlier onset of symptoms, more pronounced hypertrophy, and poor prognosis [27]. The Arg453Cys mutation of MYH7 is associated with a high incidence of terminal heart failure and premature death [28]. Several studies have found a correlation between five mutations (four in the MYH7 gene and one in the gene encoding cardiac troponin T) and high incidences of advanced cardiac death, however, these associations were not consistent with the results of other studies [29].\u003c/p\u003e\n\u003cp\u003eThe study by Olivotto et al. [30] assessed the occurrence of atrial fibrillation and outcome in 480 consecutive HCM patients (age at diagnosis, 45\u0026plusmn;20 years; 61% male) during a follow-up period of 9.1\u0026plusmn;6.4 years. In their cohort, atrial fibrillation was documented in 107 patients, with a prevalence of 22%. The authors concluded that atrial fibrillation is associated with substantial risk for heart failure-related mortality, stroke, and severe functional disability, particularly in patients with outflow obstruction, those \u0026le;50 years of age, or those developing chronic atrial fibrillation.\u003c/p\u003e\n\u003cp\u003eAtrial fibrillation tended to be more prevalent in the MYH7 group in our study. This finding is consistent with previous studies [17, 31], which reported a higher incidence of atrial fibrillation in patients with MYH7 mutation in comparison to other HCM patients. Since the development of atrial fibrillation was associated with risk factors such as LA enlargement, LV wall thickness, and LV outflow tract obstruction, these results suggest that patients with MYH7 mutation present with a more severe clinical phenotype. However, a prospective study on 237 HCM patients with a mean follow-up period of 14\u0026plusmn;10 years found no statistically significant difference in atrial fibrillation between patients with MYBPC3 and MYH7 mutations, with an incidence of 31% and 37%, respectively [32].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDetailed analysis of echocardiography parameters between the MYBPC3 and MYH7 groups in the present study revealed a somewhat similar phenotype expression with minor differences between the groups, although with slightly more severe disease presentation in the MYH7 group. Most importantly, LV wall hypertrophy was equally expressed in both groups at the posterolateral wall and interventricular septum. Previous studies on larger groups of HCM patients that analyzed myocardial wall thickness measured by both echocardiography [16-18, 33] and cardiac magnetic resonance [20] also discovered no significant differences regarding LV wall thickness between MYBPC3 and MYH7 patients. The somewhat counterintuitive finding came from the Florence group [34], stating that LV mass index was normal in about 20% of patients with definite HCM phenotype and that increased LV mass alone should not be the parameter for establishing the clinical diagnosis of HCM. The LV mass correlated weakly with maximal wall thickness and proved more sensitive in predicting outcomes.\u003c/p\u003e\n\u003cp\u003eHeart systolic function measured through ejection fraction for LV and TAPSE for right ventricle were preserved in all study patients, with no differences between the groups. This is consistent with previous findings and the current standpoint that HCM generally does not lead to systolic function deterioration. The symptoms and clinical severity are dominantly determined by the combination of diastolic dysfunction, mitral apparatus abnormalities, and LV outflow tract obstruction [35, 36]. A recent study by Miller et al. [37] established that patients with pathogenic, likely pathogenic or rare MYH7 variants had higher LV ejection fraction than those with MYBPC3 variants (68.8 vs. 59.1, p\u0026lt;0.001) and higher right ventricle ejection fraction (67.3 vs. 60.8, p = 0.018). Additionally, patients with MYBPC3 variants were more likely to have LV ejection fraction \u0026lt;55% (29.7% vs. 4.9%, p = 0.005).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA very interesting paper from Maron et al. [38] explored mitral valve abnormalities in HCM patients using cardiovascular magnetic resonance imaging. Mitral valve morphology was observed and compared between 172 patients with HCM and 172 controls without evidence of cardiovascular disease. After careful characterization, they concluded that mitral valve abnormalities (i.e. leaflet elongation) independently contribute to the severity of HCM presentation, thus expanding the area undesirable effects of HCM genes from solely sarcomere mutations to valvular structures as well. We wanted to further classify mitral valve abnormalities depending on the genetic basis. \u0026nbsp;In this regard, the MYH7 group in our study had a significantly higher number of mitral leaflet abnormalities, mitral annulus calcifications, and the most important higher number of systolic anterior motion, contributing to the worse phenotype expression of MYH7 versus MYBPC3 gene mutations. The study of Groarke et al. [39] observed an increased number of mitral valve abnormalities in patients with sarcomeric gene mutations, however, they did not analyze the difference among the particular gene mutations. Waldmuller et al. [15] on the other hand, reported a more severe level of mitral regurgitation in patients with MYH7 mutation than in patients with MYBPC3 mutation. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDiagnosis of hereditary cardiac disorders based on genetic information is particularly challenging because of the high genetic heterogeneity and overlapping and variable nature of these clinical presentations. The clinical presentation of HCM is influenced by age, lifestyle, and presence of hypertension, among other factors. Although there is still no consensus on the exact impact of gender on HCM presentation and progression, gender influence is thought to exist and that differences in gene expression and hormonal differences affect the symptoms and clinical outcomes of HCM.\u003c/p\u003e\n\u003cp\u003eOur study was able to demonstrate the subtle but clinically important difference between patients with different genetic profiles. The clinical implications that may arise from these findings point to the fact that structural abnormalities are more prevalent in MYH7 gene mutation. Patients with MYH7 mutation would probably benefit from more intense imaging surveillance that should start at a younger age as they are likely to develop mitral valve dysfunction and LVOT obstruction. Concerning diastolic dysfunction, it is reasonable to assume that patients with MYH7 gene mutation would benefit from earlier commencement and more aggressive medical treatment. Given the clinical profile, MYH7 mutation patients would be ideal candidates for cardiac myosin inhibitors such as mavacamten. Strenuous exercise should be routinely discouraged, especially in patients with the MYH7 gene mutation.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur data also suggest and confirm already established management paradigms \u0026ndash; an individualized approach concerning specific underlying clinical conditions and pathways (sudden cardiac death risk, heart failure, and atrial fibrillation). Such an approach has been proven to provide the opportunity to aggressively alter the progression of the disease, prevent mortality, and provide normal or extended life expectancy associated with improved quality of life.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStudy limitations\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe acknowledge that the large number of operators involved in echocardiographic measurements in this multicenter study represents an unavoidable limitation. However, care was taken to standardize measurements of cardiac dimension and function by prospectively providing detailed technical instructions to all participating centers.\u003c/p\u003e\n\u003cp\u003eFinally, although the number of included patients in the study is modest, we believe that patient heterogenicity (multicenter study) confers substantial power to our data. Nevertheless, the modest size is one reason to exercise caution in extrapolating these results to the broad spectrum of hypertrophic cardiomyopathy.\u003c/p\u003e\n\u003cp\u003eA cross-sectional study design does not allow monitoring of disease progression. However, disease progression and response to pharmacological and lifestyle intervention in HCM is subject to our separate ongoing longitudinal SILICOFCM study [14, 40].\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eUp to this point, numerous mutations leading to HCM have been identified and various clinical manifestations and phenotypic expressions of HCM have been described (from a completely asymptomatic condition, through outflow tract obstruction, diastolic dysfunction, to progressive heart failure and sudden cardiac death). However, no consistent association between the HCM genotype and phenotype have been identified.\u003c/p\u003e\n\u003cp\u003eIn those terms, our study is no exception. Although we focused our attention on the two most common sarcomeric gene mutations responsible for HCM \u0026ndash; MYBPC3 and MYH7 gene mutations \u0026ndash; we were not able to demonstrate any substantial differences regarding clinical and echocardiography findings. More frequent systolic anterior motion and other mitral valve abnormalities as well as increased left ventricle filling pressure in MYH7 gene mutation suggests that MYH7 gene mutation does present with a more severe disease phenotype.\u003c/p\u003e\n\u003cp\u003eCorrelation between the genetic and clinical status of HCM patients remains elusive in most of the cases - limitation with a major impact on the development of personalized medicine approaches. Our study might subtly add to the overall understanding of such complex relations and might push genetic testing results from strictly diagnostic to prognostic fashion.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eACTC: \u0026alpha;-actin; BMI: body mass index; BSA: body surface area; CO: cardiac output; E/e\u0026rsquo;: left ventricle filling pressure; HCM: hypertrophic cardiomyopathy; HR: heart rate; IVS: interventricular septum; LA: left atrium; LV: left ventricle; LVEDV: left ventricular end-diastolic volume; LVESV: left ventricle end-systolic volume; LVmass: left ventricle myocardial mass; MYBPC3: myosin-binding protein C; MYH7: \u0026beta;-myosin heavy chain; PLW: posterolateral wall; RWT: relative wall thickness; SV: stroke volume; TAPSE: tricuspid annular plane systolic excursion; TNNI3: troponin I type 3; TNNT2: troponin T type 2; TPM1: \u0026alpha;-tropomyosin.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by\u0026nbsp;the UK National Health Service Health Research Authority North East \u0026ndash; Tyne \u0026amp; Wear South Research Ethics Committee with reference number 18/NE/0318 and adopted by the\u0026nbsp;Institutional Review Board of each participating institution with study participants providing written informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConsent for publication\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAvailability of data and materials\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong style=\"text-align: inherit;\"\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work has been conducted as part of the SILICOFCM project which received funding from the European Union\u0026rsquo;s Horizon 2020 Research and Innovation Programme under Grant Agreement No 777204.\u0026nbsp;The funder did not influence the design of the study and data collection, analysis, and interpretation of data, nor writing the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthors\u0026apos; contributions\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLV, DGJ, LM, and IO conceptualized and designed the study. LV and AP analyzed and interpreted the data, and wrote the manuscript. LV, DGJ, AR, GAM, LM, and IO revised the manuscript. AP, MG, MB, AI, SS, FB, MT, NO, MT, PB, NF, and DP participated in data acquisition and database creation. All authors approved the final version of the manuscript. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAcknowledgments\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePart of this investigation was presented in the form of a poster presentation at the EuroHeartCare ACNAP Congress 2020.\u0026nbsp;\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMaron BJ, Maron MS. Hypertrophic cardiomyopathy. Lancet. 2013;381(9862):242-55.\u003c/li\u003e\n\u003cli\u003eMaron BJ. Clinical Course and Management of Hypertrophic Cardiomyopathy. The New England journal of medicine. 2018;379(20):1977.\u003c/li\u003e\n\u003cli\u003eGersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011;124(24):2761-96.\u003c/li\u003e\n\u003cli\u003eMaron BJ, Ommen SR, Semsarian C, Spirito P, Olivotto I, Maron MS. Hypertrophic cardiomyopathy: present and future, with translation into contemporary cardiovascular medicine. Journal of the American College of Cardiology. 2014;64(1):83-99.\u003c/li\u003e\n\u003cli\u003eAuthors/Task Force m, Elliott PM, Anastasakis A, Borger MA, Borggrefe M, Cecchi F, et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). European heart journal. 2014;35(39):2733-79.\u003c/li\u003e\n\u003cli\u003eForce T, Bonow RO, Houser SR, Solaro RJ, Hershberger RE, Adhikari B, et al. Research priorities in hypertrophic cardiomyopathy: report of a Working Group of the National Heart, Lung, and Blood Institute. Circulation. 2010;122(11):1130-3.\u003c/li\u003e\n\u003cli\u003eLu DY, Pozios I, Haileselassie B, Ventoulis I, Liu H, Sorensen LL, et al. Clinical Outcomes in Patients With Nonobstructive, Labile, and Obstructive Hypertrophic Cardiomyopathy. Journal of the American Heart Association. 2018;7(5).\u003c/li\u003e\n\u003cli\u003eLopes LR, Rahman MS, Elliott PM. A systematic review and meta-analysis of genotype-phenotype associations in patients with hypertrophic cardiomyopathy caused by sarcomeric protein mutations. Heart. 2013;99(24):1800-11.\u003c/li\u003e\n\u003cli\u003eGarfinkel AC, Seidman JG, Seidman CE. Genetic Pathogenesis of Hypertrophic and Dilated Cardiomyopathy. Heart failure clinics. 2018;14(2):139-46.\u003c/li\u003e\n\u003cli\u003eOlivotto I, Girolami F, Ackerman MJ, Nistri S, Bos JM, Zachara E, et al. Myofilament protein gene mutation screening and outcome of patients with hypertrophic cardiomyopathy. Mayo Clinic proceedings. 2008;83(6):630-8.\u003c/li\u003e\n\u003cli\u003eKeren A, Syrris P, McKenna WJ. Hypertrophic cardiomyopathy: the genetic determinants of clinical disease expression. Nature clinical practice Cardiovascular medicine. 2008;5(3):158-68.\u003c/li\u003e\n\u003cli\u003eMazzarotto F, Girolami F, Boschi B, Barlocco F, Tomberli A, Baldini K, et al. Defining the diagnostic effectiveness of genes for inclusion in panels: the experience of two decades of genetic testing for hypertrophic cardiomyopathy at a single center. Genetics in medicine : official journal of the American College of Medical Genetics. 2019;21(2):284-92.\u003c/li\u003e\n\u003cli\u003eMillat G, Bouvagnet P, Chevalier P, Dauphin C, Jouk PS, Da Costa A, et al. Prevalence and spectrum of mutations in a cohort of 192 unrelated patients with hypertrophic cardiomyopathy. European journal of medical genetics. 2010;53(5):261-7.\u003c/li\u003e\n\u003cli\u003eTafelmeier M, Baessler A, Wagner S, Unsoeld B, Preveden A, Barlocco F, et al. Design of the SILICOFCM study: Effect of sacubitril/valsartan vs lifestyle intervention on functional capacity in patients with hypertrophic cardiomyopathy. Clinical cardiology. 2020.\u003c/li\u003e\n\u003cli\u003eWaldmuller S, Erdmann J, Binner P, Gelbrich G, Pankuweit S, Geier C, et al. Novel correlations between the genotype and the phenotype of hypertrophic and dilated cardiomyopathy: results from the German Competence Network Heart Failure. European journal of heart failure. 2011;13(11):1185-92.\u003c/li\u003e\n\u003cli\u003eSedaghat-Hamedani F, Kayvanpour E, Tugrul OF, Lai A, Amr A, Haas J, et al. Clinical outcomes associated with sarcomere mutations in hypertrophic cardiomyopathy: a meta-analysis on 7675 individuals. Clinical research in cardiology: official journal of the German Cardiac Society. 2018;107(1):30-41.\u003c/li\u003e\n\u003cli\u003eMarsiglia JD, Credidio FL, de Oliveira TG, Reis RF, Antunes Mde O, de Araujo AQ, et al. Screening of MYH7, MYBPC3, and TNNT2 genes in Brazilian patients with hypertrophic cardiomyopathy. American heart journal. 2013;166(4):775-82.\u003c/li\u003e\n\u003cli\u003eGarcia-Castro M, Coto E, Reguero JR, Berrazueta JR, Alvarez V, Alonso B, et al. [Mutations in sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in patients with hypertrophic cardiomyopathy]. Rev Esp Cardiol. 2009;62(1):48-56.\u003c/li\u003e\n\u003cli\u003eLiu X, Jiang T, Piao C, Li X, Guo J, Zheng S, et al. Screening Mutations of MYBPC3 in 114 Unrelated Patients with Hypertrophic Cardiomyopathy by Targeted Capture and Next-generation Sequencing. Scientific reports. 2015;5:11411.\u003c/li\u003e\n\u003cli\u003eWeissler-Snir A, Hindieh W, Gruner C, Fourey D, Appelbaum E, Rowin E, et al. Lack of Phenotypic Differences by Cardiovascular Magnetic Resonance Imaging in MYH7 (beta-Myosin Heavy Chain)- Versus MYBPC3 (Myosin-Binding Protein C)-Related Hypertrophic Cardiomyopathy. Circulation Cardiovascular imaging. 2017;10(2).\u003c/li\u003e\n\u003cli\u003eOlivotto I, Maron MS, Adabag AS, Casey SA, Vargiu D, Link MS, et al. Gender-related differences in the clinical presentation and outcome of hypertrophic cardiomyopathy. Journal of the American College of Cardiology. 2005;46(3):480-7.\u003c/li\u003e\n\u003cli\u003eJang JH, Shin SH, Beak YS, Ko KY, Kwon SW, Park SD, et al. Impact of gender on heart failure presentation in non-obstructive hypertrophic cardiomyopathy. Heart and vessels. 2020;35(2):214-22.\u003c/li\u003e\n\u003cli\u003eGersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, Link MS, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011;124(24):e783-831.\u003c/li\u003e\n\u003cli\u003eSemsarian C, Ho CY. Screening children at risk for hypertrophic cardiomyopathy: balancing benefits and harms. European heart journal. 2019;40(45):3682-4.\u003c/li\u003e\n\u003cli\u003eMarian AJ, Braunwald E. Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy. Circulation research. 2017;121(7):749-70.\u003c/li\u003e\n\u003cli\u003eKraft T, Montag J, Radocaj A, Brenner B. Hypertrophic Cardiomyopathy: Cell-to-Cell Imbalance in Gene Expression and Contraction Force as Trigger for Disease Phenotype Development. Circulation research. 2016;119(9):992-5.\u003c/li\u003e\n\u003cli\u003eHallioglu Kilinc O, Giray D, Bisgin A, Tug Bozdogan S, Karpuz D. Familial hypertrophic cardiomyopathy: A case with a new mutation in the MYBPC3 gene. Turk Kardiyoloji Dernegi arsivi : Turk Kardiyoloji Derneginin yayin organidir. 2017;45(5):450-3.\u003c/li\u003e\n\u003cli\u003eTower-Rader A, Desai MY. Phenotype-Genotype Correlation in Hypertrophic Cardiomyopathy: Less Signal, More Noise? Circulation Cardiovascular imaging. 2017;10(2).\u003c/li\u003e\n\u003cli\u003eWeissler-Snir A, Adler A, Williams L, Gruner C, Rakowski H. Prevention of sudden death in hypertrophic cardiomyopathy: bridging the gaps in knowledge. European heart journal. 2017;38(22):1728-37.\u003c/li\u003e\n\u003cli\u003eOlivotto I, Cecchi F, Casey SA, Dolara A, Traverse JH, Maron BJ. Impact of atrial fibrillation on the clinical course of hypertrophic cardiomyopathy. Circulation. 2001;104(21):2517-24.\u003c/li\u003e\n\u003cli\u003eLee SP, Ashley EA, Homburger J, Caleshu C, Green EM, Jacoby D, et al. Incident Atrial Fibrillation Is Associated With MYH7 Sarcomeric Gene Variation in Hypertrophic Cardiomyopathy. Circulation Heart failure. 2018;11(9):e005191.\u003c/li\u003e\n\u003cli\u003eBongini C, Ferrantini C, Girolami F, Coppini R, Arretini A, Targetti M, et al. Impact of Genotype on the Occurrence of Atrial Fibrillation in Patients With Hypertrophic Cardiomyopathy. The American journal of cardiology. 2016;117(7):1151-9.\u003c/li\u003e\n\u003cli\u003eViswanathan SK, Sanders HK, McNamara JW, Jagadeesan A, Jahangir A, Tajik AJ, et al. Hypertrophic cardiomyopathy clinical phenotype is independent of gene mutation and mutation dosage. PloS one. 2017;12(11):e0187948.\u003c/li\u003e\n\u003cli\u003eOlivotto I, Maron MS, Autore C, Lesser JR, Rega L, Casolo G, et al. Assessment and significance of left ventricular mass by cardiovascular magnetic resonance in hypertrophic cardiomyopathy. Journal of the American College of Cardiology. 2008;52(7):559-66.\u003c/li\u003e\n\u003cli\u003eOlivotto I, Cecchi F, Poggesi C, Yacoub MH. Patterns of disease progression in hypertrophic cardiomyopathy: an individualized approach to clinical staging. Circulation Heart failure. 2012;5(4):535-46.\u003c/li\u003e\n\u003cli\u003eOmmen SR, Shah PM, Tajik AJ. Left ventricular outflow tract obstruction in hypertrophic cardiomyopathy: past, present and future. Heart. 2008;94(10):1276-81.\u003c/li\u003e\n\u003cli\u003eMiller RJH, Heidary S, Pavlovic A, Schlachter A, Dash R, Fleischmann D, et al. Defining genotype-phenotype relationships in patients with hypertrophic cardiomyopathy using cardiovascular magnetic resonance imaging. PloS one. 2019;14(6):e0217612.\u003c/li\u003e\n\u003cli\u003eMaron MS, Olivotto I, Harrigan C, Appelbaum E, Gibson CM, Lesser JR, et al. Mitral valve abnormalities identified by cardiovascular magnetic resonance represent a primary phenotypic expression of hypertrophic cardiomyopathy. Circulation. 2011;124(1):40-7.\u003c/li\u003e\n\u003cli\u003eGroarke JD, Galazka PZ, Cirino AL, Lakdawala NK, Thune JJ, Bundgaard H, et al. Intrinsic mitral valve alterations in hypertrophic cardiomyopathy sarcomere mutation carriers. European heart journal cardiovascular Imaging. 2018;19(10):1109-16.\u003c/li\u003e\n\u003cli\u003eVelicki L, Preveden A, Tafelmeier M, Olivotto I, Barlocco F, Popovic D, et al. Genetic determinants of clinical phenotype in hypertrophic cardiomyopathy. European journal of cardiovascular nursing. 2020;19(1_suppl):S43-S44.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cardiovascular-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcar","sideBox":"Learn more about [BMC Cardiovascular Disorders](http://bmccardiovascdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcar/default.aspx","title":"BMC Cardiovascular Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Hypertrophic Cardiomyopathy, Clinical Phenotype ","lastPublishedDoi":"10.21203/rs.3.rs-36810/v5","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-36810/v5","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease that affects approximately one in 500 people. HCM is a recognized genetic disorder most often caused by mutations involving myosin-binding protein C (MYBPC3) and β-myosin heavy chain (MYH7) which are responsible for approximately three-quarters of the identified mutations.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eAs a part of the international multidisciplinary SILICOFCM project (\u003ca href=\"https://d.docs.live.net/47706ef2e9746646/Documents/genetic%20determinants%20paper%20SilicoFCM/rev2/www.silicofcm.eu\" rel=\"noopener noreferrer\" target=\"_blank\"\u003e\u003cem\u003ewww.silicofcm.eu\u003c/em\u003e\u003c/a\u003e) the present study evaluated the association between underlying genetic mutations and clinical phenotype in patients with HCM. Only patients with confirmed single pathogenic mutations in either MYBPC3 or MYH7 genes were included in the study and divided into two groups accordingly. The MYBPC3 group was comprised of 48 patients (76%), while the MYH7 group included 15 patients (24%). Each patient underwent clinical examination and echocardiography.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThe most prevalent symptom in patients with MYBPC3 was dyspnea (44%), whereas in patients with MYH7 it was palpitations (33%). The MYBPC3 group had a significantly higher number of patients with a positive family history of HCM (46% vs. 7%; p=0.014). There was a numerically higher prevalence of atrial fibrillation in the MYH7 group (60% vs. 35%, p=0.085). Laboratory analyses revealed normal levels of creatinine (85.5±18.3 vs. 81.3±16.4 µmol/l; p=0.487) and blood urea nitrogen (10.2±15.6 vs. 6.9±3.9 mmol/l; p=0.472) which were similar in both groups. The systolic anterior motion presence was significantly more frequent in patients carrying MYH7 mutation (33% vs. 10%; p=0.025), as well as mitral leaflet abnormalities (40% vs. 19%; p=0.039). Calcifications of mitral annulus were registered only in MYH7 patients (20% vs. 0%; p=0.001). The difference in diastolic function, i.e. E/e’ ratio between the two groups was also noted (MYBPC3 8.8±3.3, MYH7 13.9±6.9, p=0.079).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eMajor findings of the present study corroborate the notion that MYH7 gene mutation patients are presented with more pronounced disease severity than those with MYBPC3.\u003c/p\u003e","manuscriptTitle":"Genetic Determinants of Clinical Phenotype in Hypertrophic Cardiomyopathy","msid":"","msnumber":"","nonDraftVersions":[{"code":5,"date":"2020-12-11 21:05:27","doi":"10.21203/rs.3.rs-36810/v5","editorialEvents":[{"type":"communityComments","content":0},{"type":"checksComplete","content":"","date":"2020-12-02T22:06:46+00:00","index":"","fulltext":""},{"type":"decision","content":"Accept","date":"2020-12-01T00:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2020-11-30T00:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-11-29T23:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cardiovascular-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcar","sideBox":"Learn more about [BMC Cardiovascular Disorders](http://bmccardiovascdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcar/default.aspx","title":"BMC Cardiovascular Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":4,"date":"2020-11-16 10:48:11","doi":"10.21203/rs.3.rs-36810/v4","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2020-11-26T00:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-11-25T00:00:00+00:00","index":1,"fulltext":"Recommendation: Accept without revision\nForm responses:\n---\n\nComments to Author:\n---\nThe authors addressed all the concerns. Thanks.* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **No**\n* Declaration of competing interests: **I declare that I have no competing interests**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please do not publish my name with my report. (default)**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **Yes**\n* Are the methods sufficiently described to allow the study to be repeated?: **Yes**\n* Is the use of statistics and treatment of uncertainties appropriate?: **Yes**\n* Is the presentation of the work clear?: **Yes**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"reviewerAgreed","content":"","date":"2020-11-07T00:00:00+00:00","index":1,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2020-11-04T00:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2020-11-03T00:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-11-02T23:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-11-02T23:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cardiovascular-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcar","sideBox":"Learn more about [BMC Cardiovascular Disorders](http://bmccardiovascdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcar/default.aspx","title":"BMC Cardiovascular Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":3,"date":"2020-11-03 18:19:31","doi":"10.21203/rs.3.rs-36810/v3","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2020-10-31T00:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-10-30T00:00:00+00:00","index":1,"fulltext":"Recommendation: Accept after minor essential revisions\nForm responses:\n---\n\nComments to Author:\n---\nThanks for your works in the reversion. However, I still have several concerns.\nFirst, you did not mention which methods you used to rule out other cardiovascular disease. If you only performed Echo, I don't think it would be efficient to rule out all the other types of diseases.\nSecond, did you consider any metabolic disorders? which might be subjected to cardiomyopathy.\nThird, I mentioned that although the patients demonstrated hypertrophic phenotype, it still unacceptable to only test 8 genes. They might suffered a compound mutations, and I strongly suggested to look at other related genes of ca2+ handle, sarcomere or mitochondrial.\nIn total, this research almost provide nothing new in this field, so that, the author need to emphasize their strength in the clinical observation. And what we could learn from such cases.* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **No**\n* Declaration of competing interests: **I declare that I have no competing interests**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please do not publish my name with my report. (default)**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **Yes**\n* Are the methods sufficiently described to allow the study to be repeated?: **Yes**\n* Is the use of statistics and treatment of uncertainties appropriate?: **Yes**\n* Is the presentation of the work clear?: **No**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"reviewersInvited","content":"","date":"2020-10-29T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-10-29T12:00:00+00:00","index":1,"fulltext":""},{"type":"editorAssigned","content":"","date":"2020-10-28T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-10-27T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-10-27T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cardiovascular-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcar","sideBox":"Learn more about [BMC Cardiovascular Disorders](http://bmccardiovascdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcar/default.aspx","title":"BMC Cardiovascular Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":2,"date":"2020-08-18 18:14:31","doi":"10.21203/rs.3.rs-36810/v2","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2020-10-19T12:00:00+00:00","index":2,"fulltext":"Recommendation: Major revisions required\nForm responses:\n---\n\nComments to Author:\n---\nThe authors demonstrated a cross-section of hypertrophic cardiomyopathy cohort based on genetic test, with a medium sample size around 63 patients included. They tried to underline the characters of clinical presentation. But the new opinion or perspectives are very limited. The manuscript exists several major concerns:\n1. Hypertrophic cardiomyopathy ranks the top one among all kinds of cardiomyopathies, and the mutations of MYBPC3 and MYH7 are also the most common observed among population. So that, the cohort size is not good enough to interpret their clinical manifestation in detail, which limits the meanings of the study.\n2. The authors stated all the patients has been identified as HCM, and went to genetic tests for potential genes. However, there is a great crosstalk with the genetic mutations among DCM, HCM, even ARVC. So that the author must clarify how they rule out other related genes.\n3. The authors need identify the methods they evaluate other types of cardiovascular disease, such as angiography or MRI.\n4. I must say the cross-section study design provided very limited information update. It would be much better that the authors could provided any data for follow-up. Beyond the current clinical manifestations, the readers prefer to know whether the progress of HCM according to different genetic background would be varied. And how the genetic tests guides their medication or the decision for heart transplantation?\n5. Normal echocardiography only provided basic and fundamental information for cardiac function and morphology. Could the authors provide any data on sparkle tracing or MRI? That would elevate the value of this study much.\n6. The authors need state the duration to enrolled this cohort. Whether they are continuous or nor?\n7. Holters would be good to measure the electro-activity of heart.\n8. Did the patients receive any Six-Minuets walking tests?\n9. How the authors define the \"age\"? Is it for the onset of clinical manifestation? Or confirmed by genetic tests?\n10. I would like to see any blood tests for the cohort, including BNP, cTnI, etc. And their relationship with genetic mutations. As well as the nutrition (Ca2+, Na+, VitD, Mg2+, Fe) would be best to be provided.* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **No**\n* Declaration of competing interests: **I declare that I have no competing interests**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please do not publish my name with my report. (default)**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **No**\n* Are the methods sufficiently described to allow the study to be repeated?: **No**\n* Is the use of statistics and treatment of uncertainties appropriate?: **Yes**\n* Is the presentation of the work clear?: **Yes**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **No**\n"},{"type":"decision","content":"Major revision","date":"2020-10-19T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-09-27T12:00:00+00:00","index":2,"fulltext":""},{"type":"editorAssigned","content":"","date":"2020-08-14T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewersInvited","content":"","date":"2020-08-14T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-08-14T12:00:00+00:00","index":1,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-08-14T12:00:00+00:00","index":1,"fulltext":"Recommendation: Accept after discretionary revisions\nForm responses:\n---\n\nComments to Author:\n---\nThe authors have addressed our comments and the manuscript has been improved. Just minor edits.\nRegards* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Declaration of competing interests: **I declare that I have no competing interests**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please publish my name with my report.**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **Yes**\n* Are the methods sufficiently described to allow the study to be repeated?: **Yes**\n* Is the use of statistics and treatment of uncertainties appropriate?: **Yes**\n* Is the presentation of the work clear?: **Yes**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"checksComplete","content":"","date":"2020-08-13T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-08-13T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cardiovascular-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcar","sideBox":"Learn more about [BMC Cardiovascular Disorders](http://bmccardiovascdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcar/default.aspx","title":"BMC Cardiovascular Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2020-06-25 14:57:11","doi":"10.21203/rs.3.rs-36810/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2020-07-31T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-07-29T12:00:00+00:00","index":2,"fulltext":"Recommendation: Accept without revision\nForm responses:\n---\n\nComments to Author:\n---\nPlease include all comments for the authors in this box rather than uploading your report as an attachment. Please only upload as attachments annotated versions of manuscripts, graphs, supporting materials or other aspects of your report which cannot be included in a text format.\nPlease overwrite this text when adding your comments to the authors.* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Declaration of competing interests: **I declare that I have no competing interests'**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please do not publish my name with my report. (default)**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **Yes**\n* Are the methods sufficiently described to allow the study to be repeated?: **Yes**\n* Is the use of statistics and treatment of uncertainties appropriate?: **Yes**\n* Is the presentation of the work clear?: **Yes**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"editorInvitedReview","content":"","date":"2020-07-16T12:00:00+00:00","index":1,"fulltext":"Recommendation: Accept after minor essential revisions\nForm responses:\n---\n\nComments to Author:\n---\nDear Authors,\nWe have some comments to be taken into consideration:\n1- The correlation between genetic mutation and clinical phenotypes have been studied several times before. This implies that the authors should make more efforts to improve the rationale.\n2- Baseline clinical ch.ch. including variables likes prevalence of Diabtetes mellitus, thyroid disease, chronic lung disease should be mentioned. Moreover, the significant differences in clinical phenotypes which were found between both genes should be adjusted to these variables if any (i.e., DM, thyroid disease, lung disease, etc...).\n3- The clinical implications of the current study should be highlighted in the discussion. Practical points. How these findings could affect the daily clinical practice.\nRegards* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Are the methods appropriate and well described?: **Yes**\n* Does the work include the necessary controls?: **Yes**\n* Are the conclusions drawn adequately supported by the data shown?: **Yes**\n* Are you able to assess any statistics in the manuscript or would you recommend an additional statistical review?: **I recommend additional statistical review**\n* Quality of written English: **Acceptable**\n* Declaration of competing interests: **I declare that I have no competing interests**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please publish my name with my report.**\n"},{"type":"reviewerAgreed","content":"","date":"2020-07-10T12:00:00+00:00","index":2,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2020-07-02T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-07-02T12:00:00+00:00","index":1,"fulltext":""},{"type":"editorAssigned","content":"","date":"2020-06-22T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-06-21T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-06-21T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cardiovascular-disorders","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcar","sideBox":"Learn more about [BMC Cardiovascular Disorders](http://bmccardiovascdisord.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcar/default.aspx","title":"BMC Cardiovascular Disorders","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cc8be694-a97b-4e94-aa32-799dd6892624","owner":[],"postedDate":"December 11th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":1443522,"name":"Cardiac \u0026 Cardiovascular Systems"}],"tags":[],"updatedAt":"2020-12-13T15:02:31+00:00","versionOfRecord":{"articleIdentity":"rs-36810","link":"https://doi.org/10.1186/s12872-020-01807-4","journal":{"identity":"bmc-cardiovascular-disorders","isVorOnly":false,"title":"BMC Cardiovascular Disorders"},"publishedOn":"2020-12-09 15:00:55","publishedOnDateReadable":"December 9th, 2020"},"versionCreatedAt":"2020-12-11 21:05:27","video":"","vorDoi":"10.1186/s12872-020-01807-4","vorDoiUrl":"https://doi.org/10.1186/s12872-020-01807-4","workflowStages":[]},"version":"v5","identity":"rs-36810","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-36810","identity":"rs-36810","version":["v5"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}