Wolff- Parkinson-White Syndrome And Conduction Abnormalities Have Higher Prevalence In Patients With Mitochondrial Encephalomyopathy, Lactic Acidosis, And Stroke-like Episodes (MELAS) And Mutations Associated With MELAS

Wolff- Parkinson-White Syndrome And Conduction Abnormalities Have Higher Prevalence In Patients With Mitochondrial Encephalomyopathy, Lactic Acidosis, And Stroke-like Episodes (MELAS) And Mutations Associated With MELAS | 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 Wolff- Parkinson-White Syndrome And Conduction Abnormalities Have Higher Prevalence In Patients With Mitochondrial Encephalomyopathy, Lactic Acidosis, And Stroke-like Episodes (MELAS) And Mutations Associated With MELAS Jia Yue Liu¹, Mary Kay Koenig², Kaleigh Riggs, Mohammad Numan¹ This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6530600/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 12 Aug, 2025 Read the published version in Pediatric Cardiology → Version 1 posted 9 You are reading this latest preprint version Abstract Background: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is one of the most common mitochondrial disorders. Cardiovascular involvement has been reported in up to 30% of MELAS patients with varying clinical presentations from non-specific cardiogenic abnormalities to conduction abnormalities, cardiomyopathies, heart failure, fatal arrhythmias and cardiac death. Although conduction defects are a known complication, the frequency of Wolff-Parkinson-White (WPW) syndrome among MELAS patients and mutations associated with MELAS is uncertain, and their association with cardiomyopathy and treatment outcomes have rarely been reported. Methods: A retrospective chart review of fifty patients with MELAS genotypes from January 2007 to December 2022 was conducted at the Center for the Treatment of Pediatric Neurodegenerative Disease at UT Health Science Center Houston. Medical histories, electrocardiograms, echocardiograms, electrophysiology studies were reviewed and DNA samples from buccal epithelial cells, blood and hair were analyzed to determine mitochondrial mutation and total mutation burden. Results: Forty-three patients were included. Five of twenty patients with m.3242A>G MELAS (20 %), one of three patients m.4317A>G MELAS (33.3%) and two of twenty patients with m.3242A>G had electrocardiographic findings consistent with WPW. Other conduction abnormalities were noted in ten of 20 patients (50%) with MELAS and six out of twenty patients with m.3242A>G mutation (30%). Four patients required electrophysiology studies with ablation, one for inappropriate sinus tachycardia resistant to several medications, and three patients with WPW syndrome all of whom required repeat ablations. Conduction abnormalities were noted to have positive correlation with higher heteroplasmy levels (mean 35 % vs 51%, 95% CI, p=0.019). Six patients with MELAS had cardiomyopathy of varying severity which were all associated with conduction abnormalities, including two patients with WPW syndrome (p=0.014). Conclusion: The prevalence of WPW in patients with MELAS syndrome and the m.3242A>G variant appears much higher than in the normal population and may require multiple electrophysiology studies ablations to treat. Routine cardiology screening is recommended for early detection. Figures Figure 1 1. Introduction Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a maternally inherited mitochondrial disorder, characterized by multi-system involvement with significant phenotypic variability. The most common mutation associated with MELAS is the m.3243A > G, which accounts for 80% of disease 1 . This point mutation leads to impaired oxidative phosphorylation and inadequate energy production; thus, organs that depend on aerobic energy metabolism, such as brain, eye, heart and skeletal muscle, are more severely affected 2 – 3 . In one in three hundred individuals of the general population, the m.3243A > G is present 4 , however, the presence of this point mutation does not translate into MELAS until a stroke has occurred. Many individuals possess low levels of the mutation (< 1%) and are most often asymptomatic 5 . The varying presentations can be accounted by the heteroplasmy, an unusual biologic state that forms as a result of mutation in the mitochondrial DNA (mtDNA) that creates a mixed population of wild type and mutant mtDNA in a single cell 6 . The random mitotic segregation leads to variations in heteroplasmy, resulting in different amounts of mutant mtDNA in daughter cells 7 . It is thought that the degree of heteroplasmy determines the clinical phenotype and hence the maternally inherited mutant DNA load and threshold may affect the onset and extent of clinical disease. Cardiovascular involvement has been reported in up to 20–50% of MELAS patients 3 , 8 – 10 , with the highest prevalence in patients with m.3243A > G mutations. The conduction system with varying clinical presentations from non-specific cardiogenic abnormalities to conduction abnormalities and serious cardiac complications such as cardiomyopathies, heart failure, fatal arrhythmias and cardiac death 11 – 12 . Conduction defects including frequent ventricular ectopy, atrial fibrillation, ventricular tachycardia and atrio-ventricular block. Wolff-Parkinson White Syndrome (WPW), is a congenital abnormal electrical pathway between the atria and ventricle that bypasses the atrioventricular node. The hallmark electrocardiographic (ECG) finding of this accessary pathway consists of a short PR interval and prolonged QRS with an initial slurring upstroke or delta wave. WPW has been associated with MELAS 13 , however the relationship with MELAS, the mutations and cardiomyopathy is unknown. 2. Methods This study was approved by the Committee for the Protection of Human Subjects at the UT Health Science Center Houston as a retrospective chart analysis. The Committee waived the need for patient consent. From January 2007 to December 2022, we reviewed charts of fifty patients with MELAS at the Center for the Treatment of Pediatric Neurodegenerative Diseases at UT Health Science Center Houston. Criteria for inclusion included subjects with genetic mutations associated with MELAS confirmed by polymerase chain reaction who had received a standard twelve-lead electrocardiogram and echocardiography. We excluded patients with additional genetic syndromes and those with no records of electrocardiograms and echocardiography. Age at onset of MELAS syndrome was described as the age at which the patient experienced his or her first stroke-like event based on medical records. Echocardiographic cardiac function was described as mild, moderate or severe based upon left ventricular ejection fraction (LVEF) with mild dysfunction LVEF 40–49%, moderate dysfunction LVEF 30–39%, and severe dysfunction LVEF less than 30%. Cardiac histories were reviewed for all patients, including electrocardiograms, echocardiograms, ambulatory Holter monitor reports, exercise stress tests, electrophysiology studies and radiofrequency ablations. Electrocardiograms were reviewed and analyzed independently by two pediatric cardiologists. Tissue samples from patients enrolled in this study were obtained from skin fibroblasts, blood leukocytes, hair or oral mucosa. Mutant mitochondrial DNA in each tissue type was quantified as a percentage of total mitochondrial DNA using polymerase chain reaction amplification. A total tissue burden was estimated using a mean of the percentage of mutant mitochondrial DNA in the all tissue types when more than one type was available. 2.1. Statistical analysis Variables were expressed as mean ± standard deviation for normally distributed variables, and as median and interquartile range otherwise. Categorical values were expressed as proportions. Continuous variables were compared using Student t-test. Categorical variables were compared using Pearson χ2 test or Fisher's exact test, as appropriate. P values are presented with 95% confidence intervals. 3. Results We reviewed a cohort of fifty patients in our database, forty three patients were included. Of those, forty patients carried the most common mutation associated with MELAS syndrome, m.3243A > G. Three patients carried the m.4317A > G mutation. Median age at diagnosis was 23.8 years (range 2–58 years). Median age of first stroke was 19.6 years (range 6–58 years). Median heteroplasmy level was 43.1% (2–88). WPW was documented in eight (18%) patients, at a median age of 18.9 years (range 6–32 years), including three children (6–9 years of age) and five adults (20–32 years of age). One patient was diagnosed with WPW syndrome prior to diagnosis of stroke. Cardiomyopathy was noted in six patients, at median age of 26.3 years (range 7–58 years). Cardiac involvement was not the presenting symptom in this cohort with the exception of the one patient who presented with WPW prior to occurrence of stroke. All patients were referred from the MELAS clinic to cardiology clinic for cardiac screening. Echocardiography and electrocardiograms were performed in all patients. Table. Demographic and Clinical Characteristics of Study Enrollees Characteristic All Patients (n = 43) Patients without WPW (n = 35) Patients with WPW (n = 8) Median Age (range in years) 23.8 (2–58) 24.1 (2–58) 18.9 (6–32) Median Age of 1st Stroke (range in years) 19.6 (6–58) 20.2 (7–58) 18.4 (6–31) Male sex (%) 22 (51) 18 (51) 4 (50) Heteroplasmy (%) 43.1 40.3 54.3 m.3243A > G (%) 41 (95) 34 (97) 7 (88) m.4317A > G (%) 3 (7) 2 (6) 1 (12) Stroke No. (%) 15 (35) 10 (29) 5 (62) Cardiomyopathy (%) 5 (12) 4 (11) 1 (12) EP studies 5 1 4 Abbreviations: MELAS, Mitochondrial Encephalomyopathy, Lactic Acidosis, And Stroke-like Episodes; WPW, Wolff-Parkinson-White Syndrome; N/A, not applicable 3.1 Patients with m.3243A > G and WPW Twenty patients with the m.3243A > G mutation developed stroke. Five of these twenty patients had electrocardiographic pre-excitation. The cohort median age of stroke occurrence was 21.4 years (range 6–31 years) with a mean heteroplasmy of 58.5% (range 37–76%) and mean age of WPW diagnosis of 22.2 years (range 7–35 years). One patient presented with WPW at twelve years old, three years prior to their 1st stroke. Four patients were noted to have WPW at the time of their MELAS diagnosis and one patient was noted to have WPW eight years after occurrence of their 1st stroke. One patient with a previously normal EKG was noted to have pre-excitation during an acute MELAS crisis, however the persistence of pre-excitation is unclear as no follow up EKGs were available. Two of the five m.3243A > G MELAS patients underwent ablation for left sided accessory pathways and both required a total of three ablations for recurrent left sided accessory pathways. One patient had pathways in slightly different positions on each ablation. The electrophysiology procedure report was not available in the other patient. Two of the twenty patients with m.3242A > G mutation and strokes had electrocardiographic findings consistent with WPW. One patient, aged six years, with a heteroplasmy level of 76%, was found to have WPW at age eleven years and had successful ablation of a left sided pathway. The other patient, who was initially diagnosed at age thirty-one years, with 10% heteroplasmy, was noted to have WPW at age thirty-six years and has not undergone an electrophysiology study. 3.2. Patients with m.3243A > G and other conduction abnormalities Other conduction abnormalities were noted in ten of the twenty m.3243A > G MELAS patients (50%). Three patients had left axis deviation, two had right atrial enlargement, two had premature ventricular contractions, two had sinus tachycardia, and one patient’s electrocardiogram showed right axis deviation. Of these twenty patients, four had abnormal cardiac function on echocardiography with having mildly depressed LV function, one moderately depressed LV function and one severely depressed LV function. One patient had inappropriate sinus tachycardia refractory to medical management for which radiofrequency modification of the sinus node was performed. Among the twenty patients with m.3242A > G mutation who did not have strokes, of which six of them (30%), had other conduction abnormalities with a mean heteroplasmy level of 47%. One patient had significant sinus bradycardia, two had left ventricular hypertrophy by voltage criteria and one had left bundle branch block. One patient had complete heart block with slow atrial flutter requiring a pacemaker and mildly depressed cardiac function. There may be some correlation with increasing heteroplasmy levels and abnormal conduction as a statistically significant positive correlation was noted (p = 0.019). 3.3 Patients with m.3243A > G and cardiomyopathy Six patients with m.3242A > G MELAS were found to have cardiomyopathy of varying severity. Three patients below eighteen years had cardiomyopathy and three patients were diagnosed as adults with cardiomyopathy. At initial evaluation, two of the six patients (33%) reported functional limitation during ordinary physical activity (NYHA Class II), one patient (12.5%) presented with marked limitation (NYHA Class III) and three were asymptomatic (NYHA Class I). ECG anomalies were noted in all cardiomyopathy patients, including right atrial enlargement with left axis deviation in three patients (50%). Ventricular preexcitation was present in two patients (25%, p = 0.014), and ventricular ectopy at 24-hour Holter was present in one. Two patients had sinus tachycardia which was refractory to medications in one patient and ultimately underwent sinus node ablation for inappropriate sinus tachycardia. One patient had complete heart block with a slow atrial flutter, requiring pacemaker. On echocardiography, three patients had normal ventricular wall size and thickness with mild to moderately depressed systolic function which slightly improved with medical treatment. Two patients had hypertrophic cardiomyopathy, one with mildly depressed LV function and one with moderately depressed LV function. Dilated cardiomyopathy could be documented only in one patient (12%), who had an LVEF of 20%. In two patients, dyslipidemia was identified. One patient underwent coronary angioplasty with stent placement three times and eventually had placement of an internal defibrillator. One patient who had complete atrioventricular block developed pacemaker induced cardiomyopathy with moderately depressed LV function. One patient underwent cardiac magnetic resonance (CMR) as part of the diagnostic work-up, which showed mildly depressed LV function with LVEF of 52%. There was evidence of delayed enhancement in mid and apical anterolateral segment in the subepicardial area as well as in the inferior insertion point subepicardally and in the anterior mid-ventricular subepicardial area. The left ventricular thickness was normal. Those patients with cardiomyopathy received pharmacologic treatment including beta-blockers, loop diuretics, ace-inhibitors, calcium-antagonist (amlodipine), and digoxin. All patients with MELAS were treated with carnitine and coenzyme Q10. Mean follow-up of our cardiomyopathy cohort was 5.6 years with a survival rate of 88% (n = 5). The distribution of cardiac involvement in MELAS was bimodal with regard to age of onset and outcome. The two young patients with m.3243A > G MELAS experiencing early-onset cardiomyopathy, one of whom also had WPW, and the pediatric patient with m.4317A > G MELAS WPW all died prior to their eighteenth birthday. In all patients, death occurred due to infection, respiratory failure or cerebral events rather than primary cardiac causes. Of the four cardiac patients who survived, three with adult-onset cardiomyopathy and one with cardiomyopathy diagnosed at seven years, the three adults were asymptomatic at last evaluation (NHYA Class I), and the pediatric patient was in NHYA Class III. The pediatric patient had improvement of her cardiac function from an EF of 20% to near normal and was doing well for a few years. However, at age thirteen, she had a prolonged hospitalization for MELAS and her EF decreased to 30%. In children and adolescents with MELAS, cardiomyopathy and WPW appear to be a hallmark of severity, implying risk of early death without necessarily being the main determinant of outcome. Conversely, patients with adult-onset cardiomyopathy remained stable over time, requiring only clinical follow-up in the absence of adverse arrhythmic events or worsening heart failure. 3.4 Patients with m.4317A > G Our cohort identified three patients, a mother and her two sons, with the m.4317A > G mutation. The mother and one son have MELAS. The son with a heteroplasmy level of 94% presented with an acute stroke at age six years and was diagnosed with WPW at age eight years. On electrophysiology study, there was both antegrade and retrograde conduction through the accessory pathway and a left lateral pathway that was successfully ablated. One year post-ablation, this patient had recurrence of his left sided accessory pathway pre-excitation which was slightly different from the previous location. The patient subsequently remained in sinus rhythm until he passed at age seventeen years due to MELAS complications. Both his mother who’s heteroplasmy level is unknown, and brother who has 88% heteroplamsy, have normal EKGs and echocardiograms. 4. Discussion This study showed high prevalence of cardiac conduction abnormalities in patients harboring the genetic mutation m.3243A > G. Conduction abnormalities were seen in 50% of our MELAS patients with m.3243A > G and 30% in non-stroke m.3243A > G patients. Specifically WPW was noted in 25% of our patients with m.3243A > G with MELAS and 10% of our patients with m.3243A > G who had not had a stroke. The presence of tachyarrhythmias is seen in patients with MELAS, and Wolff–Parkinson–White (WPW) syndrome has been reported in 13–39% of these patients 9 , 14 – 15 . All pediatric patients with WPW underwent electrophysiology study with ablation, whereas no adults underwent electrophysiology study or ablation. Two were discovered to have pre-excitation on retrospective review performed for this study. One patient with m.3243A > G and WPW has yet to have stroke, and another had a stroke three years after WPW diagnosis. No deaths occurred in this subgroup. However, the presence of WPW may indicate an increased risk of stroke development in patients harboring the m.3243A > G mutation. Regardless, all patients with WPW should undergo an electrophysiology study for therapeutic treatment of WPW. All WPW accessory pathways were noted to have left sided pathways, often requiring multiple radiofrequency ablations, indicating perhaps a propensity for recurrent left sided accessory pathways in these patients. The association of left sided accessory pathways in patients with MELAS has not been previously described in the literature. The pathophysiology remains unclear. A mutation of the PRKAG2 gene, an adenosine monophosphate (AMP)–activated protein kinase mapped to the locus 7q34-q36, has been linked to the development of WPW syndrome and hypertrophic cardiomyopathy in 2 families 16 . The AMP–activated protein kinase encoded by the PRKAG2 gene has been described as a metabolic sensor 17 . When the sensor fails, there is altered cellular responsiveness to energy-depleting stressors, which may explain the underlying the pathogenesis of this mutation 16 . A mitochondrial defect may act in a similar manner to create a relatively energy-depleted state, preventing the normal maturation, thus leading to the generation of an abnormal conductive circuit. Conversely, WPW has not been reported in increased frequency in other mitochondrial myopathies such as Kearns-Sayre or Leigh syndromes. In the current literature, there is no reported association with WPW and m.4317A > G; however, m.4317A > G has been associated with fetal cardiomyopathy 18 . A point mutation at m.4317A > G induces a small but significant change in isoleucylation 20 leading to a decrease in both complex I and complex IV activities in heart muscle 18 . Deficiency of mitochondrial complex I of the electron transport chain has been observed in cardiomyopathy and heart failure 20 – 21 through increased reactive oxygen species and increased protein acetylation, accelerating cell death and heart failure during chronic increases of workload 22 which can be seen in MELAS. Conduction abnormalities were also noted to have a positive correlation with higher heteroplasmy levels regardless of stroke (mean 35% vs 51%, 95% CI, p = 0.019). The phenotypic variability and rate of progression in MELAS is incompletely understood, but may be due to the degree of heteroplasmy, along with the cellular energy requirement 23 . There are varying proportions of mutant and wild type mutant DNA in different tissues carried by different individuals. Some authors believe that an increase in mutant DNA not only affects mitochondrial function but also the severity of cardiovascular disease 24 . As a consequence of heteroplasmy principle, even organs with high metabolic demands, such as the heart, may be capable of preserving a metabolic balance in MELAS patients, accounting for lack of cardiomyopathy at the end of follow-up in over 70% of our patients. There is no clarity about the signaling mechanisms that may be associated with heart failure and mitochondrial dynamics 24 . Further understanding of signaling pathways, precipitating and protective mechanisms may be crucial in developing treatments for this condition. Although, in our study the cause of death in patients was not cardiac, there are reports of pediatric patients dying of congestive heart failure in their teenage years 25 – 27 . Conversely Malfatti et al. 15 and Wahbi et al. 10 , documented a high incidence of cardiac death and life- threatening events in adult MELAS patients albeit both cohorts had an older age, which may account for this discrepancy. Therefore, it is prudent to perform routine cardiac screening in these patients as longer observation periods may unmask cardiac morbidity 28 . Multicenter registries and extended follow-up periods are therefore warranted in mitochondrial diseases. 4.6. Study limitations While this is one of the larger studies conducted in MELAS patients, the limited sample of patients was the main constraint, which attenuates the statistical significance of our findings. Additionally, there were only three patients with m.4317A > G and while one of the three patients had clinically significant WPW requiring multiple ablations, little can be concluded with m.4317A > G and WPW. Given the rarity of the disease, further multi-centric and prospective studies are advocated to confirm our results. As a retrospective observational study, some information (i.e. heteroplasmy levels, exercise testing, lipid panels, NT-Pro BNP plasma level) was not available for many patients. Moreover, the heteroplasmy rates varied widely depending on the specific tissue sampled, which may reflect the different extent of organ involvement. The heterogeneity of the samples therefore made heteroplasmy rates unsuitable for comparison. To better confirm a correlation between heteroplasmy rates and the severity of cardiac involvement, the most reliable tool would be a myocardial biopsy, which is rarely performed in clinical practice but could be a topic of interest for future prospective studies. 5. Conclusions Cardiac involvement was found in over half of patients with MELAS syndrome, with conduction abnormalities seemingly more prevalent with increasing heteroplasmy. Those with MELAS and WPW were all noted to have left sided pathways, which often required multiple ablations, necessitating long term cardiology follow for recurrent WPW. Pediatric-onset cardiomyopathy and WPW represented a hallmark of systemic disease severity, without being the main determinant of outcome. Thus, it is important for all patients with MELAS to have a cardiac evaluation with screening echocardiogram and electrocardiogram with subsequent referral for electrophysiology study if WPW is present. As important, when neurologists see patients with mitochondrial diseases, cardiac pathologies should be considered in the evaluation of symptoms. Declarations No authors have conflict of interests Author Contribution J.Y.L. and M.T.N. wrote the main manuscript text and J.L. prepared figures 1-2. K.R. performed the statistical analysis. All authors reviewed the manuscript. 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Mitochondrion 13:681–687 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 12 Aug, 2025 Read the published version in Pediatric Cardiology → Version 1 posted Editorial decision: Revision requested 19 May, 2025 Reviews received at journal 12 May, 2025 Reviews received at journal 06 May, 2025 Reviewers agreed at journal 29 Apr, 2025 Reviewers agreed at journal 29 Apr, 2025 Reviewers invited by journal 29 Apr, 2025 Editor assigned by journal 29 Apr, 2025 Submission checks completed at journal 29 Apr, 2025 First submitted to journal 25 Apr, 2025 You are reading this latest preprint version 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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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6530600","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":449839302,"identity":"5b6bcfef-cfa3-4d1d-a755-d424dde81928","order_by":0,"name":"Jia Yue Liu¹","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6klEQVRIiWNgGAWjYBACxmYog4+ZgfEBA8MBKJeNCC1szAzMBgwJBxh4CGmBA6AaNgmitDC3Mz9g5m2zYWBj5zGr5v1xh8Fe7PADhg9lh/E4jM0AqCUN6DAes9s8Cc8YeKTTDBhnnMOnhQGk5TBMy2GglhwGsAhuLewfgAr+g7UUw7X8xauFB2TLAbAWZrgWRvxaCg7OOZfMw8bMViw5J+0wD8/tNIODPefScWox7D++8cGbMjs5fv7DGz+8sTksxz47+eGDH2XWuLU0MDAcAkYFD0wAzDiAUz0QyIMc9wOfilEwCkbBKBgFAPGwRIPbVAq3AAAAAElFTkSuQmCC","orcid":"","institution":"The University of Texas Health Science Center at Houston","correspondingAuthor":true,"prefix":"","firstName":"Jia","middleName":"Yue","lastName":"Liu¹","suffix":""},{"id":449839303,"identity":"7cf96697-c717-452e-a91c-c2f33d6b854e","order_by":1,"name":"Mary Kay Koenig²","email":"","orcid":"","institution":"The University of Texas Health Science Center at Houston","correspondingAuthor":false,"prefix":"","firstName":"Mary","middleName":"Kay","lastName":"Koenig²","suffix":""},{"id":449839304,"identity":"6f866dec-76f5-4b3b-a130-81f63e874fb3","order_by":2,"name":"Kaleigh Riggs","email":"","orcid":"","institution":"The University of Texas Health Science Center at Houston","correspondingAuthor":false,"prefix":"","firstName":"Kaleigh","middleName":"","lastName":"Riggs","suffix":""},{"id":449839305,"identity":"952b6fed-077d-4b21-9619-3841f9ba07a6","order_by":3,"name":"Mohammad Numan¹","email":"","orcid":"","institution":"The University of Texas Health Science Center at Houston","correspondingAuthor":false,"prefix":"","firstName":"Mohammad","middleName":"","lastName":"Numan¹","suffix":""}],"badges":[],"createdAt":"2025-04-25 16:38:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6530600/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6530600/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00246-025-03985-4","type":"published","date":"2025-08-12T15:57:18+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82166863,"identity":"9388716f-f9da-45ec-92a2-d3d7cde86006","added_by":"auto","created_at":"2025-05-07 09:17:08","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":582177,"visible":true,"origin":"","legend":"\u003cp\u003eUnnumbered image in the Result section.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6530600/v1/acff3912b2341a8442615cae.png"},{"id":89310531,"identity":"5f69394a-4ded-42ff-be30-7e90571ec5bf","added_by":"auto","created_at":"2025-08-18 16:07:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1271895,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6530600/v1/c2086960-6a78-4c27-8702-18d75b818265.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Wolff- Parkinson-White Syndrome And Conduction Abnormalities Have Higher Prevalence In Patients With Mitochondrial Encephalomyopathy, Lactic Acidosis, And Stroke-like Episodes (MELAS) And Mutations Associated With MELAS","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eMitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a maternally inherited mitochondrial disorder, characterized by multi-system involvement with significant phenotypic variability. The most common mutation associated with MELAS is the m.3243A\u0026thinsp;\u0026gt;\u0026thinsp;G, which accounts for 80% of disease\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. This point mutation leads to impaired oxidative phosphorylation and inadequate energy production; thus, organs that depend on aerobic energy metabolism, such as brain, eye, heart and skeletal muscle, are more severely affected\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn one in three hundred individuals of the general population, the m.3243A\u0026thinsp;\u0026gt;\u0026thinsp;G is present\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e, however, the presence of this point mutation does not translate into MELAS until a stroke has occurred. Many individuals possess low levels of the mutation (\u0026lt;\u0026thinsp;1%) and are most often asymptomatic\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. The varying presentations can be accounted by the heteroplasmy, an unusual biologic state that forms as a result of mutation in the mitochondrial DNA (mtDNA) that creates a mixed population of wild type and mutant mtDNA in a single cell\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. The random mitotic segregation leads to variations in heteroplasmy, resulting in different amounts of mutant mtDNA in daughter cells\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. It is thought that the degree of heteroplasmy determines the clinical phenotype and hence the maternally inherited mutant DNA load and threshold may affect the onset and extent of clinical disease.\u003c/p\u003e \u003cp\u003eCardiovascular involvement has been reported in up to 20\u0026ndash;50% of MELAS patients\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e, with the highest prevalence in patients with m.3243A\u0026thinsp;\u0026gt;\u0026thinsp;G mutations. The conduction system with varying clinical presentations from non-specific cardiogenic abnormalities to conduction abnormalities and serious cardiac complications such as cardiomyopathies, heart failure, fatal arrhythmias and cardiac death\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Conduction defects including frequent ventricular ectopy, atrial fibrillation, ventricular tachycardia and atrio-ventricular block.\u003c/p\u003e \u003cp\u003eWolff-Parkinson White Syndrome (WPW), is a congenital abnormal electrical pathway between the atria and ventricle that bypasses the atrioventricular node. The hallmark electrocardiographic (ECG) finding of this accessary pathway consists of a short PR interval and prolonged QRS with an initial slurring upstroke or delta wave. WPW has been associated with MELAS\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e, however the relationship with MELAS, the mutations and cardiomyopathy is unknown.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cp\u003eThis study was approved by the Committee for the Protection of Human Subjects at the UT Health Science Center Houston as a retrospective chart analysis. The Committee waived the need for patient consent.\u003c/p\u003e \u003cp\u003eFrom January 2007 to December 2022, we reviewed charts of fifty patients with MELAS at the Center for the Treatment of Pediatric Neurodegenerative Diseases at UT Health Science Center Houston.\u003c/p\u003e \u003cp\u003eCriteria for inclusion included subjects with genetic mutations associated with MELAS confirmed by polymerase chain reaction who had received a standard twelve-lead electrocardiogram and echocardiography. We excluded patients with additional genetic syndromes and those with no records of electrocardiograms and echocardiography. Age at onset of MELAS syndrome was described as the age at which the patient experienced his or her first stroke-like event based on medical records.\u003c/p\u003e \u003cp\u003eEchocardiographic cardiac function was described as mild, moderate or severe based upon left ventricular ejection fraction (LVEF) with mild dysfunction LVEF 40\u0026ndash;49%, moderate dysfunction LVEF 30\u0026ndash;39%, and severe dysfunction LVEF less than 30%.\u003c/p\u003e \u003cp\u003eCardiac histories were reviewed for all patients, including electrocardiograms, echocardiograms, ambulatory Holter monitor reports, exercise stress tests, electrophysiology studies and radiofrequency ablations. Electrocardiograms were reviewed and analyzed independently by two pediatric cardiologists.\u003c/p\u003e \u003cp\u003eTissue samples from patients enrolled in this study were obtained from skin fibroblasts, blood leukocytes, hair or oral mucosa. Mutant mitochondrial DNA in each tissue type was quantified as a percentage of total mitochondrial DNA using polymerase chain reaction amplification. A total tissue burden was estimated using a mean of the percentage of mutant mitochondrial DNA in the all tissue types when more than one type was available.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Statistical analysis\u003c/h2\u003e \u003cp\u003eVariables were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation for normally distributed variables, and as median and interquartile range otherwise. Categorical values were expressed as proportions. Continuous variables were compared using Student t-test. Categorical variables were compared using Pearson χ2 test or Fisher's exact test, as appropriate. P values are presented with 95% confidence intervals.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003eWe reviewed a cohort of fifty patients in our database, forty three patients were included. Of those, forty patients carried the most common mutation associated with MELAS syndrome, m.3243A\u0026thinsp;\u0026gt;\u0026thinsp;G. Three patients carried the m.4317A\u0026thinsp;\u0026gt;\u0026thinsp;G mutation. Median age at diagnosis was 23.8 years (range 2\u0026ndash;58 years). Median age of first stroke was 19.6 years (range 6\u0026ndash;58 years). Median heteroplasmy level was 43.1% (2\u0026ndash;88). WPW was documented in eight (18%) patients, at a median age of 18.9 years (range 6\u0026ndash;32 years), including three children (6\u0026ndash;9 years of age) and five adults (20\u0026ndash;32 years of age). One patient was diagnosed with WPW syndrome prior to diagnosis of stroke. Cardiomyopathy was noted in six patients, at median age of 26.3 years (range 7\u0026ndash;58 years). Cardiac involvement was not the presenting symptom in this cohort with the exception of the one patient who presented with WPW prior to occurrence of stroke. All patients were referred from the MELAS clinic to cardiology clinic for cardiac screening. Echocardiography and electrocardiograms were performed in all patients.\u003c/p\u003e \u003cp\u003eTable. Demographic and Clinical Characteristics of Study Enrollees\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll Patients (n\u0026thinsp;=\u0026thinsp;43)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePatients without WPW (n\u0026thinsp;=\u0026thinsp;35)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePatients with WPW (n\u0026thinsp;=\u0026thinsp;8)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian Age (range in years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23.8 (2\u0026ndash;58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24.1 (2\u0026ndash;58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18.9 (6\u0026ndash;32)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian Age of 1st Stroke (range in years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19.6 (6\u0026ndash;58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20.2 (7\u0026ndash;58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18.4 (6\u0026ndash;31)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale sex (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (50)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeteroplasmy (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e54.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003em.3243A\u0026thinsp;\u0026gt;\u0026thinsp;G (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41 (95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34 (97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (88)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003em.4317A\u0026thinsp;\u0026gt;\u0026thinsp;G (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (12)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStroke No. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (62)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiomyopathy (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (12)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEP studies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eAbbreviations: MELAS, Mitochondrial Encephalomyopathy, Lactic Acidosis, And Stroke-like Episodes; WPW, Wolff-Parkinson-White Syndrome; N/A, not applicable\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Patients with m.3243A\u0026thinsp;\u0026gt;\u0026thinsp;G and WPW\u003c/h2\u003e \u003cp\u003eTwenty patients with the m.3243A\u0026thinsp;\u0026gt;\u0026thinsp;G mutation developed stroke. Five of these twenty patients had electrocardiographic pre-excitation. The cohort median age of stroke occurrence was 21.4 years (range 6\u0026ndash;31 years) with a mean heteroplasmy of 58.5% (range 37\u0026ndash;76%) and mean age of WPW diagnosis of 22.2 years (range 7\u0026ndash;35 years). One patient presented with WPW at twelve years old, three years prior to their 1st stroke. Four patients were noted to have WPW at the time of their MELAS diagnosis and one patient was noted to have WPW eight years after occurrence of their 1st stroke. One patient with a previously normal EKG was noted to have pre-excitation during an acute MELAS crisis, however the persistence of pre-excitation is unclear as no follow up EKGs were available. Two of the five m.3243A\u0026thinsp;\u0026gt;\u0026thinsp;G MELAS patients underwent ablation for left sided accessory pathways and both required a total of three ablations for recurrent left sided accessory pathways. One patient had pathways in slightly different positions on each ablation. The electrophysiology procedure report was not available in the other patient.\u003c/p\u003e \u003cp\u003eTwo of the twenty patients with m.3242A\u0026thinsp;\u0026gt;\u0026thinsp;G mutation and strokes had electrocardiographic findings consistent with WPW. One patient, aged six years, with a heteroplasmy level of 76%, was found to have WPW at age eleven years and had successful ablation of a left sided pathway. The other patient, who was initially diagnosed at age thirty-one years, with 10% heteroplasmy, was noted to have WPW at age thirty-six years and has not undergone an electrophysiology study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e3.2. Patients with m.3243A\u0026thinsp;\u0026gt;\u0026thinsp;G and other conduction abnormalities\u003c/h2\u003e \u003cp\u003eOther conduction abnormalities were noted in ten of the twenty m.3243A\u0026thinsp;\u0026gt;\u0026thinsp;G MELAS patients (50%). Three patients had left axis deviation, two had right atrial enlargement, two had premature ventricular contractions, two had sinus tachycardia, and one patient\u0026rsquo;s electrocardiogram showed right axis deviation. Of these twenty patients, four had abnormal cardiac function on echocardiography with having mildly depressed LV function, one moderately depressed LV function and one severely depressed LV function. One patient had inappropriate sinus tachycardia refractory to medical management for which radiofrequency modification of the sinus node was performed.\u003c/p\u003e \u003cp\u003eAmong the twenty patients with m.3242A\u0026thinsp;\u0026gt;\u0026thinsp;G mutation who did not have strokes, of which six of them (30%), had other conduction abnormalities with a mean heteroplasmy level of 47%. One patient had significant sinus bradycardia, two had left ventricular hypertrophy by voltage criteria and one had left bundle branch block. One patient had complete heart block with slow atrial flutter requiring a pacemaker and mildly depressed cardiac function. There may be some correlation with increasing heteroplasmy levels and abnormal conduction as a statistically significant positive correlation was noted (p\u0026thinsp;=\u0026thinsp;0.019).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Patients with m.3243A\u0026thinsp;\u0026gt;\u0026thinsp;G and cardiomyopathy\u003c/h2\u003e \u003cp\u003eSix patients with m.3242A\u0026thinsp;\u0026gt;\u0026thinsp;G MELAS were found to have cardiomyopathy of varying severity. Three patients below eighteen years had cardiomyopathy and three patients were diagnosed as adults with cardiomyopathy. At initial evaluation, two of the six patients (33%) reported functional limitation during ordinary physical activity (NYHA Class II), one patient (12.5%) presented with marked limitation (NYHA Class III) and three were asymptomatic (NYHA Class I). ECG anomalies were noted in all cardiomyopathy patients, including right atrial enlargement with left axis deviation in three patients (50%). Ventricular preexcitation was present in two patients (25%, p\u0026thinsp;=\u0026thinsp;0.014), and ventricular ectopy at 24-hour Holter was present in one. Two patients had sinus tachycardia which was refractory to medications in one patient and ultimately underwent sinus node ablation for inappropriate sinus tachycardia. One patient had complete heart block with a slow atrial flutter, requiring pacemaker. On echocardiography, three patients had normal ventricular wall size and thickness with mild to moderately depressed systolic function which slightly improved with medical treatment. Two patients had hypertrophic cardiomyopathy, one with mildly depressed LV function and one with moderately depressed LV function. Dilated cardiomyopathy could be documented only in one patient (12%), who had an LVEF of 20%. In two patients, dyslipidemia was identified. One patient underwent coronary angioplasty with stent placement three times and eventually had placement of an internal defibrillator. One patient who had complete atrioventricular block developed pacemaker induced cardiomyopathy with moderately depressed LV function.\u003c/p\u003e \u003cp\u003eOne patient underwent cardiac magnetic resonance (CMR) as part of the diagnostic work-up, which showed mildly depressed LV function with LVEF of 52%. There was evidence of delayed enhancement in mid and apical anterolateral segment in the subepicardial area as well as in the inferior insertion point subepicardally and in the anterior mid-ventricular subepicardial area. The left ventricular thickness was normal.\u003c/p\u003e \u003cp\u003eThose patients with cardiomyopathy received pharmacologic treatment including beta-blockers, loop diuretics, ace-inhibitors, calcium-antagonist (amlodipine), and digoxin. All patients with MELAS were treated with carnitine and coenzyme Q10.\u003c/p\u003e \u003cp\u003eMean follow-up of our cardiomyopathy cohort was 5.6 years with a survival rate of 88% (n\u0026thinsp;=\u0026thinsp;5). The distribution of cardiac involvement in MELAS was bimodal with regard to age of onset and outcome. The two young patients with m.3243A\u0026thinsp;\u0026gt;\u0026thinsp;G MELAS experiencing early-onset cardiomyopathy, one of whom also had WPW, and the pediatric patient with m.4317A\u0026thinsp;\u0026gt;\u0026thinsp;G MELAS WPW all died prior to their eighteenth birthday. In all patients, death occurred due to infection, respiratory failure or cerebral events rather than primary cardiac causes. Of the four cardiac patients who survived, three with adult-onset cardiomyopathy and one with cardiomyopathy diagnosed at seven years, the three adults were asymptomatic at last evaluation (NHYA Class I), and the pediatric patient was in NHYA Class III. The pediatric patient had improvement of her cardiac function from an EF of 20% to near normal and was doing well for a few years. However, at age thirteen, she had a prolonged hospitalization for MELAS and her EF decreased to 30%.\u003c/p\u003e \u003cp\u003eIn children and adolescents with MELAS, cardiomyopathy and WPW appear to be a hallmark of severity, implying risk of early death without necessarily being the main determinant of outcome. Conversely, patients with adult-onset cardiomyopathy remained stable over time, requiring only clinical follow-up in the absence of adverse arrhythmic events or worsening heart failure.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Patients with m.4317A\u0026thinsp;\u0026gt;\u0026thinsp;G\u003c/h2\u003e \u003cp\u003eOur cohort identified three patients, a mother and her two sons, with the m.4317A\u0026thinsp;\u0026gt;\u0026thinsp;G mutation. The mother and one son have MELAS. The son with a heteroplasmy level of 94% presented with an acute stroke at age six years and was diagnosed with WPW at age eight years. On electrophysiology study, there was both antegrade and retrograde conduction through the accessory pathway and a left lateral pathway that was successfully ablated. One year post-ablation, this patient had recurrence of his left sided accessory pathway pre-excitation which was slightly different from the previous location. The patient subsequently remained in sinus rhythm until he passed at age seventeen years due to MELAS complications. Both his mother who\u0026rsquo;s heteroplasmy level is unknown, and brother who has 88% heteroplamsy, have normal EKGs and echocardiograms.\u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis study showed high prevalence of cardiac conduction abnormalities in patients harboring the genetic mutation m.3243A\u0026thinsp;\u0026gt;\u0026thinsp;G. Conduction abnormalities were seen in 50% of our MELAS patients with m.3243A\u0026thinsp;\u0026gt;\u0026thinsp;G and 30% in non-stroke m.3243A\u0026thinsp;\u0026gt;\u0026thinsp;G patients. Specifically WPW was noted in 25% of our patients with m.3243A\u0026thinsp;\u0026gt;\u0026thinsp;G with MELAS and 10% of our patients with m.3243A\u0026thinsp;\u0026gt;\u0026thinsp;G who had not had a stroke. The presence of tachyarrhythmias is seen in patients with MELAS, and Wolff\u0026ndash;Parkinson\u0026ndash;White (WPW) syndrome has been reported in 13\u0026ndash;39% of these patients\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. All pediatric patients with WPW underwent electrophysiology study with ablation, whereas no adults underwent electrophysiology study or ablation. Two were discovered to have pre-excitation on retrospective review performed for this study. One patient with m.3243A\u0026thinsp;\u0026gt;\u0026thinsp;G and WPW has yet to have stroke, and another had a stroke three years after WPW diagnosis. No deaths occurred in this subgroup. However, the presence of WPW may indicate an increased risk of stroke development in patients harboring the m.3243A\u0026thinsp;\u0026gt;\u0026thinsp;G mutation. Regardless, all patients with WPW should undergo an electrophysiology study for therapeutic treatment of WPW.\u003c/p\u003e \u003cp\u003eAll WPW accessory pathways were noted to have left sided pathways, often requiring multiple radiofrequency ablations, indicating perhaps a propensity for recurrent left sided accessory pathways in these patients. The association of left sided accessory pathways in patients with MELAS has not been previously described in the literature. The pathophysiology remains unclear. A mutation of the \u003cem\u003ePRKAG2\u003c/em\u003egene, an adenosine monophosphate (AMP)\u0026ndash;activated protein kinase mapped to the locus 7q34-q36, has been linked to the development of WPW syndrome and hypertrophic cardiomyopathy in 2 families\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. The AMP\u0026ndash;activated protein kinase encoded by the \u003cem\u003ePRKAG2\u003c/em\u003e gene has been described as a metabolic sensor\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. When the sensor fails, there is altered cellular responsiveness to energy-depleting stressors, which may explain the underlying the pathogenesis of this mutation\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. A mitochondrial defect may act in a similar manner to create a relatively energy-depleted state, preventing the normal maturation, thus leading to the generation of an abnormal conductive circuit. Conversely, WPW has not been reported in increased frequency in other mitochondrial myopathies such as Kearns-Sayre or Leigh syndromes.\u003c/p\u003e \u003cp\u003eIn the current literature, there is no reported association with WPW and m.4317A\u0026thinsp;\u0026gt;\u0026thinsp;G; however, m.4317A\u0026thinsp;\u0026gt;\u0026thinsp;G has been associated with fetal cardiomyopathy\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. A point mutation at m.4317A\u0026thinsp;\u0026gt;\u0026thinsp;G induces a small but significant change in isoleucylation\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e leading to a decrease in both complex I and complex IV activities in heart muscle\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Deficiency of mitochondrial complex I of the electron transport chain has been observed in cardiomyopathy and heart failure\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e through increased reactive oxygen species and increased protein acetylation, accelerating cell death and heart failure during chronic increases of workload\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e which can be seen in MELAS.\u003c/p\u003e \u003cp\u003eConduction abnormalities were also noted to have a positive correlation with higher heteroplasmy levels regardless of stroke (mean 35% vs 51%, 95% CI, p\u0026thinsp;=\u0026thinsp;0.019). The phenotypic variability and rate of progression in MELAS is incompletely understood, but may be due to the degree of heteroplasmy, along with the cellular energy requirement\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. There are varying proportions of mutant and wild type mutant DNA in different tissues carried by different individuals. Some authors believe that an increase in mutant DNA not only affects mitochondrial function but also the severity of cardiovascular disease\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. As a consequence of heteroplasmy principle, even organs with high metabolic demands, such as the heart, may be capable of preserving a metabolic balance in MELAS patients, accounting for lack of cardiomyopathy at the end of follow-up in over 70% of our patients. There is no clarity about the signaling mechanisms that may be associated with heart failure and mitochondrial dynamics\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. Further understanding of signaling pathways, precipitating and protective mechanisms may be crucial in developing treatments for this condition.\u003c/p\u003e \u003cp\u003eAlthough, in our study the cause of death in patients was not cardiac, there are reports of pediatric patients dying of congestive heart failure in their teenage years\u003csup\u003e\u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. Conversely Malfatti et al.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e and Wahbi et al.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e, documented a high incidence of cardiac death and life- threatening events in adult MELAS patients albeit both cohorts had an older age, which may account for this discrepancy. Therefore, it is prudent to perform routine cardiac screening in these patients as longer observation periods may unmask cardiac morbidity\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. Multicenter registries and extended follow-up periods are therefore warranted in mitochondrial diseases.\u003c/p\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e4.6. Study limitations\u003c/h2\u003e \u003cp\u003eWhile this is one of the larger studies conducted in MELAS patients, the limited sample of patients was the main constraint, which attenuates the statistical significance of our findings. Additionally, there were only three patients with m.4317A\u0026thinsp;\u0026gt;\u0026thinsp;G and while one of the three patients had clinically significant WPW requiring multiple ablations, little can be concluded with m.4317A\u0026thinsp;\u0026gt;\u0026thinsp;G and WPW. Given the rarity of the disease, further multi-centric and prospective studies are advocated to confirm our results.\u003c/p\u003e \u003cp\u003eAs a retrospective observational study, some information (i.e. heteroplasmy levels, exercise testing, lipid panels, NT-Pro BNP plasma level) was not available for many patients. Moreover, the heteroplasmy rates varied widely depending on the specific tissue sampled, which may reflect the different extent of organ involvement. The heterogeneity of the samples therefore made heteroplasmy rates unsuitable for comparison. To better confirm a correlation between heteroplasmy rates and the severity of cardiac involvement, the most reliable tool would be a myocardial biopsy, which is rarely performed in clinical practice but could be a topic of interest for future prospective studies.\u003c/p\u003e \u003c/div\u003e"},{"header":"5. Conclusions","content":"\u003cp\u003eCardiac involvement was found in over half of patients with MELAS syndrome, with conduction abnormalities seemingly more prevalent with increasing heteroplasmy. Those with MELAS and WPW were all noted to have left sided pathways, which often required multiple ablations, necessitating long term cardiology follow for recurrent WPW. Pediatric-onset cardiomyopathy and WPW represented a hallmark of systemic disease severity, without being the main determinant of outcome. Thus, it is important for all patients with MELAS to have a cardiac evaluation with screening echocardiogram and electrocardiogram with subsequent referral for electrophysiology study if WPW is present.\u003c/p\u003e \u003cp\u003eAs important, when neurologists see patients with mitochondrial diseases, cardiac pathologies should be considered in the evaluation of symptoms.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eNo authors have conflict of interests\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eJ.Y.L. and M.T.N. wrote the main manuscript text and J.L. prepared figures 1-2. K.R. performed the statistical analysis. All authors reviewed the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSong S-K, Lee SH (2019) Cardiomyopathy Associated with Mitochondrial Encephalopathy, Lactic Acidosis and Stroke-Like Episodes (MELAS) Syndrome. 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Front Cell Dev Biol 9:625020. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fcell.2021.625020\u003c/span\u003e\u003cspan address=\"10.3389/fcell.2021.625020\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003ePMID: 33692999; PMCID: PMC7937615\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNishizawa M, Tanaka K, Shinozawa K, Kuwabara T, Atsumi T, Miyatake T, Ohama E (1987) A mitochondrial encephalomyopathy with cardiomyopathy: a case revealing a defect of complex I in the respiratory chain. J Neurol Sci 78:189\u0026ndash;201\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNemoto T, Satoh W, Harada K, Komatsu K, Gotoh A, Matsuno K, Kobayashi Y, Miura Y, Takada G, Ozawa T (1989) Cardiac involvement in four cases of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) [in Japanese with English abstract]. Jpn J Pediatr 93:1416\u0026ndash;1421\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHsu YHR, Yogasundaram H, Parajuli N et al (2016) MELAS syndrome and cardiomyopathy: linking mitochondrial function to heart failure pathogenesis. Heart Fail Rev 21:103\u0026ndash;116. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s10741-015-9524-5\u003c/span\u003e\u003cspan address=\"10.1007/s10741-015-9524-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eParikh S, Goldstein A, Koenig MK et al (2013) Practice patterns of mitochondrial disease physicians in North America. Part 2: treatment, care and management. Mitochondrion 13:681\u0026ndash;687\u003c/span\u003e\u003c/li\u003e\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":"pediatric-cardiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pedc","sideBox":"Learn more about [Pediatric Cardiology](http://link.springer.com/journal/246)","snPcode":"246","submissionUrl":"https://submission.nature.com/new-submission/246/3","title":"Pediatric Cardiology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6530600/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6530600/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is one of the most common mitochondrial disorders. Cardiovascular involvement has been reported in up to 30% of MELAS patients with varying clinical presentations from non-specific cardiogenic abnormalities to conduction abnormalities, cardiomyopathies, heart failure, fatal arrhythmias and cardiac death. Although conduction defects are a known complication, the frequency of Wolff-Parkinson-White (WPW) syndrome among MELAS patients and mutations associated with MELAS is uncertain, and their association with cardiomyopathy and treatment outcomes have rarely been reported.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e A retrospective chart review of fifty patients with MELAS genotypes from January 2007 to December 2022 was conducted at the Center for the Treatment of Pediatric Neurodegenerative Disease at UT Health Science Center Houston. Medical histories, electrocardiograms, echocardiograms, electrophysiology studies were reviewed and DNA samples from buccal epithelial cells, blood and hair were analyzed to determine mitochondrial mutation and total mutation burden.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Forty-three patients were included. Five of twenty patients with m.3242A\u0026gt;G MELAS (20 %), one of three patients m.4317A\u0026gt;G MELAS (33.3%) and two of twenty patients with m.3242A\u0026gt;G had electrocardiographic findings consistent with WPW. Other conduction abnormalities were noted in ten of 20 patients (50%) with MELAS and six out of twenty patients with m.3242A\u0026gt;G mutation (30%). Four patients required electrophysiology studies with ablation, one for inappropriate sinus tachycardia resistant to several medications, and three patients with WPW syndrome all of whom required repeat ablations. Conduction abnormalities were noted to have positive correlation with higher heteroplasmy levels (mean 35 % vs 51%, 95% CI, p=0.019). Six patients with MELAS had cardiomyopathy of varying severity which were all associated with conduction abnormalities, including two patients with WPW syndrome (p=0.014).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e The prevalence of WPW in patients with MELAS syndrome and the m.3242A\u0026gt;G variant appears much higher than in the normal population and may require multiple electrophysiology studies ablations to treat. Routine cardiology screening is recommended for early detection.\u003c/p\u003e","manuscriptTitle":"Wolff- Parkinson-White Syndrome And Conduction Abnormalities Have Higher Prevalence In Patients With Mitochondrial Encephalomyopathy, Lactic Acidosis, And Stroke-like Episodes (MELAS) And Mutations Associated With MELAS","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-07 09:08:48","doi":"10.21203/rs.3.rs-6530600/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-05-19T23:31:23+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-12T22:09:16+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-06T12:34:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"284021295934571235269343409676680148829","date":"2025-04-29T17:51:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"25413190080953113320815944707087322631","date":"2025-04-29T15:30:45+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-29T15:02:10+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-29T11:56:14+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-29T11:55:13+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pediatric Cardiology","date":"2025-04-25T16:25:21+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pediatric-cardiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pedc","sideBox":"Learn more about [Pediatric Cardiology](http://link.springer.com/journal/246)","snPcode":"246","submissionUrl":"https://submission.nature.com/new-submission/246/3","title":"Pediatric Cardiology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"8c0fe1c8-6667-453e-931a-273b3c455b95","owner":[],"postedDate":"May 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-08-18T16:00:13+00:00","versionOfRecord":{"articleIdentity":"rs-6530600","link":"https://doi.org/10.1007/s00246-025-03985-4","journal":{"identity":"pediatric-cardiology","isVorOnly":false,"title":"Pediatric Cardiology"},"publishedOn":"2025-08-12 15:57:18","publishedOnDateReadable":"August 12th, 2025"},"versionCreatedAt":"2025-05-07 09:08:48","video":"","vorDoi":"10.1007/s00246-025-03985-4","vorDoiUrl":"https://doi.org/10.1007/s00246-025-03985-4","workflowStages":[]},"version":"v1","identity":"rs-6530600","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6530600","identity":"rs-6530600","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}