Altered Global Longitudinal Strain is a common finding in Liver Transplant Recipients with Mild Cardiometabolic Burden

Altered Global Longitudinal Strain is a common finding in Liver Transplant Recipients with Mild Cardiometabolic Burden | 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 Altered Global Longitudinal Strain is a common finding in Liver Transplant Recipients with Mild Cardiometabolic Burden Arianna Toscano, Rosario La Delfa, Hannah Stephens, Melissa Orlandi, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8319992/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Background and aim of the study : Liver transplant (LT) recipients are a population at elevated cardiovascular (CV) risk, yet conventional assessment tools often fail to capture early myocardial dysfunction. Global longitudinal strain (GLS) has emerged as a sensitive marker of subclinical myocardial dysfunction, although its role in the long-term post-transplant setting remains insufficiently defined. The study aimed to evaluate left ventricular (LV)-GLS in a population of stable LT recipients with mild cardiometabolic burden and explored the possible associations with metabolic, lifestyle, inflammatory, and transplant-related variables. Secondary aims included longitudinal GLS variation over 12 months. Subjects and methods: We conducted a cross-sectional observational study in 40 LT recipients. Data on cardiometabolic parameters, body composition (including bioimpedance analysis), diet, physical activity were collected. Carotid ultrasound and echocardiography were performed. Levels of circulating inflammatory cytokines were measured. CV risk scores were calculated. Results : GLS impairment was detected in 47.5% of patients, despite preserved ejection fraction. Antihypertensive therapy correlated with more favorable GLS, whereas higher IL-17A and IL-1β levels were paradoxically linked to preserved strain. No association emerged with immunosuppressive regimen or lifestyle indices. GLS remained unchanged at 12 months, irrespective of weight loss or dietary improvement. Conclusions : GLS appears more sensitive than EF in detecting subclinical myocardial dysfunction in LT recipients, highlighting its potential role in post-transplant CV surveillance. Antihypertensive treatment may exert protective effects, whereas cytokine patterns suggest non-traditional mechanisms of cardiac modulation. Larger longitudinal studies are needed to confirm prognostic implications and integrate GLS into CV risk stratification pathways post-LT. liver transplantation GLS subclinical myocardial dysfunction cardiovascular risk immunomodulation Figures Figure 1 1. INTRODUCTION Liver transplant (LT) is the treatment of choice for acute and chronic liver failure when conservative measures are no longer effective( 1 ). Advances in surgical techniques, patient selection, and immunosuppressive regimens have substantially improved post-transplant survival, with current 1- and 5-year survival rates of approximately 85–90% and 75–80%, respectively( 2 , 3 ). Cardiovascular (CV) complications have long posed a significant threat to long-term survival after liver transplantation (LT), ranking as the second leading cause of non-liver-related post-transplant death( 2 ). Although historically acknowledged, the clinical relevance of this issue is intensifying as metabolic dysfunction–associated steatotic liver disease (MASLD) is becoming an increasingly common indication for liver transplantation, thereby resulting in a recipient population with a substantially greater baseline CV burden( 4 , 5 ). Nonetheless, critical gaps in knowledge remain, and there is no conclusive evidence that CV risk assessment tools validated in the general population are reliably applicable to LT recipients( 6 – 8 ). Innovative and more refined diagnostic parameters may provide a more accurate evaluation of risk in this unique population. Global longitudinal strain (GLS) – assessed by 2-dimensional speckle tracking echocardiography - has gained attention as a method for assessing left ventricular (LV) function and as a sensitive marker of early myocardial dysfunction ( 9 ). Over the years, GLS has been studied in several patient settings and conditions predisposing to CV disease, including modifiable and non-modifiable CV risk factors( 10 – 24 ). Preliminary data indicate that evaluation of GLS in LT candidates is promising to identify patients at increased risk of cardiac complications ( 25 , 26 ). However, its application in long-term liver transplant recipients has not yet been investigated. The identification of early markers of CV damage in liver transplant recipients clearly remains an unmet need. Here we report the results of a cross-sectional evaluation of GLS in a well-characterized population of liver transplant (LT) recipients with mild cardiometabolic burden. We had also the following secondary aims: (a) to provide a descriptive analysis of cardiometabolic parameters in order to better characterize their CV and metabolic risk profile in the post-transplant setting; (b) to identify potential predictive factors associated with GLS alterations; and (c) to analyze the longitudinal modifications of GLS. 2. SUBJECTS AND METHODS 2a. Study population, ethical standards and clinical assessments This study was developed in accordance with the ethical standards reported in the 1964 Declaration of Helsinki and its later amendments and was approved by the local Ethics Committee (“Comitato Etico Area Vasta Centro”; approval number: 22028). All enrolled patients, before participating, signed an informed consent. The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology guidelines(27). Inclusion criteria were age of >18 years and LT performed not earlier than 6 months before enrollment. Exclusion criteria included: (a) history of major adverse CV events (MACE), (b) current or previous therapy with antidiabetic or lipid-lowering medications; (c) presence of chronic systemic diseases or unstable conditions in the 6 months before enrollment, including hospital admission except for prescheduled surgery; (d) pregnancy, or lactation; (e) adherence to a weight loss treatment program in the previous 6 months; (f) retransplantation; (g) multiorgan transplantation; (h) HIV infection or coinfection. Forty LT recipients were consecutively enrolled from October 2022 to June 2023 in the outpatient transplant clinic of Azienda Ospedaliero-Universitaria Careggi, Florence, Italy. Patients underwent general medical examination, including detailed medical and family history and anthropometric data registration, during one of the prescheduled follow-up visits. Personal and clinical data were collected in anonymized files dedicated to the study. At the time of visit, blood was drawn from an antecubital vein for planned biohumoral tests requested for follow-up of the transplanted patients. Additional blood was drawn for the specific tests of the present study and processed as described below. CV risk assessment included calculation of Systematic COronary Risk Evaluation 2 (SCORE2) and Pooled Cohort Equation (PCE) scores using validated web-based calculators: SCORE2 was calculated using the official ESC CV Risk Collaboration tool (ESC CVD Risk app), while PCE scores were obtained from the ACC/AHA ASCVD Risk Estimator Plus, available at http://tools.acc.org/ASCVD-Risk-Estimator-Plus. Risk categories were assigned according to guideline-recommended thresholds for each model(28,29). Enrolled patients underwent liver stiffness and controlled attenuation parameter (CAP) measurement by vibration-controlled transient elastography, and determination of intima-medial thickness and detection of plaques by carotid Doppler ultrasound. Transthoracic echocardiography was also performed, as described in detail in a subsequent section. Physical activity levels were assessed using the International Physical Activity Questionnaire (IPAQ), and results were expressed as MET-min/week according to standardized scoring protocols(30). The Medi-Lite score, a validated tool for evaluating adherence to the Mediterranean diet, was calculated for each participant according to their reported frequency of consumption across the nine food categories included in the scoring system(31). Although primarily designed as a cross-sectional case-control study, a longitudinal follow-up at 12 months was conducted to assess temporal changes in selected cardiometabolic and echocardiographic parameters, with a particular focus on GLS. 2b. Levels of circulating cytokines Serum levels of 4 cytokines were evaluated by Human HS Cytokine B premixed meg Luminex performance assay for Luminex MAGPIX detection system (Bio-techne, Minneapolis USA) and following the manufacturers’ instructions. Specifically, we analyzed interleukin (IL)-1β, IL-6, IL-17A and tumor necrosis factor-α (TNFα). The levels of cytokines were estimated using a 5‐parameter polynomial curve (Bio-Plex Manager software), and the results were managed with Bio-Plex DataPro Software (Bio-rad Laboratories Inc.). 2c. Echocardiographic study and strain analysis Transthoracic echocardiography (TTE) was performed by an experienced board-certified cardiologist (L.S.) using a MyLabTM 50 echocardiograph (Esaote-Italy) equipped with a 2.5 MHz probe. Prior to the addition of 2D Speckle Tracking analysis (ST), heart function was estimated by a traditional 2D measure of LVEF. All echocardiograms were evaluated according to guidelines established by the American Society of Echocardiography, and details on each measure can be found there(32). All subjects completed an echo examination including LV global longitudinal strain assessment (XStrainTM— ESAOTE, Genoa, Italy). The 2D standard echo examination was performed at rest conditions, positioning the subject in left lateral position, and equipped with an SP2430 a 1–4 MHz broad bandwidth electronic phased array probe for adult cardiology examination. According to the segmentation criteria set in EACVI/ASE Consensus document(33) and the software solution in use provided, for each of the apical views, strain curves divided in six segments (left/right basal segments, left/right middle segment and left/right apical segments. For this study, the overall LV GLS and the GLSmean were calculated as the mean of A4C, A2C and ALAX GLS values. In addition, the peak of the segmental values in median, basal and apical segments of the LV chamber were calculated. In accordance with current EACVI/ASE recommendations(33), altered GLS was defined as a peak systolic value ≥–18%, consistent with subclinical impairment of left ventricular systolic function. 2d. Bioimpedance analysis Bioelectrical impedance was measured with phase-sensitive impedance plethysmography (BIA101 Sport Edition, Akern, Florence, Italy). Electrodes were positioned in the middle of the dorsal surfaces of the hands and feet, proximal to the metacarpal–phalangeal and metatarsal–phalangeal joints, respectively, and medially between the distal prominences of the radius and the ulna and between the medial and lateral malleoli at the ankle. Specifically, the proximal edge of one detector electrode was in line with the proximal edge of the ulnar tubercle at the wrist, and the proximal edge of the other detecting electrode was in line with the medial malleolus of the ankle. The current introducing electrodes were placed at a minimum distance of the diameter of the wrist or ankle beyond the paired detector electrode. The upper limbs were apart from the trunk (30°). The lower limbs were also apart (45°). In obese subjects, an insulating cloth was put between the armpits and between the thighs. The subject was instructed not to move; eventual sweat was cleansed with ethyl or isopropyl alcohol. The environment was ventilated or had low relative humidity. The room temperature was the typical medical office temperature, between 24–27 °C. Subjects had to have been fasting for at least 2 h, without having consumed alcohol. They were not to have taken diuretics and were not to be in a febrile state [41] From the values of Resistance (Rz, Ω) and Reactance (Xc, Ω), through regression equations, the following body compartments are estimated: Fat-Free Mass (FFM), Extra Cellular Mass (ECM), Total Body Water (TBW), Extra Cellular Water (ECW), and Intra Cellular Water (ICW). A dedicated software provided the final data of the nutritional and hydration condition of the patient. 2e. Statistical analysis The distribution of continuous variables was assessed using the Kolmogorov–Smirnov test, which indicated non-normality for most parameters. Consequently, non-parametric statistical methods were employed throughout the analysis. Descriptive statistics are reported as medians and interquartile ranges [IQR] for continuous variables, and as absolute frequencies and percentages for categorical variables, as appropriate. Group comparisons were conducted using contingency tables. The Mann–Whitney U test was used for continuous variables, while Fisher’s exact test was applied for binary categorical variables. Correlations between variables were evaluated using Spearman’s rank correlation coefficient. To identify potential predictors of GLS, two analytical approaches were used: binary logistic regression was performed with GLS dichotomized as altered vs preserved, and linear regression was applied using GLS as a continuous dependent variable. Longitudinal changes in GLS between baseline (T0) and 12 months (T12) were assessed using the Friedman test for repeated measures. All statistical analyses were performed using IBM SPSS Statistics, version 26. A p-value < 0.05 was considered statistically significant; p-values between 0.05 and 0.10 were interpreted as indicative of a statistical trend. 3. RESULTS 3a. Baseline characteristics of the population A total of 40 liver transplant recipients were included in the present analysis. Table 1 summarizes the general characteristics of the study cohort at the time of liver transplantation (LT) and at the time of study inclusion. 3b. CV and metabolic characteristics of the cohort None of the enrolled subjects had a previous history of atherosclerotic CV disease (ASCVD), nor did any develop ASCVD during the 12-month follow-up; a family history of ASCVD was, however, present in 30% of patients. Assessment of traditional cardiovascular risk factors included the presence/absence of arterial hypertension and diabetes mellitus, smoking history, and corresponding measurable parameters, such as blood pressure levels, lipid profile, and glycemic indices. A diagnosis of arterial hypertension was present in 60% of patients, and treatment mainly consisted of angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs) (32.5%) or calcium channel blockers (CCB) (30%). Median systolic and diastolic BP values were 128 mmHg [120–139] and 80 mmHg [75–85], respectively. Diabetic patients were excluded at enrollment, and no incident cases occurred during the 12-month follow-up. Median FPG was within the normal range (88 mg/dL [75–99]), and only 15% of subjects were insulin-resistant according to the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). At the time of assessment, 27.5% of patients were active smokers. Many others had a prior history of tobacco use, as reflected by a median of 10 pack-years [0–28], indicating a relevant cumulative burden even among those who had subsequently quit. Anthropometric data showed a median BMI of 27 kg/m² [26–29] and waist circumference of 101 cm [96–108], consistent with overweight or mildly obese profiles typical of post-transplant populations. Body composition parameters derived from bioimpedance analysis were also evaluated and are presented in the Supplementary Table 1 . CV risk estimated by SCORE2 and PCE classified the cohort as being at median moderate 10-year risk according to SCORE2 (8% [4–11]) and intermediate risk according to PCE (15% [6–20]). Median IMT values were within normal ranges (≤900 µm); no patient showed carotid stenosis >50%, whereas subclinical atherosclerosis (i.e., presence of any plaque) was detected in 35% of cases. No patient showed impaired left ventricular ejection fraction (EF); however, strain analysis revealed altered values in 47.5% of the cohort. Full echocardiographic data are reported in Table 2 . 3c. Comparison according to GLS Clinical, biochemical, and transplant-related variables were compared between patients with preserved and altered GLS. Median age at OLT was slightly higher in the preserved GLS group (56 [54–65] vs. 55 [48–58] years), as was age at randomization (63 [58–71] vs. 59 [51–63] years). The proportion of male patients was similar (71.4% vs. 77.8%). MASLD was reported as the etiology of liver disease only in the impaired GLS group (16.7%), while HCC was more frequent in the preserved GLS group (71.4% vs. 55.6%). Donor age and BMI were comparable. Graft steatosis was found in 42.9% of patients with preserved GLS and in 33.3% of those with impaired GLS. Immunosuppressive regimens did not differ significantly between groups. CNIs were used in most patients (81.0% vs. 94.4%), and combination strategies were employed in 42.9% vs. 55.6%, respectively. Mycophenolate mofetil was found to be used only in the preserved GLS group (14.3%). Fasting plasma glucose was higher in the preserved GLS group (93 [85–104] vs. 79 [67–89] mg/dL), while HDL-C was lower (50 [45–53] vs. 61 [46–74] mg/dL). Other metabolic and anthropometric parameters, including BMI, waist circumference, HOMA-IR, and lipid profile, were similar between groups. Blood pressure values and antihypertensive therapy use were higher in the preserved GLS group. The prevalence of metabolic syndrome was 38.1% vs. 27.8%. Carotid plaque was found in 42.9% of patients with preserved GLS and 22.2% with impaired GLS. Median SCORE2 and PCE were higher in the preserved group (9% and 18%, respectively). Liver stiffness, CAP values, physical activity (IPAQ), and adherence to the Mediterranean diet (MediLite) were similar between groups; however, patients with impaired GLS tended to report lower IPAQ scores. Full comparative data are provided in Table 3. No significant differences in bioimpedance-derived variables were observed between patients with preserved and impaired GLS ( Supplementary Table 2 ). 3d. Cytokine analysis Circulating cytokine levels were assessed in the overall cohort and stratified by GLS category, as reported in Table 4 . No significant differences were observed between groups, except for IL-17A, which was lower in patients with impaired GLS (5.5 [5.1–5.9] vs. 5.9 [5.7–7.1] pg/mL; p=0.007). 3e. Correlation analysis A significant negative correlation was observed between EF and GLS (ρ = -0.392, p = 0.013), consistent with the expected relationship between these two measures of systolic function. Spearman correlation analysis of additional physiologically relevant variables identified a limited number of significant associations with GLS: higher blood glucose levels were associated with lower (i.e., better) GLS values (ρ = -0.362, p = 0.024), and IL-17A levels also showed an inverse correlation with GLS (ρ = -0.479, p = 0.004). Although not statistically significant, two variables demonstrated trends of potential interest: HDL cholesterol (HDL-C) levels showed a positive correlation with GLS ( p = 0.066), indicating that higher HDL-C may be associated with less favorable GLS value, and CV risk as estimated by the PCE showed a trend of inverse correlation with GLS ( p = 0.089). 3f. Regression analysis Univariate linear regression models were performed to identify potential predictors of GLS. IL-17A emerged as a significant predictor, with each one-unit increase associated with a 0.559 unit decrease in GLS (β = -0.559, p = 0.022). Similarly, IL-1β levels were significantly associated with GLS (β = -0.277, p = 0.049), reinforcing a possible immuno-inflammatory influence on cardiac function. Fasting plasma glucose also showed a significant association: for each 1 mg/dL increase, GLS improved by approximately 0.082 units (β = -0.082, p = 0.015). In contrast, higher HDL-C levels were associated with worse GLS values (β = +0.082, p = 0.027), consistent with the positive trend observed in correlation analyses. Interestingly, patients receiving antihypertensive therapy exhibited significantly better GLS (β = -2.405, p = 0.025). Binary logistic regression models examining dichotomous variables did not identify any statistically significant predictors of altered GLS. Nonetheless, a notable borderline association was observed for donor liver steatosis, which tended to be associated with a reduced likelihood of GLS impairment (OR = 0.33, p = 0.080). 3g. Longitudinal assessment Longitudinal evaluation of GLS using the Friedman test did not demonstrate any statistically significant changes in GLS between baseline (T0) and 12 months (T12). This lack of variation was consistent across the entire study population. Subgroup analyses further confirmed the absence of change over time. Specifically, no significant differences in GLS were observed when stratifying participants by randomization arm—whether assigned to the dietary intervention group or the control group. Moreover, no longitudinal changes in GLS were detected among individuals who achieved a weight loss of more than 7% or more than 5% of their baseline body weight. 4. DISCUSSION LT recipients represent a unique clinical population, exposed to metabolic dysfunction arising both from post-LT renewed health status and to the dysmetabolic effects of immunosuppressive therapy( 34 ). Calcineurin inhibitors (CNI), which represent the cornerstone of current immunosuppressive regimens, further increase CV risk through nephrotoxicity, as chronic kidney disease is itself recognized as independent risk factor for adverse CV outcomes( 34 , 35 ). Within this context, our study aimed to evaluate subclinical myocardial dysfunction in stable LT recipients, using GLS as a sensitive marker of left ventricular systolic function. The main finding of our study is that GLS appears to offer greater sensitivity than EF for identifying subclinical myocardial dysfunction in asymptomatic, hemodynamically stable, post-LT patients with mild cardiometabolic burden. Although nearly half of the cohort exhibited altered GLS, all patients had preserved EF, confirming that conventional measures may underestimate myocardial dysfunction in this setting. This aligns with findings from several settings, including cardio-oncology, where GLS has been adopted for early detection of cardiotoxicity, often preceding changes in EF( 10 ). Interestingly, while literature highlights distinct cardiotoxicity profiles among immunosuppressive agents( 36 ), GLS impairment in our cohort was not associated with any specific immunosuppressive regimen. Notably, the use of combination strategies did not translate into greater subclinical myocardial dysfunction – a reassuring observation, particularly in a clinical context where current guidelines rarely support long-term monotherapy in LT recipients( 1 ). Over the years, GLS has been extensively characterized in both the general population and in individuals with cardiometabolic comorbidities. Progressive strain deterioration has been consistently linked ageing ( 13 – 15 ), hypertension ( 11 , 20 ), diabetes( 21 , 22 ), obesity( 23 , 24 ), and hypertrygliceridemia( 37 ), while evidence regarding smoking remains controversial ( 19 , 38 , 39 ). In our cohort, the only notable association was the apparently protective effect of antihypertensive therapy on GLS. This observation is consistent with previous evidence showing that pharmacological blood pressure control is associated with improved strain values in hypertensive patients ( 40 ). In line with prior observations, we found no significant differences between different anti-hypertensive drug classes, suggesting that GLS improvement is related to the decrease in blood pressure rather than to anti-remodeling properties of drugs ( 41 ). Taken together, these findings support the hypothesis that early blood pressure control, even when values fall within borderline values, may contribute to attenuating subclinical myocardial dysfunction in LT recipients. Conversely, associations involving fasting glucose and HDL-C should be interpreted with caution. In our cohort, glucose values were predominantly within the normal range, which may have limited the ability to detect clinically meaningful differences between metabolic phenotypes. This raises the possibility that the observed association could reflect random variability, residual confounding or statistical noise rather than a true biological effect. A similar consideration applies to HDL-C: although traditionally cardioprotective, HDL-C functionality rather than concentration now appears to play a greater role in vascular homeostasis. In inflammatory and immunosuppressed states, HDL-C may undergo oxidative and structural modifications, becoming dysfunctional despite normal or elevated levels, a mechanism described in other transplant recipients and chronic inflammatory settings ( 42 – 44 ). Aligned with these paradoxical results, the behavior of GLS relative to conventional CV risk scores also offered an unexpected pattern. Despite placing most patients in a moderate risk category—which aligns with current estimates for the Italian general population under the revised SCORE2 framework—both SCORE2 and PCE values were paradoxically higher among individuals with preserved GLS. This mirrors the Copenhagen City Heart Study, where Biering-Sørensen et al. demonstrated added prognostic value of GLS beyond Framingham, SCORE and PCE( 45 ) and findings in psoriasis where GLS enhanced SCORE2 prediction of MACE( 46 ). Moreover, carotid plaque burden—although not statistically different—was more frequent in patients with preserved GLS, suggesting that subclinical atherosclerosis and early myocardial dysfunction may not progress in parallel. In our cohort, patients with impaired GLS tended to report lower IPAQ scores, suggesting a possible link between sedentary behavior and early myocardial dysfunction. This aligns with evidence from breast cancer survivors and kidney transplant recipients, where increasing physical activity—particularly when moving from inactivity to moderate levels—was associated with improvements in GLS( 47 , 48 ), reinforcing the concept that physical activity should not only be encouraged but actively promoted among LT recipients as part of CV risk management. Finally, despite good adherence to a Mediterranean diet, we observed a median weight loss of 3% with no significant differences in GLS. No clinical studies have yet evaluated the impact of the Mediterranean diet on myocardial strain, and available evidence derives mainly from preclinical models showing early GLS impairment only in mice fed a high-fat diet despite preserved LVEF( 49 ). These findings suggest that a 12-month intervention may be insufficient to produce measurable diet-related effects on cardiac function in LT recipients. Additionally, an unexpected but noteworthy finding of our study was the inverse association between IL-17A and IL-1β levels and GLS values, with higher cytokine levels linked to better myocardial function. While both are traditionally considered markers of inflammation-driven cardiac injury ( 50 , 51 ), their suppression in chronically immunosuppressed liver transplant recipients may instead reflect an over-suppressed or dysregulated immune profile( 52 ). Experimental evidence suggests that a minimal level of pro-inflammatory signaling may be necessary for vascular homeostasis and myocardial integrity( 52 ). Hence, their suppression in stable, chronically immunosuppressed liver transplant recipients may reflect a state of immune exhaustion rather than a protective anti-inflammatory profile( 50 , 52 ). These findings reinforce the notion that liver transplant recipients often exhibit atypical immunometabolic responses, as also reported in studies showing unexpected oxidative modifications of fibrinogen linked to CV risk in this population( 53 ) and deserve further investigations. Finally, donor liver steatosis did not correlate with GLS impairment, yet showed a non-significant trend toward a more favorable profile (OR = 0.33, p = 0.080). Although this may indicate that graft steatosis has limited impact on cardiac outcomes, the finding remains exploratory and warrants validation in larger studies. Our study has several limitations. First, the modest sample size inevitably reduces statistical power and precludes robust multivariable modelling. Second, although a 12-month follow-up was available, this interval may be insufficient to detect structural cardiac effects related to lifestyle modification. Third, the absence of intraoperative, early post-transplant and particularly pre-transplant cardiac data limits our ability to describe the full trajectory of cardiac function over time. Finally, the study was not originally powered for cardiovascular endpoints, and therefore causal interpretation must remain cautious. Despite these limitations, to our knowledge this is the first study to simultaneously evaluate metabolic parameters, advanced echocardiographic indices including GLS, body composition assessed by bioimpedance, dietary patterns and physical activity in LT recipients, and the first to explore how these variables relate to myocardial strain. In conclusion, our study demonstrates that GLS appears to offer greater sensitivity than EF for identifying subclinical myocardial dysfunction in LT patients. Antihypertensive treatment and physical activity emerged as possible protective factors, while no significant effect was observed for dietary changes over 12 months. However, strain patterns did not consistently parallel traditional CV risk indicators, potentially because of the influence of chronic immunosuppression and post-LT unique metabolic milieu. GLS may therefore represent a valuable addition to clinical assessment pathways in this population. Larger prospective studies are needed to identify predictors of early cardiac dysfunction and clarify the role of GLS in long-term CV risk stratification post-transplant. Declarations Authors’ roles: Conceptualization: AT, SG, FM, LS, DG; Methodology: AT, SG, LS, FS, MC, FS, DG; Investigation: AT. RLD, MO, MC, GM, CF, TZ, AAv: Data curation: HS, RLD, TZ; AAv, DG, SB; Formal analysis: AT, SG; Echocardiography and GLS Analysis: MO, MC, LS; Laboratory and Cytokine Analysis MC, CF, AAm; Nutritional and Lifestyle Assessment: FS, GM; Writing – Original Draft AT; Writing – Review & Editing: HS, SG, MF, LS; Supervision: SG, FM, LS; Final Approval of the Manuscript: All authors References European Association for the Study of the Liver. EASL Clinical Practice Guidelines on liver transplantation. J Hepatol. dicembre 2024;81(6):1040–86. Watt KDS, Pedersen RA, Kremers WK, Heimbach JK, Charlton MR. Evolution of causes and risk factors for mortality post-liver transplant: results of the NIDDK long-term follow-up study. Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg. giugno 2010;10(6):1420–7. Fatourou EM, Tsochatzis EA. Management of metabolic syndrome and cardiovascular risk after liver transplantation. Lancet Gastroenterol Hepatol. settembre 2019;4(9):731–41. 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Curr Cardiol Rep. 3 luglio 2021;23(8):110. von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP, et al. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. BMJ. 20 ottobre 2007;335(7624):806–8. Mendez K, Rane M, Orkaby AR, Gaziano JM. A tool to help patients visualize ASCVD risk and the potential impact of risk-lowering interventions. Int J Cardiol Cardiovasc Risk Prev. dicembre 2022;15:200159. Mach F, Koskinas KC, Roeters van Lennep JE, Tokgözoğlu L, Badimon L, Baigent C, et al. 2025 Focused Update of the 2019 ESC/EAS Guidelines for the management of dyslipidaemias. Eur Heart J. 7 novembre 2025;46(42):4359–78. Hagströmer M, Oja P, Sjöström M. The International Physical Activity Questionnaire (IPAQ): a study of concurrent and construct validity. Public Health Nutr. settembre 2006;9(6):755–62. Sofi F, Dinu M, Pagliai G, Marcucci R, Casini A. Validation of a literature-based adherence score to Mediterranean diet: the MEDI-LITE score. Int J Food Sci Nutr. settembre 2017;68(6):757–62. American College of Cardiology Foundation Appropriate Use Criteria Task Force, American Society of Echocardiography, American Heart Association, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, et al. ACCF/ASE/AHA/ASNC/HFSA/HRS/SCAI/SCCM/SCCT/SCMR 2011 Appropriate Use Criteria for Echocardiography. A Report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, American Society of Echocardiography, American Heart Association, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, Society of Critical Care Medicine, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance American College of Chest Physicians. J Am Soc Echocardiogr Off Publ Am Soc Echocardiogr. marzo 2011;24(3):229–67. Voigt JU, Pedrizzetti G, Lysyansky P, Marwick TH, Houle H, Baumann R, et al. Definitions for a common standard for 2D speckle tracking echocardiography: consensus document of the EACVI/ASE/Industry Task Force to standardize deformation imaging. Eur Heart J Cardiovasc Imaging. gennaio 2015;16(1):1–11. Gabrielli F, Bernasconi E, Toscano A, Avossa A, Cavicchioli A, Andreone P, et al. Side Effects of Immunosuppressant Drugs After Liver Transplant. Pharmaceuticals. 27 febbraio 2025;18(3):342. Sarnak MJ, Levey AS, Schoolwerth AC, Coresh J, Culleton B, Hamm LL, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Hypertens Dallas Tex 1979. novembre 2003;42(5):1050–65. 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Barter P, Gotto AM, LaRosa JC, Maroni J, Szarek M, Grundy SM, et al. HDL Cholesterol, Very Low Levels of LDL Cholesterol, and Cardiovascular Events. N Engl J Med. 27 settembre 2007;357(13):1301–10. Biering-Sørensen T, Biering-Sørensen SR, Olsen FJ, Sengeløv M, Jørgensen PG, Mogelvang R, et al. Global Longitudinal Strain by Echocardiography Predicts Long-Term Risk of Cardiovascular Morbidity and Mortality in a Low-Risk General Population: The Copenhagen City Heart Study. Circ Cardiovasc Imaging. marzo 2017;10(3):e005521. Makavos G, Ikonomidis I, Lambadiari V, Koliou GA, Pavlidis G, Thymis J, et al. Additive prognostic value of longitudinal myocardial deformation to SCORE2 in psoriasis. Eur Heart J Open. marzo 2023;3(2):oead016. Enrico M, Klika R, Ingletto C, Mascherini G, Pedrizzetti G, Stefani L. Changes in global longitudinal strain in renal transplant recipients following 12 months of exercise. Intern Emerg Med. agosto 2018;13(5):805–9. Naaktgeboren WR, Groen WG, Jacobse JN, Steggink LC, Walenkamp AME, van Harten WH, et al. Physical Activity and Cardiac Function in Long-Term Breast Cancer Survivors: A Cross-Sectional Study. JACC CardioOncology. giugno 2022;4(2):183–91. Sartorio A, Dal Pont C, Romano S. Standard and New Echocardio Techniques, Such as Global Longitudinal Strain, to Monitor the Impact of Diets on Cardiovascular Diseases and Heart Function. Nutrients. 13 maggio 2024;16(10):1471. Bujak M, Dobaczewski M, Chatila K, Mendoza LH, Li N, Reddy A, et al. Interleukin-1 receptor type I signaling critically regulates infarct healing and cardiac remodeling. Am J Pathol. luglio 2008;173(1):57–67. Huang L. The role of IL-17 family cytokines in cardiac fibrosis. Front Cardiovasc Med. 2024;11:1470362. Mills KHG. IL-17 and IL-17-producing cells in protection versus pathology. Nat Rev Immunol. gennaio 2023;23(1):38–54. Gitto S, Fiorillo C, Argento FR, Fini E, Borghi S, Falcini M, et al. Oxidative stress-induced fibrinogen modifications in liver transplant recipients: unraveling a novel potential mechanism for cardiovascular risk. Res Pract Thromb Haemost. agosto 2024;8(6):102555. Tables Tables 1 to 4 are available in the Supplementary Files section. Supplementary Files TablesFinal.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 29 Jan, 2026 Reviewers invited by journal 07 Jan, 2026 Editor assigned by journal 11 Dec, 2025 First submitted to journal 10 Dec, 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. We do this by developing innovative software and high quality services for the global research community. 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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-8319992","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":570757485,"identity":"79c18d01-62dc-4092-ad20-699d42e38a85","order_by":0,"name":"Arianna 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1","display":"","copyAsset":false,"role":"figure","size":241274,"visible":true,"origin":"","legend":"\u003cp\u003eExample of GLS analysis in a liver transplant recipient using XStrain™ software (ESAOTE, Italy). The image shows the details of the global longitudinal strain (GLS) values expressed in percentage. The values include GLS, mean strain and strain data for each left ventricle segment.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8319992/v1/7ee81d13ddb0fc5c39cc774d.jpeg"},{"id":100381056,"identity":"b1e31a6c-4bb4-4bed-94ba-5265391a46ba","added_by":"auto","created_at":"2026-01-16 10:37:15","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":975725,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8319992/v1/98e80fdc-6435-40ba-9af1-0463921302e3.pdf"},{"id":100362185,"identity":"68293049-42fc-4fd3-a906-8a10c0e708ba","added_by":"auto","created_at":"2026-01-16 07:46:17","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":32184,"visible":true,"origin":"","legend":"","description":"","filename":"TablesFinal.docx","url":"https://assets-eu.researchsquare.com/files/rs-8319992/v1/fe093e4862a8f8b9e0968b39.docx"}],"financialInterests":"","formattedTitle":"Altered Global Longitudinal Strain is a common finding in Liver Transplant Recipients with Mild Cardiometabolic Burden","fulltext":[{"header":"1. INTRODUCTION","content":"\u003cp\u003eLiver transplant (LT) is the treatment of choice for acute and chronic liver failure when conservative measures are no longer effective(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Advances in surgical techniques, patient selection, and immunosuppressive regimens have substantially improved post-transplant survival, with current 1- and 5-year survival rates of approximately 85\u0026ndash;90% and 75\u0026ndash;80%, respectively(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eCardiovascular (CV) complications have long posed a significant threat to long-term survival after liver transplantation (LT), ranking as the second leading cause of non-liver-related post-transplant death(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Although historically acknowledged, the clinical relevance of this issue is intensifying as metabolic dysfunction\u0026ndash;associated steatotic liver disease (MASLD) is becoming an increasingly common indication for liver transplantation, thereby resulting in a recipient population with a substantially greater baseline CV burden(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Nonetheless, critical gaps in knowledge remain, and there is no conclusive evidence that CV risk assessment tools validated in the general population are reliably applicable to LT recipients(\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eInnovative and more refined diagnostic parameters may provide a more accurate evaluation of risk in this unique population. Global longitudinal strain (GLS) \u0026ndash; assessed by 2-dimensional speckle tracking echocardiography - has gained attention as a method for assessing left ventricular (LV) function and as a sensitive marker of early myocardial dysfunction (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Over the years, GLS has been studied in several patient settings and conditions predisposing to CV disease, including modifiable and non-modifiable CV risk factors(\u003cspan additionalcitationids=\"CR11 CR12 CR13 CR14 CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22 CR23\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Preliminary data indicate that evaluation of GLS in LT candidates is promising to identify patients at increased risk of cardiac complications (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). However, its application in long-term liver transplant recipients has not yet been investigated.\u003c/p\u003e \u003cp\u003eThe identification of early markers of CV damage in liver transplant recipients clearly remains an unmet need. Here we report the results of a cross-sectional evaluation of GLS in a well-characterized population of liver transplant (LT) recipients with mild cardiometabolic burden. We had also the following secondary aims: (a) to provide a descriptive analysis of cardiometabolic parameters in order to better characterize their CV and metabolic risk profile in the post-transplant setting; (b) to identify potential predictive factors associated with GLS alterations; and (c) to analyze the longitudinal modifications of GLS.\u003c/p\u003e"},{"header":"2. SUBJECTS AND METHODS","content":"\u003cp\u003e\u003cstrong\u003e2a. Study population, ethical standards and clinical assessments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was developed in accordance with the ethical standards reported in the 1964 Declaration of Helsinki and its later amendments and was approved by the local Ethics Committee (\u0026ldquo;Comitato Etico Area Vasta Centro\u0026rdquo;; approval number: 22028). All enrolled patients, before participating, signed an informed consent. The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology guidelines(27).\u003c/p\u003e\n\u003cp\u003eInclusion criteria were age of \u0026gt;18 years and LT performed not earlier than 6 months before enrollment. Exclusion criteria included: (a) history of major adverse CV events (MACE), (b) current or previous therapy with antidiabetic or lipid-lowering medications; (c) presence of chronic systemic diseases or unstable conditions in the 6 months before enrollment, including hospital admission except for prescheduled surgery; (d) pregnancy, or lactation; (e) adherence to a weight loss treatment program in the previous 6 months; (f) retransplantation; (g) multiorgan transplantation; (h) HIV infection or coinfection.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eForty LT recipients were consecutively enrolled from October 2022 to June 2023 in the outpatient transplant clinic of Azienda Ospedaliero-Universitaria Careggi, Florence, Italy. Patients underwent general medical examination, including detailed medical and family history and anthropometric data registration, during one of the prescheduled follow-up visits. Personal and clinical data were collected in anonymized files dedicated to the study. At the time of visit, blood was drawn from an antecubital vein for planned biohumoral tests requested for follow-up of the transplanted patients. Additional blood was drawn for the specific tests of the present study and processed as described below. CV risk assessment included calculation of Systematic COronary Risk Evaluation 2 (SCORE2) and Pooled Cohort Equation (PCE) scores using validated web-based calculators: SCORE2 was calculated using the official ESC CV Risk Collaboration tool (ESC CVD Risk app), while PCE scores were obtained from the ACC/AHA ASCVD Risk Estimator Plus, available at http://tools.acc.org/ASCVD-Risk-Estimator-Plus. Risk categories were assigned according to guideline-recommended thresholds for each model(28,29).\u003c/p\u003e\n\u003cp\u003eEnrolled patients underwent liver stiffness and controlled attenuation parameter (CAP) measurement by vibration-controlled transient elastography, and determination of intima-medial thickness and detection of plaques by carotid Doppler ultrasound. Transthoracic echocardiography was also performed, as described in detail in a subsequent section. Physical activity levels were assessed using the International Physical Activity Questionnaire (IPAQ), and results were expressed as MET-min/week according to standardized scoring protocols(30). The Medi-Lite score, a validated tool for evaluating adherence to the Mediterranean diet, was calculated for each participant according to their reported frequency of consumption across the nine food categories included in the scoring system(31). Although primarily designed as a cross-sectional case-control study, a longitudinal follow-up at 12 months was conducted to assess temporal changes in selected cardiometabolic and echocardiographic parameters, with a particular focus on GLS.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2b. Levels of circulating cytokines\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSerum levels of 4 cytokines were evaluated by Human HS Cytokine B premixed meg Luminex performance assay for Luminex MAGPIX detection system (Bio-techne, Minneapolis USA) and following the manufacturers\u0026rsquo; instructions. Specifically, we analyzed interleukin (IL)-1\u0026beta;, IL-6, IL-17A and tumor necrosis factor-\u0026alpha; (TNF\u0026alpha;). The levels of cytokines were estimated using a 5‐parameter polynomial curve (Bio-Plex Manager software), and the results were managed with Bio-Plex DataPro Software (Bio-rad Laboratories Inc.).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2c. Echocardiographic study and strain analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTransthoracic echocardiography (TTE) was performed by an experienced board-certified cardiologist (L.S.) using a MyLabTM 50 echocardiograph (Esaote-Italy) equipped with a 2.5 MHz probe. Prior to the addition of 2D Speckle Tracking analysis (ST), heart function was estimated by a traditional 2D measure of LVEF. All echocardiograms were evaluated according to guidelines established by the American Society of Echocardiography, and details on each measure can be found there(32).\u003c/p\u003e\n\u003cp\u003eAll subjects completed an echo examination including LV global longitudinal strain assessment (XStrainTM\u0026mdash; ESAOTE, Genoa, Italy). The 2D standard echo examination was performed at rest conditions, positioning the subject in left lateral position, and equipped with an SP2430 a 1\u0026ndash;4 MHz broad bandwidth electronic phased array probe for adult cardiology examination. According to the segmentation criteria set in EACVI/ASE Consensus document(33) and the software solution in use provided, for each of the apical views, strain curves divided in six segments (left/right basal segments, left/right middle segment and left/right apical segments. For this study, the overall LV GLS and the GLSmean were calculated as the mean of A4C, A2C and ALAX GLS values. In addition, the peak of the segmental values in median, basal and apical segments of the LV chamber were calculated. In accordance with current EACVI/ASE recommendations(33), altered GLS was defined as a peak systolic value \u0026ge;\u0026ndash;18%, consistent with subclinical impairment of left ventricular systolic function.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2d. Bioimpedance analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBioelectrical impedance was measured with phase-sensitive impedance plethysmography (BIA101 Sport Edition, Akern, Florence, Italy). Electrodes were positioned in the middle of the dorsal surfaces of the hands and feet, proximal to the metacarpal\u0026ndash;phalangeal and metatarsal\u0026ndash;phalangeal joints, respectively, and medially between the distal prominences of the radius and the ulna and between the medial and lateral malleoli at the ankle. Specifically, the proximal edge of one detector electrode was in line with the proximal edge of the ulnar tubercle at the wrist, and the proximal edge of the other detecting electrode was in line with the medial malleolus of the ankle. The current introducing electrodes were placed at a minimum distance of the diameter of the wrist or ankle beyond the paired detector electrode. The upper limbs were apart from the trunk (30\u0026deg;). The lower limbs were also apart (45\u0026deg;). In obese subjects, an insulating cloth was put between the armpits and between the thighs. The subject was instructed not to move; eventual sweat was cleansed with ethyl or isopropyl alcohol. The environment was ventilated or had low relative humidity. The room temperature was the typical medical office temperature, between 24\u0026ndash;27 \u0026deg;C. Subjects had to have been fasting for at least 2 h, without having consumed alcohol. They were not to have taken diuretics and were not to be in a febrile state [41]\u003c/p\u003e\n\u003cp\u003eFrom the values of Resistance (Rz, \u0026Omega;) and Reactance (Xc, \u0026Omega;), through regression equations, the following body compartments are estimated: Fat-Free Mass (FFM), Extra Cellular Mass (ECM), Total Body Water (TBW), Extra Cellular Water (ECW), and Intra Cellular Water (ICW). A dedicated software provided the final data of the nutritional and hydration condition of the patient.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2e. Statistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe distribution of continuous variables was assessed using the Kolmogorov\u0026ndash;Smirnov test, which indicated non-normality for most parameters. Consequently, non-parametric statistical methods were employed throughout the analysis.\u003c/p\u003e\n\u003cp\u003eDescriptive statistics are reported as medians and interquartile ranges [IQR] for continuous variables, and as absolute frequencies and percentages for categorical variables, as appropriate. Group comparisons were conducted using contingency tables. The Mann\u0026ndash;Whitney U test was used for continuous variables, while Fisher\u0026rsquo;s exact test was applied for binary categorical variables. Correlations between variables were evaluated using Spearman\u0026rsquo;s rank correlation coefficient. To identify potential predictors of GLS, two analytical approaches were used: binary logistic regression was performed with GLS dichotomized as altered vs preserved, and linear regression was applied using GLS as a continuous dependent variable. Longitudinal changes in GLS between baseline (T0) and 12 months (T12) were assessed using the Friedman test for repeated measures.\u003c/p\u003e\n\u003cp\u003eAll statistical analyses were performed using IBM SPSS Statistics, version 26. A p-value \u0026lt; 0.05 was considered statistically significant; p-values between 0.05 and 0.10 were interpreted as indicative of a statistical trend.\u003c/p\u003e"},{"header":"3. RESULTS","content":"\u003cp\u003e\u003cstrong\u003e3a. Baseline characteristics of the population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 40 liver transplant recipients were included in the present analysis. \u003cstrong\u003eTable 1\u0026nbsp;\u003c/strong\u003esummarizes the general characteristics of the study cohort at the time of liver transplantation (LT) and at the time of study inclusion.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3b. CV and metabolic characteristics of the cohort\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone of the enrolled subjects had a previous history of atherosclerotic CV disease (ASCVD), nor did any develop ASCVD during the 12-month follow-up; a family history of ASCVD was, however, present in 30% of patients.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAssessment of traditional cardiovascular risk factors included the presence/absence of arterial hypertension and diabetes mellitus, smoking history, and corresponding measurable parameters, such as blood pressure levels, lipid profile, and glycemic indices.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA diagnosis of arterial hypertension was present in 60% of patients, and treatment mainly consisted of angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs) (32.5%) or calcium channel blockers (CCB) (30%). Median systolic and diastolic BP values were 128 mmHg [120\u0026ndash;139] and 80 mmHg [75\u0026ndash;85], respectively.\u003c/p\u003e\n\u003cp\u003eDiabetic patients were excluded at enrollment, and no incident cases occurred during the 12-month follow-up. Median FPG was within the normal range (88 mg/dL [75\u0026ndash;99]), and only 15% of subjects were insulin-resistant according to the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). At the time of assessment, 27.5% of patients were active smokers. Many others had a prior history of tobacco use, as reflected by a median of 10 pack-years [0\u0026ndash;28], indicating a relevant cumulative burden even among those who had subsequently quit.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAnthropometric data showed a median BMI of 27 kg/m\u0026sup2; [26\u0026ndash;29] and waist circumference of 101 cm [96\u0026ndash;108], consistent with overweight or mildly obese profiles typical of post-transplant populations. Body composition parameters derived from bioimpedance analysis were also evaluated and are presented in the \u003cstrong\u003eSupplementary Table 1\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eCV risk estimated by SCORE2 and PCE classified the cohort as being at median moderate 10-year risk according to SCORE2 (8% [4\u0026ndash;11]) and intermediate risk according to PCE (15% [6\u0026ndash;20]). Median IMT values were within normal ranges (\u0026le;900 \u0026micro;m); no patient showed carotid stenosis \u0026gt;50%, whereas subclinical atherosclerosis (i.e., presence of any plaque) was detected in 35% of cases.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNo patient showed impaired left ventricular ejection fraction (EF); however, strain analysis revealed altered values in 47.5% of the cohort. Full echocardiographic data are reported in \u003cstrong\u003eTable 2\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3c. Comparison according to GLS\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eClinical, biochemical, and transplant-related variables were compared between patients with preserved and altered GLS. Median age at OLT was slightly higher in the preserved GLS group (56 [54\u0026ndash;65] vs. 55 [48\u0026ndash;58] years), as was age at randomization (63 [58\u0026ndash;71] vs. 59 [51\u0026ndash;63] years). The proportion of male patients was similar (71.4% vs. 77.8%). MASLD was reported as the etiology of liver disease only in the impaired GLS group (16.7%), while HCC was more frequent in the preserved GLS group (71.4% vs. 55.6%). Donor age and BMI were comparable. Graft steatosis was found in 42.9% of patients with preserved GLS and in 33.3% of those with impaired GLS.\u003c/p\u003e\n\u003cp\u003eImmunosuppressive regimens did not differ significantly between groups. CNIs were used in most patients (81.0% vs. 94.4%), and combination strategies were employed in 42.9% vs. 55.6%, respectively. Mycophenolate mofetil was found to be used only in the preserved GLS group (14.3%).\u003c/p\u003e\n\u003cp\u003eFasting plasma glucose was higher in the preserved GLS group (93 [85\u0026ndash;104] vs. 79 [67\u0026ndash;89] mg/dL), while HDL-C was lower (50 [45\u0026ndash;53] vs. 61 [46\u0026ndash;74] mg/dL). Other metabolic and anthropometric parameters, including BMI, waist circumference, HOMA-IR, and lipid profile, were similar between groups. Blood pressure values and antihypertensive therapy use were higher in the preserved GLS group. The prevalence of metabolic syndrome was 38.1% vs. 27.8%.\u003c/p\u003e\n\u003cp\u003eCarotid plaque was found in 42.9% of patients with preserved GLS and 22.2% with impaired GLS. Median SCORE2 and PCE were higher in the preserved group (9% and 18%, respectively). Liver stiffness, CAP values, physical activity (IPAQ), and adherence to the Mediterranean diet (MediLite) were similar between groups; however, patients with impaired GLS tended to report lower IPAQ scores. Full comparative data are provided in \u003cstrong\u003eTable 3.\u0026nbsp;\u003c/strong\u003eNo significant differences in bioimpedance-derived variables were observed between patients with preserved and impaired GLS (\u003cstrong\u003eSupplementary Table 2\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3d. Cytokine analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCirculating cytokine levels were assessed in the overall cohort and stratified by GLS category, as reported in \u003cstrong\u003eTable 4\u003c/strong\u003e. No significant differences were observed between groups, except for IL-17A, which was lower in patients with impaired GLS (5.5 [5.1\u0026ndash;5.9] vs. 5.9 [5.7\u0026ndash;7.1] pg/mL; p=0.007).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3e. Correlation analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA significant negative correlation was observed between EF and GLS (\u0026rho; = -0.392, \u003cem\u003ep\u003c/em\u003e = 0.013), consistent with the expected relationship between these two measures of systolic function. Spearman correlation analysis of additional physiologically relevant variables identified a limited number of significant associations with GLS: higher blood glucose levels were associated with lower (i.e., better) GLS values (\u0026rho; = -0.362, p = 0.024), and IL-17A levels also showed an inverse correlation with GLS (\u0026rho; = -0.479, p = 0.004).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAlthough not statistically significant, two variables demonstrated trends of potential interest: HDL cholesterol (HDL-C) levels showed a positive correlation with GLS (\u003cem\u003ep\u003c/em\u003e = 0.066), indicating that higher HDL-C may be associated with less favorable GLS value, and CV risk as estimated by the PCE showed a trend of inverse correlation with GLS (\u003cem\u003ep\u003c/em\u003e = 0.089).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3f. Regression analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eUnivariate linear regression models were performed to identify potential predictors of GLS. IL-17A emerged as a significant predictor, with each one-unit increase associated with a 0.559 unit decrease in GLS (\u0026beta; = -0.559, p = 0.022). Similarly, IL-1\u0026beta; levels were significantly associated with GLS (\u0026beta; = -0.277, p = 0.049), reinforcing a possible immuno-inflammatory influence on cardiac function.\u003c/p\u003e\n\u003cp\u003eFasting plasma glucose also showed a significant association: for each 1 mg/dL increase, GLS improved by approximately 0.082 units (\u0026beta; = -0.082, \u003cem\u003ep\u003c/em\u003e = 0.015). In contrast, higher HDL-C levels were associated with worse GLS values (\u0026beta; = +0.082, \u003cem\u003ep\u003c/em\u003e = 0.027), consistent with the positive trend observed in correlation analyses.\u003c/p\u003e\n\u003cp\u003eInterestingly, patients receiving antihypertensive therapy exhibited significantly better GLS (\u0026beta; = -2.405, p = 0.025). Binary logistic regression models examining dichotomous variables did not identify any statistically significant predictors of altered GLS. Nonetheless, a notable borderline association was observed for donor liver steatosis, which tended to be associated with a reduced likelihood of GLS impairment (OR = 0.33, p = 0.080).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3g. Longitudinal assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLongitudinal evaluation of GLS using the Friedman test did not demonstrate any statistically significant changes in GLS between baseline (T0) and 12 months (T12). This lack of variation was consistent across the entire study population. Subgroup analyses further confirmed the absence of change over time. Specifically, no significant differences in GLS were observed when stratifying participants by randomization arm\u0026mdash;whether assigned to the dietary intervention group or the control group. Moreover, no longitudinal changes in GLS were detected among individuals who achieved a weight loss of more than 7% or more than 5% of their baseline body weight.\u003c/p\u003e"},{"header":"4. DISCUSSION","content":"\u003cp\u003eLT recipients represent a unique clinical population, exposed to metabolic dysfunction arising both from post-LT renewed health status and to the dysmetabolic effects of immunosuppressive therapy(\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). Calcineurin inhibitors (CNI), which represent the cornerstone of current immunosuppressive regimens, further increase CV risk through nephrotoxicity, as chronic kidney disease is itself recognized as independent risk factor for adverse CV outcomes(\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). Within this context, our study aimed to evaluate subclinical myocardial dysfunction in stable LT recipients, using GLS as a sensitive marker of left ventricular systolic function. The main finding of our study is that GLS appears to offer greater sensitivity than EF for identifying subclinical myocardial dysfunction in asymptomatic, hemodynamically stable, post-LT patients with mild cardiometabolic burden. Although nearly half of the cohort exhibited altered GLS, all patients had preserved EF, confirming that conventional measures may underestimate myocardial dysfunction in this setting. This aligns with findings from several settings, including cardio-oncology, where GLS has been adopted for early detection of cardiotoxicity, often preceding changes in EF(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Interestingly, while literature highlights distinct cardiotoxicity profiles among immunosuppressive agents(\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e), GLS impairment in our cohort was not associated with any specific immunosuppressive regimen. Notably, the use of combination strategies did not translate into greater subclinical myocardial dysfunction \u0026ndash; a reassuring observation, particularly in a clinical context where current guidelines rarely support long-term monotherapy in LT recipients(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOver the years, GLS has been extensively characterized in both the general population and in individuals with cardiometabolic comorbidities. Progressive strain deterioration has been consistently linked ageing (\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e), hypertension (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e), diabetes(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e), obesity(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e), and hypertrygliceridemia(\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e), while evidence regarding smoking remains controversial (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). In our cohort, the only notable association was the apparently protective effect of antihypertensive therapy on GLS. This observation is consistent with previous evidence showing that pharmacological blood pressure control is associated with improved strain values in hypertensive patients (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e). In line with prior observations, we found no significant differences between different anti-hypertensive drug classes, suggesting that GLS improvement is related to the decrease in blood pressure rather than to anti-remodeling properties of drugs (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e). Taken together, these findings support the hypothesis that early blood pressure control, even when values fall within borderline values, may contribute to attenuating subclinical myocardial dysfunction in LT recipients.\u003c/p\u003e \u003cp\u003eConversely, associations involving fasting glucose and HDL-C should be interpreted with caution. In our cohort, glucose values were predominantly within the normal range, which may have limited the ability to detect clinically meaningful differences between metabolic phenotypes. This raises the possibility that the observed association could reflect random variability, residual confounding or statistical noise rather than a true biological effect. A similar consideration applies to HDL-C: although traditionally cardioprotective, HDL-C functionality rather than concentration now appears to play a greater role in vascular homeostasis. In inflammatory and immunosuppressed states, HDL-C may undergo oxidative and structural modifications, becoming dysfunctional despite normal or elevated levels, a mechanism described in other transplant recipients and chronic inflammatory settings (\u003cspan additionalcitationids=\"CR43\" citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAligned with these paradoxical results, the behavior of GLS relative to conventional CV risk scores also offered an unexpected pattern. Despite placing most patients in a moderate risk category\u0026mdash;which aligns with current estimates for the Italian general population under the revised SCORE2 framework\u0026mdash;both SCORE2 and PCE values were paradoxically higher among individuals with preserved GLS. This mirrors the Copenhagen City Heart Study, where Biering-S\u0026oslash;rensen et al. demonstrated added prognostic value of GLS beyond Framingham, SCORE and PCE(\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e) and findings in psoriasis where GLS enhanced SCORE2 prediction of MACE(\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e). Moreover, carotid plaque burden\u0026mdash;although not statistically different\u0026mdash;was more frequent in patients with preserved GLS, suggesting that subclinical atherosclerosis and early myocardial dysfunction may not progress in parallel.\u003c/p\u003e \u003cp\u003eIn our cohort, patients with impaired GLS tended to report lower IPAQ scores, suggesting a possible link between sedentary behavior and early myocardial dysfunction. This aligns with evidence from breast cancer survivors and kidney transplant recipients, where increasing physical activity\u0026mdash;particularly when moving from inactivity to moderate levels\u0026mdash;was associated with improvements in GLS(\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e), reinforcing the concept that physical activity should not only be encouraged but actively promoted among LT recipients as part of CV risk management.\u003c/p\u003e \u003cp\u003eFinally, despite good adherence to a Mediterranean diet, we observed a median weight loss of 3% with no significant differences in GLS. No clinical studies have yet evaluated the impact of the Mediterranean diet on myocardial strain, and available evidence derives mainly from preclinical models showing early GLS impairment only in mice fed a high-fat diet despite preserved LVEF(\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e). These findings suggest that a 12-month intervention may be insufficient to produce measurable diet-related effects on cardiac function in LT recipients.\u003c/p\u003e \u003cp\u003eAdditionally, an unexpected but noteworthy finding of our study was the inverse association between IL-17A and IL-1β levels and GLS values, with higher cytokine levels linked to better myocardial function. While both are traditionally considered markers of inflammation-driven cardiac injury (\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e, \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e), their suppression in chronically immunosuppressed liver transplant recipients may instead reflect an over-suppressed or dysregulated immune profile(\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e). Experimental evidence suggests that a minimal level of pro-inflammatory signaling may be necessary for vascular homeostasis and myocardial integrity(\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e). Hence, their suppression in stable, chronically immunosuppressed liver transplant recipients may reflect a state of immune exhaustion rather than a protective anti-inflammatory profile(\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e). These findings reinforce the notion that liver transplant recipients often exhibit atypical immunometabolic responses, as also reported in studies showing unexpected oxidative modifications of fibrinogen linked to CV risk in this population(\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e) and deserve further investigations.\u003c/p\u003e \u003cp\u003eFinally, donor liver steatosis did not correlate with GLS impairment, yet showed a non-significant trend toward a more favorable profile (OR\u0026thinsp;=\u0026thinsp;0.33, p\u0026thinsp;=\u0026thinsp;0.080). Although this may indicate that graft steatosis has limited impact on cardiac outcomes, the finding remains exploratory and warrants validation in larger studies.\u003c/p\u003e \u003cp\u003eOur study has several limitations. First, the modest sample size inevitably reduces statistical power and precludes robust multivariable modelling. Second, although a 12-month follow-up was available, this interval may be insufficient to detect structural cardiac effects related to lifestyle modification. Third, the absence of intraoperative, early post-transplant and particularly pre-transplant cardiac data limits our ability to describe the full trajectory of cardiac function over time. Finally, the study was not originally powered for cardiovascular endpoints, and therefore causal interpretation must remain cautious.\u003c/p\u003e \u003cp\u003eDespite these limitations, to our knowledge this is the first study to simultaneously evaluate metabolic parameters, advanced echocardiographic indices including GLS, body composition assessed by bioimpedance, dietary patterns and physical activity in LT recipients, and the first to explore how these variables relate to myocardial strain.\u003c/p\u003e \u003cp\u003eIn conclusion, our study demonstrates that GLS appears to offer greater sensitivity than EF for identifying subclinical myocardial dysfunction in LT patients. Antihypertensive treatment and physical activity emerged as possible protective factors, while no significant effect was observed for dietary changes over 12 months. However, strain patterns did not consistently parallel traditional CV risk indicators, potentially because of the influence of chronic immunosuppression and post-LT unique metabolic milieu. GLS may therefore represent a valuable addition to clinical assessment pathways in this population. Larger prospective studies are needed to identify predictors of early cardiac dysfunction and clarify the role of GLS in long-term CV risk stratification post-transplant.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; roles:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization: AT, SG, FM, LS, DG; Methodology: AT, SG, LS, FS, MC, FS, DG; Investigation: AT. RLD, MO, MC, GM, CF, TZ, AAv: Data curation: HS, RLD, TZ; AAv, DG, SB; Formal analysis: AT, SG; Echocardiography and GLS Analysis: MO, MC, LS; Laboratory and Cytokine Analysis MC, CF, AAm; Nutritional and Lifestyle Assessment: FS, GM; Writing \u0026ndash; Original Draft AT; Writing \u0026ndash; Review \u0026amp; Editing: HS, SG, MF, LS; Supervision: SG, FM, LS; Final Approval of the Manuscript: All authors\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eEuropean Association for the Study of the Liver. EASL Clinical Practice Guidelines on liver transplantation. J Hepatol. dicembre 2024;81(6):1040\u0026ndash;86. \u003c/li\u003e\n\u003cli\u003eWatt KDS, Pedersen RA, Kremers WK, Heimbach JK, Charlton MR. Evolution of causes and risk factors for mortality post-liver transplant: results of the NIDDK long-term follow-up study. Am J Transplant Off J Am Soc Transplant Am Soc Transpl Surg. giugno 2010;10(6):1420\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eFatourou EM, Tsochatzis EA. Management of metabolic syndrome and cardiovascular risk after liver transplantation. Lancet Gastroenterol Hepatol. settembre 2019;4(9):731\u0026ndash;41. \u003c/li\u003e\n\u003cli\u003eGoldberg D, Ditah IC, Saeian K, Lalehzari M, Aronsohn A, Gorospe EC, et al. Changes in the Prevalence of Hepatitis C Virus Infection, Nonalcoholic Steatohepatitis, and Alcoholic Liver Disease Among Patients With Cirrhosis or Liver Failure on the Waitlist for Liver Transplantation. Gastroenterology. aprile 2017;152(5):1090-1099.e1. \u003c/li\u003e\n\u003cli\u003eLuca LD, Westbrook R, Tsochatzis EA. Metabolic and cardiovascular complications in the liver transplant recipient. Ann Gastroenterol. 2015;28(2):183\u0026ndash;92. \u003c/li\u003e\n\u003cli\u003eTunstall-Pedoe H. 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Circulation. 10 luglio 2018;138(2):198\u0026ndash;205. \u003c/li\u003e\n\u003cli\u003eBaron T, Christersson C, Hjorth\u0026eacute;n G, Hedin EM, Flachskampf FA. Changes in global longitudinal strain and left ventricular ejection fraction during the first year after myocardial infarction: results from a large consecutive cohort. Eur Heart J Cardiovasc Imaging. 1 ottobre 2018;19(10):1165\u0026ndash;73. \u003c/li\u003e\n\u003cli\u003ePavlopoulos H, Grapsa J, Stefanadi E, Philippou E, Dawson D, Nihoyannopoulos P. Is it only diastolic dysfunction? Segmental relaxation patterns and longitudinal systolic deformation in systemic hypertension. Eur J Echocardiogr J Work Group Echocardiogr Eur Soc Cardiol. novembre 2008;9(6):741\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eNakai H, Takeuchi M, Nishikage T, Lang RM, Otsuji Y. Subclinical left ventricular dysfunction in asymptomatic diabetic patients assessed by two-dimensional speckle tracking echocardiography: correlation with diabetic duration. Eur J Echocardiogr J Work Group Echocardiogr Eur Soc Cardiol. dicembre 2009;10(8):926\u0026ndash;32. \u003c/li\u003e\n\u003cli\u003eSilverii GA, Toncelli L, Casatori L, Bossini R, Nannelli F, Pala L, et al. Assessment of left ventricular global longitudinal strain in patients with type 2 diabetes: Relationship with microvascular damage and glycemic control. Nutr Metab Cardiovasc Dis NMCD. aprile 2022;32(4):994\u0026ndash;1000. \u003c/li\u003e\n\u003cli\u003eBayat F, Khani M, Hooshmand E. Evaluation of Systolic Function using Global Longitudinal Strain in Isolated Obese and Overweight People. Cardiovasc Hematol Disord Drug Targets. 2023;23(1):31\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eBlomstrand P, Sj\u0026ouml;blom P, Nilsson M, Wijkman M, Engvall M, L\u0026auml;nne T, et al. Overweight and obesity impair left ventricular systolic function as measured by left ventricular ejection fraction and global longitudinal strain. Cardiovasc Diabetol. 14 agosto 2018;17(1):113. \u003c/li\u003e\n\u003cli\u003eHawwa N, Shrestha K, Hammadah M, Yeo PSD, Fatica R, Tang WHW. Reverse Remodeling and Prognosis Following Kidney Transplantation in Contemporary Patients With Cardiac Dysfunction. J Am Coll Cardiol. 20 ottobre 2015;66(16):1779\u0026ndash;87. \u003c/li\u003e\n\u003cli\u003eKakar P, Gubitosa J, Gerula C. Echocardiography in the Liver Transplant Patient. Curr Cardiol Rep. 3 luglio 2021;23(8):110. \u003c/li\u003e\n\u003cli\u003evon Elm E, Altman DG, Egger M, Pocock SJ, G\u0026oslash;tzsche PC, Vandenbroucke JP, et al. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. BMJ. 20 ottobre 2007;335(7624):806\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eMendez K, Rane M, Orkaby AR, Gaziano JM. A tool to help patients visualize ASCVD risk and the potential impact of risk-lowering interventions. Int J Cardiol Cardiovasc Risk Prev. dicembre 2022;15:200159. \u003c/li\u003e\n\u003cli\u003eMach F, Koskinas KC, Roeters van Lennep JE, Tokg\u0026ouml;zoğlu L, Badimon L, Baigent C, et al. 2025 Focused Update of the 2019 ESC/EAS Guidelines for the management of dyslipidaemias. Eur Heart J. 7 novembre 2025;46(42):4359\u0026ndash;78. \u003c/li\u003e\n\u003cli\u003eHagstr\u0026ouml;mer M, Oja P, Sj\u0026ouml;str\u0026ouml;m M. The International Physical Activity Questionnaire (IPAQ): a study of concurrent and construct validity. Public Health Nutr. settembre 2006;9(6):755\u0026ndash;62. \u003c/li\u003e\n\u003cli\u003eSofi F, Dinu M, Pagliai G, Marcucci R, Casini A. Validation of a literature-based adherence score to Mediterranean diet: the MEDI-LITE score. Int J Food Sci Nutr. settembre 2017;68(6):757\u0026ndash;62. \u003c/li\u003e\n\u003cli\u003eAmerican College of Cardiology Foundation Appropriate Use Criteria Task Force, American Society of Echocardiography, American Heart Association, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, et al. ACCF/ASE/AHA/ASNC/HFSA/HRS/SCAI/SCCM/SCCT/SCMR 2011 Appropriate Use Criteria for Echocardiography. A Report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, American Society of Echocardiography, American Heart Association, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, Society of Critical Care Medicine, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance American College of Chest Physicians. J Am Soc Echocardiogr Off Publ Am Soc Echocardiogr. marzo 2011;24(3):229\u0026ndash;67. \u003c/li\u003e\n\u003cli\u003eVoigt JU, Pedrizzetti G, Lysyansky P, Marwick TH, Houle H, Baumann R, et al. Definitions for a common standard for 2D speckle tracking echocardiography: consensus document of the EACVI/ASE/Industry Task Force to standardize deformation imaging. Eur Heart J Cardiovasc Imaging. gennaio 2015;16(1):1\u0026ndash;11. \u003c/li\u003e\n\u003cli\u003eGabrielli F, Bernasconi E, Toscano A, Avossa A, Cavicchioli A, Andreone P, et al. Side Effects of Immunosuppressant Drugs After Liver Transplant. Pharmaceuticals. 27 febbraio 2025;18(3):342. \u003c/li\u003e\n\u003cli\u003eSarnak MJ, Levey AS, Schoolwerth AC, Coresh J, Culleton B, Hamm LL, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Hypertens Dallas Tex 1979. novembre 2003;42(5):1050\u0026ndash;65. \u003c/li\u003e\n\u003cli\u003eAttachaipanich T, Chattipakorn SC, Chattipakorn N. Cardiovascular toxicities by calcineurin inhibitors: Cellular mechanisms behind clinical manifestations. Acta Physiol Oxf Engl. settembre 2024;240(9):e14199. \u003c/li\u003e\n\u003cli\u003eMochizuki Y, Tanaka H, Matsumoto K, Sano H, Toki H, Shimoura H, et al. Clinical features of subclinical left ventricular systolic dysfunction in patients with diabetes mellitus. Cardiovasc Diabetol. 17 aprile 2015;14:37. \u003c/li\u003e\n\u003cli\u003eHuttin O, Girerd N, Coiro S, Bozec E, Selton-Suty C, Lamiral Z, et al. Association Between Layer-Specific Longitudinal Strain and Risk Factors of Heart Failure and Dyspnea: A Population-Based Study. J Am Soc Echocardiogr Off Publ Am Soc Echocardiogr. luglio 2019;32(7):854-865.e8. \u003c/li\u003e\n\u003cli\u003eMandraffino G, Imbalzano E, Lo Gullo A, Zito C, Morace C, Cinquegrani M, et al. Abnormal left ventricular global strain during exercise-test in young healthy smokers. Sci Rep. 30 marzo 2020;10(1):5700. \u003c/li\u003e\n\u003cli\u003eUziębło-Życzkowska B, Krzesiński P, Gielerak G, Skrobowski A. Speckle tracking echocardiography and tissue Doppler imaging reveal beneficial effect of pharmacotherapy in hypertensives with asymptomatic left ventricular dysfunction. J Am Soc Hypertens JASH. giugno 2017;11(6):334\u0026ndash;42. \u003c/li\u003e\n\u003cli\u003eJorge JA, Foppa M, Santos ABS, Cichelero FT, Martinez D, Lucca MB, et al. Effects of Antihypertensive Treatment on Left and Right Ventricular Global Longitudinal Strain and Diastolic Parameters in Patients with Hypertension and Obstructive Sleep Apnea: Randomized Clinical Trial of Chlorthalidone plus Amiloride vs. Amlodipine. J Clin Med. 31 maggio 2023;12(11):3785. \u003c/li\u003e\n\u003cli\u003eRohatgi A, Khera A, Berry JD, Givens EG, Ayers CR, Wedin KE, et al. HDL Cholesterol Efflux Capacity and Incident Cardiovascular Events. N Engl J Med. 18 dicembre 2014;371(25):2383\u0026ndash;93. \u003c/li\u003e\n\u003cli\u003eBarbagallo CA, Averna MR, Sparacino V, Cefal\u0026ugrave; AB, Caputo F, Noto D, et al. HDL subfractions distribution in renal transplant recipients: lack of evidence of a reduction of HDL2 particles. Nephron. 1996;72(3):407\u0026ndash;12. \u003c/li\u003e\n\u003cli\u003eBarter P, Gotto AM, LaRosa JC, Maroni J, Szarek M, Grundy SM, et al. HDL Cholesterol, Very Low Levels of LDL Cholesterol, and Cardiovascular Events. N Engl J Med. 27 settembre 2007;357(13):1301\u0026ndash;10. \u003c/li\u003e\n\u003cli\u003eBiering-S\u0026oslash;rensen T, Biering-S\u0026oslash;rensen SR, Olsen FJ, Sengel\u0026oslash;v M, J\u0026oslash;rgensen PG, Mogelvang R, et al. Global Longitudinal Strain by Echocardiography Predicts Long-Term Risk of Cardiovascular Morbidity and Mortality in a Low-Risk General Population: The Copenhagen City Heart Study. Circ Cardiovasc Imaging. marzo 2017;10(3):e005521. \u003c/li\u003e\n\u003cli\u003eMakavos G, Ikonomidis I, Lambadiari V, Koliou GA, Pavlidis G, Thymis J, et al. Additive prognostic value of longitudinal myocardial deformation to SCORE2 in psoriasis. Eur Heart J Open. marzo 2023;3(2):oead016. \u003c/li\u003e\n\u003cli\u003eEnrico M, Klika R, Ingletto C, Mascherini G, Pedrizzetti G, Stefani L. Changes in global longitudinal strain in renal transplant recipients following 12 months of exercise. Intern Emerg Med. agosto 2018;13(5):805\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eNaaktgeboren WR, Groen WG, Jacobse JN, Steggink LC, Walenkamp AME, van Harten WH, et al. Physical Activity and Cardiac Function in Long-Term Breast Cancer Survivors: A Cross-Sectional Study. JACC CardioOncology. giugno 2022;4(2):183\u0026ndash;91. \u003c/li\u003e\n\u003cli\u003eSartorio A, Dal Pont C, Romano S. Standard and New Echocardio Techniques, Such as Global Longitudinal Strain, to Monitor the Impact of Diets on Cardiovascular Diseases and Heart Function. Nutrients. 13 maggio 2024;16(10):1471. \u003c/li\u003e\n\u003cli\u003eBujak M, Dobaczewski M, Chatila K, Mendoza LH, Li N, Reddy A, et al. Interleukin-1 receptor type I signaling critically regulates infarct healing and cardiac remodeling. Am J Pathol. luglio 2008;173(1):57\u0026ndash;67. \u003c/li\u003e\n\u003cli\u003eHuang L. The role of IL-17 family cytokines in cardiac fibrosis. Front Cardiovasc Med. 2024;11:1470362. \u003c/li\u003e\n\u003cli\u003eMills KHG. IL-17 and IL-17-producing cells in protection versus pathology. Nat Rev Immunol. gennaio 2023;23(1):38\u0026ndash;54. \u003c/li\u003e\n\u003cli\u003eGitto S, Fiorillo C, Argento FR, Fini E, Borghi S, Falcini M, et al. Oxidative stress-induced fibrinogen modifications in liver transplant recipients: unraveling a novel potential mechanism for cardiovascular risk. Res Pract Thromb Haemost. agosto 2024;8(6):102555. \u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 4 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"internal-and-emergency-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"iaem","sideBox":"Learn more about [Internal and Emergency Medicine](http://link.springer.com/journal/11739)","snPcode":"11739","submissionUrl":"https://www.editorialmanager.com/iaem/default.aspx","title":"Internal and Emergency Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"liver transplantation, GLS, subclinical myocardial dysfunction, cardiovascular risk, immunomodulation","lastPublishedDoi":"10.21203/rs.3.rs-8319992/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8319992/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground and aim of the study\u003c/strong\u003e: Liver transplant (LT) recipients are a population at elevated cardiovascular (CV) risk, yet conventional assessment tools often fail to capture early myocardial dysfunction. Global longitudinal strain (GLS) has emerged as a sensitive marker of subclinical myocardial dysfunction, although its role in the long-term post-transplant setting remains insufficiently defined. The study aimed to evaluate left ventricular (LV)-GLS in a population of stable LT recipients with mild cardiometabolic burden and explored the possible associations with metabolic, lifestyle, inflammatory, and transplant-related variables. Secondary aims included longitudinal GLS variation over 12 months.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSubjects and methods:\u003c/strong\u003e We conducted a cross-sectional observational study in 40 LT recipients. Data on cardiometabolic parameters, body composition (including bioimpedance analysis), diet, physical activity were collected. Carotid ultrasound and echocardiography were performed. Levels of circulating inflammatory cytokines were measured. CV risk scores were calculated.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: GLS impairment was detected in 47.5% of patients, despite preserved ejection fraction. Antihypertensive therapy correlated with more favorable GLS, whereas higher IL-17A and IL-1β levels were paradoxically linked to preserved strain. No association emerged with immunosuppressive regimen or lifestyle indices. GLS remained unchanged at 12 months, irrespective of weight loss or dietary improvement.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: GLS appears more sensitive than EF in detecting subclinical myocardial dysfunction in LT recipients, highlighting its potential role in post-transplant CV surveillance. Antihypertensive treatment may exert protective effects, whereas cytokine patterns suggest non-traditional mechanisms of cardiac modulation. Larger longitudinal studies are needed to confirm prognostic implications and integrate GLS into CV risk stratification pathways post-LT.\u003c/p\u003e","manuscriptTitle":"Altered Global Longitudinal Strain is a common finding in Liver Transplant Recipients with Mild Cardiometabolic Burden","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-12 06:11:01","doi":"10.21203/rs.3.rs-8319992/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2026-01-29T18:44:57+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-07T10:31:47+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-11T10:45:08+00:00","index":"","fulltext":""},{"type":"submitted","content":"Internal and Emergency Medicine","date":"2025-12-10T09:07:12+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"internal-and-emergency-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"iaem","sideBox":"Learn more about [Internal and Emergency Medicine](http://link.springer.com/journal/11739)","snPcode":"11739","submissionUrl":"https://www.editorialmanager.com/iaem/default.aspx","title":"Internal and Emergency Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"06361a84-abaa-4204-9f64-cf02165da4ee","owner":[],"postedDate":"January 12th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-09T17:29:11+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-12 06:11:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8319992","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8319992","identity":"rs-8319992","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}