Left Ventricular Dysfunction Research Articles

Incident HFpEF and time-dependent changes in markers of LVDD severity in women and men with pre-clinical LVDD

Abstract Background Over time, left ventricular diastolic dysfunction (LVDD) can progress towards heart failure with preserved ejection fraction (HFpEF). Yet, the identification of those at high risk of progression is challenging, and guidance on follow-up or preventive treatment is lacking. Purpose To study the incidence of HFpEF and changes over time in markers of LVDD severity in women and men with pre-clinical LVDD. In addition, we evaluate whether blood pressure and kidney function affect progression of LVDD. Methods We reinvited 146 participants from the HELPFul study (58% women and 42% men) with pre-clinical LVDD after a median follow-up of 4.3 [IQR: 3.9-4.7] years (Figure 1). The follow-up measurements were similar to baseline and encompassed a structured interview, physical examination, blood draw, electrocardiogram and (exercise) echocardiography. We determined HFpEF incidence and report changes over time in cardiovascular risk factors as well as echocardiographic characteristics and biomarkers of LVDD. Additionally, we studied whether changes in blood pressure and kidney function affected LVDD progression using generalized mixed models. LVDD progression was defined as an increase in plasma NT-proBNP levels and HFA-PEFF major functional and morphological abnormalities. All analyses were performed for women and men combined as well as stratified by sex. Results Fifteen (10%) of the 146 participants developed HF of whom 13 had HFpEF (9 women and 4 men) during follow-up. Over time, systolic and diastolic blood pressure levels remained stable while mean kidney function (eGFR) declined from 89±14 to 81±17 mL/min/1.73m2. Median NT-proBNP plasma levels increased from 71 [IQR: 44, 120] to 100 [IQR: 51, 157] pg/mL. The prevalence of major functional abnormalities according to the HFA-PEFF score increased from 84 to 91%, while the prevalence of morphological abnormalities increased from 25% to 39% (Figure 2). A higher systolic blood pressure in women and a higher diastolic blood pressure in men was associated with an increase in NT-proBNP plasma levels over time. Additionally, lower eGFR levels were related to increased NT-proBNP plasma levels over time in both men and women. There was a significant rise in the prevalence of major functional and morphological abnormalities with time, but blood pressure and kidney function did not affect this change over time. Conclusions A small proportion of women and men with preclinical LVDD developed incident HF over a 5-year follow-up period. High blood pressure and reduced kidney function were associated with increased levels of NT-proBNP over time. This highlights the need to further explore cardiorenal protection as a method to prevent HFpEF.Study design and HF outcomesLongitudinal changes in LVDD markers

Preserved left ventricular ejection fraction with abnormal myocardial work in sepsis

Abstract Background Sepsis is a life-threatening condition associated with a dysregulated response to infection, leading to an increased risk of multi-organ dysfunction and death. Left ventricular (LV) dysfunction has been reported in up to 60% of patients with sepsis. Still, it’s true incidence is difficult to determine as defined by standard methods like left ventricular ejection fraction (LVEF) due to its dependency on loading conditions. Myocardial work (MW) is a validated novel parameter informing true LV contractility. MW is calculated using echocardiography strain data, noninvasive BP measurements, and GE Healthcare proprietary software. There are four MW indices; here, we evaluated the global work index (GWI), the indexed total work performed by the LV through mechanical systole, including isovolumic relaxation and contraction. Purpose To describe our patient population diagnosed with sepsis with GWI calculated as part of their echocardiography. We also sought to compare the GWI values with GWI normal reference values reported in current literature to determine whether our observed mean GWI in a cohort of patients with sepsis deviates significantly from these established benchmarks in an average healthy population. Methods This report was a retrospective analysis of 179 consecutive patients ≥18 years with sepsis as defined by the Third International Consensus Definitions for Sepsis and Septic Shock who presented at our center from January 2020 to October 2023. LVEF (%) and GWI (mm Hg%) were reported as mean (±SD). A one-sample t-test was used to determine if the mean MWI for males and females diagnosed with sepsis at our center significantly differed from the reported GWI literature of reference patients without sepsis. Results Males (n=90, 50.3%) from our center had a significantly lower GWI mean (1353.06 ± 490.75) than the literature-reported male reference value of 2062 (P < 0.001) and a 95% confidence interval (1250 to 1455.84). See the Table. In 89 (49.7%) females with sepsis, mean GWI was also significantly lower, 1511 ± 595.79 (P < 0.001), than the normal reported female reference GWI value 2155 with a 95% CI (1385.57 to 1636.58). The pooled GWI mean was 1440.0±561.8 (ref: 2118±277). Septic males and females had preserved mean LVEF values of 51.6±13.11 and 56.8±14.4, respectively. The pooled mean LVEF was 54.0±13.8. Conclusion These findings revealed preserved LVEF alongside decreased global work index in patients with sepsis. To our knowledge, this is the first description of MW indices in septic patients. The results highlight the importance of further investigations into the role of MW indices in sepsis and the potential for these indices to enhance our understanding and clinical approach to myocardial dysfunction in sepsis.

Advanced versus conventional echocardiographic parameters of right ventricular-arterial coupling in heart failure

Abstract Background Right ventricular-arterial coupling (RVAC) is an important predictor of prognosis in heart failure (HF). Several echocardiographic RVAC parameters have been described. However, which one best reflects patient’s prognosis is still matter of debate. Purpose The aim of this study was to compare the predictive value of RVAC parameters derived from advanced echocardiography with that obtained from conventional echocardiography in HF patients. Methods Consecutive patients with stable HF and left ventricular (LV) systolic dysfunction (LVEF<50%, n=193) were studied by echocardiography. RVAC was assessed by tricuspid annular plane systolic excursion (TAPSE)/pulmonary artery systolic pressure (PASP), tissue Doppler imaging Sm velocity (TDI Sm)/PASP, RV free wall longitudinal strain (RVFWLS)/PASP and tridimensional RVEF (3D-RVEF)/PASP. Primary composite endpoint was all-cause death/HF hospitalization. Results After a median follow-up time of 16.3 months, the endpoint occurred in 45 patients. At univariable analysis, all RVAC parameters were significantly associated with the outcome [TAPSE/PASP: HR 0.31 (95% CI 0.17-0.55), P<0.001; TDI Sm/PASP: HR 0.27 (95% CI 0.15-0.49), P<0.001; RVFWLS/PASP: HR 0.19 (95% CI 0.10-0.36), P<0.001; 3D-RVEF/PASP: HR 0.30 (95% CI 0.17-0.55), P<0.001; figure 1]. At multivariable analysis, after adjustment for MAGGIC risk score and NT-proBNP, TAPSE/PASP [HR 0.71 (95% CI 0.38-1.35), P = NS] and TDI Sm/PASP [HR 0.59 (95% CI 0.31-1.10), P = NS] were no longer statistically associated with the endpoint; however, both RVFWLS/PASP [HR 0.36 (95% CI 0.18-0.70), P < 0.01] and 3D-RVEF/PASP [HR 0.55 (95% CI 0.31-0.99), P < 0.05] maintained their prognostic value (figure 2). Conclusions Advanced RVAC echocardiographic parameters (RVFWLS/PASP and 3D-RVEF/PASP) are superior predictors of prognosis than those derived from conventional echocardiography (TAPSE/PASP and TDI Sm/PASP) in a contemporary cohort of HF patients with left ventricular systolic dysfunction.Figure 1Figure 2

The impact of comorbidities on therapy-optimization and their prognostics role among hospitalized patients with heart failure with reduced ejection fraction

Abstract Background The early, accurate diagnosis and proper treatment of comorbidities (CMs) are of strategic importance in heart failure (HF), as stated in the current ESC HF Guidelines. Unquestionably, the presence of CMs is associated with worse prognosis. Moreover, CMs can unfavourably affect the implementation of the guideline-directed medical therapy (GDMT) in heart failure with reduced ejection fraction (HFrEF). Aim To assess the prevalence of the relevant prognosis-modifying CMs among patients requiring hospitalization due to HFrEF, investigate their effect on the implementation and optimization of GDMT, and examine the impact of the presence of CMs on the prognosis in HFrEF. Patients and methods The data of 313 patients requiring hospitalization at our Institution due to HFrEF between 2021-2023 (male: 77%, age: 60[50-70]years, coronary artery disease: 46%, diabetes: 36%, hypertension: 65%, atrial fibrillation: 42%, LVEF: 24[20-30]%, eGFR at admission: 57[46-74]mL/min/1.73m², NT-proBNP at admission: 5035[2376-9369]pg/mL, SBP: 121[110-140]mmHg; GDMT at admission - RASi[ACEi/ARB/ARNI]: 60%, βB: 59%, MRA: 44%, SGLT2i: 14%) were analyzed retrospectively. Based on the number of diagnosed CMs, patients were divided into 3 categories: 0-1 vs. 2-3 vs. ≥4 CMs. The implemented GDMT at discharge was compared among CM categories with Chi-square test, while all-cause mortality (ACM) rates were investigated with Kaplan-Meier method and multivariate Cox-regression analysis. Results During the hospitalization in the total cohort the proportion of patients on GDMT increased significantly (RASi: 91%, βB: 85%, MRA: 96%, SGLT2i: 57%; patients on triple [TT] therapy [RASi+βB+MRA]: 83%, patients on quadruple therapy [TT+SGLT2i]: 52%; p＜0.05). However, among patients with higher rates of CMs, the application of GDMT was less favourable (RASi: 97% vs. 94% vs. 82%; βB: 93% vs. 89% vs. 75%; p＜0.05; 0-1 vs. 2-3 vs. ≥4 CMs), the proportion of patients on TT and QT remained remarkably high even among those with ≥4 CMs (TT: 93% vs. 87% vs. 71%; QT: 65% vs. 52% vs. 45%; p＜0.05). During the median follow-up period of 1.3 year, the ACM of patients with increased burden of CMs was higher (12% vs. 18% vs. 37%, p＜0.001). According to the results of the multivariate Cox-regression analysis, more advanced left ventricular systolic dysfunction (/1%), previously confirmed diagnosis of HFrEF, the growing number of CMs proved to be negative independent predictors of ACM, while the application of TT or QT reduced the risk of ACM significantly (HR: 0.471, 95% CI: 0.271-0.819, p=0.008). Conclusions According to our real-world analysis, although among HFrEF patients with an increased burden of CMs, less favourable prognosis can be expected, the application of modern GDMT is even possible among them, resulting in a significantly improved prognosis. Thus, clinicians should insist on the early, conscious implementation of GDMT among these patients as well.

Trimethylamine N-oxide as a Novel Biomarker for Left Ventricular Diastolic Dysfunction and Functional Remodeling in ST-Elevation Myocardial Infarction Patients

Abstract Background Over the last three decades, the mortality from ST-elevation myocardial infarction (STEMI) has halved. However, the incidence of heart failure or persistent angina remains high after STEMI, and the post-STEMI left ventricular (LV) systolic and diastolic function remains unpredictable. Thus, there is an unmet need to identify patients at risk of LV diastolic dysfunction or adverse remodeling. Purpose This study aims to investigate the potential of Trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite associated with heart failure, and atherosclerosis, as a biomarker for adverse LV remodeling and diastolic dysfunction following STEMI. Methods In this prospective, observational cohort study, 210 STEMI patients with multivessel coronary artery disease (CAD) were enrolled after primary PCI. At 3 months follow-up, all patients underwent complete revascularization with FFR-guided PCI. Plasma TMAO, C-reactive protein (CRP), and brain natriuretic peptide (BNP) levels at 3 months follow-up and peak troponin level at primary PCI were collected. Echocardiographies were performed within 24 hours of STEMI and at 12-month follow-ups. Diastolic dysfunction was defined according to the ASE 2016 guidelines.(1) Functional LV remodeling (FLVR) was categorized into 4 categories according to Chimed et al.(2) Receiver operating characteristic (ROC) curve analysis, including the Delong test and Youden index, was performed to compare the biomarkers' diagnostic value and determine the optimal cutoffs for predicting diastolic dysfunction and FLVR, respectively. Results Of the 210 patients enrolled, 85 (40.48%) were female, with a median age of 65 years [interquartile range (IQR): 58.00, 76.00] and a median body mass index (BMI) of 27.39 kg/m² (IQR: [24.56, 30.69]). The area under the ROC curve for predicting post-PCI LV diastolic dysfunction ≥ grade II was 0.72 (95% CI 0.63–0.81; p<0.001) for TMAO (Figure 1). The optimal TMAO cutoff value of 3.80 yielded a sensitivity of 0.75 (95% CI 0.63–0.86) and a specificity of 0.82 (95% CI 0.76–0.88). For FLVR grade 3 or 4, the area under the ROC curve was 0.62 (95% CI 0.50–0.74) and 0.72 (95% CI 0.62 -0.83) for TMAO and BNP, respectively (Figure 2), but the AUC was not significantly different (p= 0.191). In multivariable logistic regression analysis, TMAO was independently associated with FLVR grade 3 or 4 (OR 1.18, 95% CI 1.00-1.38, p = 0.046) and diastolic dysfunction ≥grade 2 (OR 1.30, 95% CI 1.12-1.50, p < 0.001). Conclusion The novel parameter of TMAO is a useful predictor for LV diastolic dysfunction after STEMI. TMAO is independently associated with an increased risk of LV diastolic dysfunction and worse FLVR. These results suggest that monitoring plasma TMAO levels could be an effective and cost-efficient strategy for monitoring patients with an elevated risk of LV diastolic dysfunction or adverse LV remodeling.Figure 1Figure 2

Conduction system versus right ventricular pacing for atrioventricular block: a reconstructed individual participant data meta-analysis

Abstract Background Right ventricular pacing (RVP) is typically offered to patients with established or impending atrioventricular block (AVB) in the absence of left ventricular systolic dysfunction. Direct stimulation of His-Purkinje fibres via conduction system pacing (CSP) is an emerging alternative to RVP to prevent pacing-induced cardiomyopathy. Purpose To perform a systematic review and meta-analysis testing CSP versus RVP in patients with AVB and a left ventricular ejection fraction ≥35%. Methods Observational studies comparing CSP with RVP that reported clinical outcomes were systematically identified. The primary outcome was time-to-first all-cause mortality, heart failure hospitalisation (HFH) or upgrade to biventricular pacing. Secondary endpoints included the individual components of the primary endpoint. Individual participant time-to-event data (IPD) was obtained through data-sharing agreements or reconstructed from digitisation of Kaplan-Meier curves where available. Mixed-effects Cox proportional hazards regression that modelled between-study heterogeneity as a random intercept to account for differing baseline hazards between distinct study populations was performed on these data. Conventional pairwise random effects meta-analyses were also performed. This analysis was prospectively registered. Results 12 eligible studies enrolling 4627 patients were included. In reconstructed IPD pooled survival analyses, CSP associated with a 38% reduced hazard of the primary endpoint compared with RVP [hazard ratio 0.62, 95% CI 0.51 to 0.76, p<0.001] (Figure 1). In pairwise meta-analyses, CSP associated with a 46% risk reduction in the primary endpoint [relative risk (RR) 0.54, 95% CI 0.41 to 0.71, p<0.001] (Figure 2A). CSP also associated with reductions in risk of all-cause mortality [RR 0.60, 95% CI 0.45 to 0.80, p<0.001], HFH [RR 0.39, 95% CI 0.28 to 0.55, p<0.001] and upgrade to biventricular pacing [RR 0.19, 95% CI 0.07 to 0.52, p=0.001] compared with RVP (Figure 2B-D). Conclusions In reconstructed IPD pooled survival analyses, CSP associated with reductions in the primary composite endpoint of all-cause mortality, heart failure hospitalisation or upgrade to biventricular pacing compared with RVP, independent of ventricular pacing burden. This was mirrored in conventional meta-analyses of the primary composite endpoint, and when individual components of the composite were analysed. It may not be necessary to predict which patients will have an elevated pacing burden when applying this therapy. Until randomised data from the PROTECT-HF trial becomes available, this analysis offers the most precise summary estimate of the comparative effects of CSP versus RVP in patients with an AVB indication for pacing, but no evidence of heart failure.Kaplan-Meier plot comparing CSP vs RVPForest plots for major endpoints

Comparative analysis of a novel preoperative stratification method versus traditional scores in patients with severe aortic stenosis undergoing aortic valve surgery

Abstract Introduction It is crucial to consider factors that complicate the indication of transcatheter aortic valve replacement (TAVR) in patients with aortic stenosis (AS), such as narrow valve ring, extensive calcification or inadequate vascular access. (1-4) Thus, aortic valve replacement surgery (SAVR) remains a recommended indication, with its pre-surgical stratification being a challenge. (1-3) Despite the widespread use of scores like the STS and EuroSCORE II, they exhibit limitations, being validated primarily for populations outside Latin America and focusing predominantly on individual factors while often neglecting structural parameters like left ventricular hypertrophy, diastolic dysfunction, or left atrium volume. (3-5) Purpose This study aimed to assess whether a novel modified Généreux stratification method offers superior predictive value for postoperative mortality in AS patients compared to traditional scoring systems. Methods We conducted a retrospective, single-center study involving patients with confirmed severe AS who underwent aortic valve replacement surgery between January 2017 and December 2021. The new stratification method categorized patients into three stages based on echocardiographic parameters (see Figure 1). Univariate and multivariate Cox regression analyses were conducted to identify predictors of mortality, with survival analysis performed using Kaplan-Meier curves. A p-value <0.05 was considered statistically significant. Results A total of 508 patients were included in the study. Stage 1 patients had a lower median age (62 years vs. 67 years in stages 2 and 3). The median EuroSCORE and STS were 2.75 and 2.62%, respectively, with stage 3 showing significantly higher scores (p ≤0.001). Over a median follow-up of 81 months, 56 deaths occurred (11%). Kaplan-Meier curve analysis revealed significant differences in all-cause mortality among the three groups (HR 4.073, log-rank p≤0.001), as illustrated in Figure 1. Multivariate analysis identified the three preoperative stages (HR 3.22, [95% CI 1.44-7.20], p=0.004) and mean transaortic gradient (HR 0.96, [95% CI 0.92-0.99], p=0.021) as independent predictors of mortality. The new stages demonstrated a superior area under the ROC curve of 0.758 compared to traditional scores (see Figure 1). Conclusions The novel three-stage preoperative classification and low transaortic gradient serve as significant predictors of mortality in patients undergoing SAVR. These stages exhibit robust predictive capability for mortality compared to EuroSCORE II and STS.Baseline and multivariate analysisKaplan-meier and ROC curve

Prediction of 10-year risk for recurrent atherosclerotic cardiovascular events in a secondary prevention population: Insights from CHART-2 and Suita studies in the Japanese population

Abstract Background Despite the European Society of Cardiology (ESC) guidelines advocating risk prediction models for secondary prevention in established atherosclerotic cardiovascular disease (ASCVD) patients, such models for Japanese individuals remain limited, owing to their comparatively lower ASCVD risk than Western populations. Given this gap, there is a need to develop tailored risk assessment tools for Japanese ASCVD patients to optimize secondary prevention strategies. Purpose Leveraging data from two large-scale, long-term cardiovascular cohorts in Japan, our aim was to develop and externally validate a 10-year risk model predicting recurrent cardiovascular events among patients with established ASCVD. Methods The CHART-2 and Suita studies, large-scale prospective observational multicenter cohort studies in Japan, served as the primary data sources for this investigation. From the CHART-2 study, which comprised 3,560 patients with a history of coronary artery disease or ischemic stroke, we derived our risk model. External validation was conducted using data from the Suita study, which included 445 patients with similar ASCVD backgrounds. The primary outcome of interest was a composite endpoint encompassing cardiovascular death, myocardial infarction, or stroke. Variable selection was performed based on clinically relevant factors previously employed in established risk scores (SMART, REACH, and TRS 2°P risk scores). Logistic regression was utilized for model development, and the predictive performance was assessed using the C-index. Results Over a median follow-up of 10.1 years, the derivation cohort experienced 756 cardiovascular events. Patients in the derivation cohort had an average age of 68.9 ± 10.6 years, with 91% and 24% having a history of coronary artery disease and ischemic stroke, respectively. Using logistic regression, the multivariate model revealed a higher recurrent risk associated with several factors including age, smoking status, systolic blood pressure, diabetes, renal function, number of ASCVD events, atrial fibrillation, lipid levels, left ventricular systolic dysfunction, and statin use. A simple risk score based on these predictors demonstrated a >5-fold gradient of 10-year recurrent risk with a C-index of 0.65 (95% CI 0.63-0.68, Figure). The prediction model was externally validated in the Suita study wit 245 cardiovascular events and a median follow-up of 10.4 years, showing good discriminative ability with a C-index of 0.64 (95% CI 0.60–0.68). Conclusion Our newly developed prediction model offers a valuable tool for identifying individuals at heightened risk of recurrent cardiovascular events over a 10-year period, thereby facilitating more targeted and effective secondary prevention strategies tailored to the unique characteristics of Japanese ASCVD patients.

Left atrial morpho-functional parameters and their correlation with other phenotypic and functional characteristics of hypertrophic cardiomyopathy

Abstract Background Left atrial (LA) volume index (LAVI), LA reservoir strain (LARS) and total atrial conduction time (TACT) (estimated by tissue Doppler imaging) are morphological and functional parameters reflecting LA structural and electrical remodeling, connected to atrial fibrillation development and heart failure progression in various substrates. In hypertrophic cardiomyopathy (HCM), correlation of the above-mentioned parameters with other disease characteristics is not fully investigated. Purpose Aim of this study was to estimate the prevalence of atrial myopathy characteristics such as increased LAVI, impaired LARS and elongated TACT in a cohort of HCM patients without AF history and investigate their correlation with other phenotypic and functional characteristics of the disease such as left ventricular (LV) hypertrophy magnitude, fibrosis extent and diastolic dysfunction grade. Methods We included 100 HCM patients (54±21 years, 75% male, maximum wall thickness 19±3.4mm) without history of atrial fibrillation who have consecutively undergone 2D-speckle tracking echocardiography and cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE). TACT and LARS measurement is shown on left panel. Burden of fibrosis (percentage of LV mass) was defined by LGE extent (>5 standard deviations compared to nulled myocardium) in CMR slices. Results All HCM patients had preserved EF (60±7.5%), while 28 (28%) presented outflow tract obstruction and 10 (10%) diastolic dysfunction stage≥2. LGE was observed in 64 patients (64%) occupying 8±5% of left ventricular (LV) mass. Mean TACT was 140±22 msec, with LAVI being 32±16 mL/m2 and LARS 26±14%. Among HCM demographic, phenotypic and functional characteristics tested, age and LV mass index were found to be the only independent regressors of TACT (r=0.54, p<0.0005 and r=0.44, p=0.002 respectively, right upper panel), while E/E’ (r=-0.44, p=0.003) and fibrosis extent (r=0.36, p=0.02) were the strongest predictors of LARS and LAVI values respectively (right lower panel). Conclusions Atrial myopathy parameters seem to correlate with various morphological and functional characteristics of HCM. Atrial electro-mechanical delay assessed through TDI based TACT correlates significantly with LVMI, whereas LARS and LAVI are strong regressors of elasticity properties, partially expressed through diastolic function and underlying fibrosis.

Role of CT-derived global longitudinal strain in identifying left ventricular dysfunction in patients with severe aortic stenosis and preserved left ventricular ejection fraction

Abstract Introduction In patients with severe aortic stenosis, LVEF <50% is a current class 1 indication for aortic valve replacement. There are however studies showing increased mortality in patients with asymptomatic severe aortic stenosis and LVEF between 50-59% [1, 2]. Global longitudinal strain (GLS) has emerged as a more sensitive predictor of systolic dysfunction than ejection fraction in a wide number of cardiac diseases [3]. Purpose The aim of our study was to analyze left ventricular global longitudinal strain (GLS) by cardiac computed tomography (CT) in patients with severe aortic stenosis. We hypothesized that a larger portion of patients with LVEF 50-59% have signs of systolic dysfunction by GLS as compared to patients with LVEF ≥60%. Methods We identified 238 patients (median age 81, 51.3% females) with severe aortic stenosis, assessed by cardiac CT before undergoing transcatheter aortic valve replacement at Uppsala University hospital between 2016-2019. Patients in atrial fibrillation was excluded due to suboptimal image quality. Left ventricular mass index (LVMi), EF and peak GLS were calculated. The patients were divided into three groups based on LVEF (Reduced LVEF <50%, Low-Normal LVEF 50-59% and Normal LVEF ≥60%) and compared with each other regarding GLS, biomarkers and background variables. The cut off for significantly reduced GLS was set at <16%, in accordance with recently proposed criteria [4]. Results As expected GLS was significantly reduced in all patients with LVEF <50%. Among patients with Low-Normal LVEF, 62.3% had significantly reduced GLS as compared to only 3.8% patients with Normal LVEF >60% (p < 0.001). Median GLS in Low-Normal LVEF was 15.5% (IQR 14.1 - 17.4) as compared to 20.2% (IQR 18.4 - 21.9) in Normal LVEF (p < 0.001). Patients with Low-Normal LVEF had a significantly higher LV mass as compared to patients with Normal LVEF (median LVMi 85.8 g/m² vs. 75.8 g/m², p < 0.001). NT-pro-BNP was significantly higher in patients with Low-Normal LVEF compared to Normal LVEF (median 1130 vs. 664 ng/l, p = 0.003). Conclusions Almost two third of patients with severe aortic stenosis and lower range of normal LVEF (50-59%) had abnormally reduced GLS, reflecting systolic LV dysfunction, which was uncommon among those with LVEF >60%. Patients with LVEF 50-59% also presented with higher LV mass index and higher levels of NT-pro-BNP than patients with normal LVEF >60%, reflecting hypertrophic response of the myocardium to pressure overload which over time may lead to progressive myocardial decompensation. LVEF in the range of 50-59% might be an early sign of LV decompensation in severe aortic stenosis.

High incidence of malignant arrhythmias and heart failure in patients with RBM20-associated cardiomyopathy: a multicenter cohort study and review of the literature

Abstract Background Patients with RBM20 cardiomyopathy commonly experience malignant arrhythmias, sudden cardiac death (SCD), and progressive heart failure (HF). Objective The aim of this study is to investigate genotype-phenotype correlations, clinical outcomes and causes of death in patients with RBM20-associated cardiomyopathy in a multicenter cohort, combined with an overview of the current literature. Methods This international, multicenter cohort included all patients with cardiomyopathy who had a pathogenic (P) or likely pathogenic (LP) RBM20 variant. For survival and regression analysis, we matched a control group based on sex, age, and presence of left ventricular dysfunction. Additionally, we conducted a literature search on studies investigating RBM20-associated cardiomyopathy. Results Sixty-two patients (45% male) were included in the study, with a mean age of 42 ± 15 years at presentation. Of the LP/P RBM20 variants identified, 9 were novel. Eleven variants were truncating, while the remaining variants consisted of missense and splice-site variants. Patients with a truncating variant who developed HF were on average older at the time of diagnosis compared to patients with missense variants (mean age 62 ± 9 vs. 45 ± 14; p=0.01). After a median follow-up duration of 5.0 [1.0 – 10.5] years, 21 (34%) patients reached the composite endpoint of ventricular arrhythmias (VA), implantable cardioverter-defibrillator therapy, heart transplantation (HTx), left ventricular assist device (LVAD) implantation, or cardiovascular death. Of these, 19 (31%) patients experienced malignant VA (mean age 45 ± 15 years, 63% males). Males were at higher risk for the composite endpoint (log-rank p= 0.02), particularly for VA (log-rank p=0.007). The literature review analyzed 34 studies with a total of 678 patients, of whom 53% were male. In these studies, 123 (24%) patients experienced a VA, 58 (12%) underwent HTx or were treated with LVAD, and 52 (11%) died. Conclusion In this multicenter study the patients carrying a LP/P variant in RBM20 variants had a severe phenotype, with a high incidence of VA, particularly in males. Additionally, this study presents 9 novel DNA variants, of which 8 were truncating, and were mainly observed in older individuals. Finally, we report a lower mortality rate compared to the literature, possibly due to a higher number of heart transplantations performed in our patient cohort.Survival composite endpoint for sex

Is the incidence of cerebral embolic events underestimated in Takotsubo cardiomyopathy?

Abstract Introduction Although initially considered a benign cause of transient left ventricular dysfunction, Takotsubo cardiomyopathy (TCM or stress cardiomyopathy) has become an increasingly recognized cause of cerebral embolic events. Prior case series have suggested a 0.9% to 3% risk of ischemic stroke following the diagnosis of TCM. With the growing number of cases of stress cardiomyopathy reported since the COVID pandemic, we want to evaluate if the risk of stroke in the literature has been underestimated. Purpose In our study, we want to evaluate the risk of ischemic stroke one year following the diagnosis of Takotsubo cardiomyopathy in our university health centre. We also want to evaluate the time interval between the incidence of stroke and the initial diagnosis of TCM. Methods In this retrospective single-centre observational study, we collected data from 267 consecutive patients hospitalized for a diagnosis of Takotsubo cardiomyopathy (confirmed by echocardiography and cardiac catheterization) between May 2008 and December 2017 at our medical centre in Sherbrooke. All patients were followed for a minimum of one year. We excluded 14 patients with a prior history of stroke or a diagnosis of atrial fibrillation in the year following the diagnosis of TCM. We used a descriptive statistical analysis to evaluate the rate and time to event up to 1 year after the diagnosis. Results 253 patients were included in the study. The cohort was composed of 220 females (88% of the population), and the mean age was 69 years (SD: 11.8 years). Among this population, we identified 15 patients presenting with a stroke within a year after the diagnosis of stress cardiomyopathy, with a crude incidence of 5.9%. The median time interval between the incidence of stroke and the initial diagnosis of TCM was 17 days (2 to 298 days; an inter-quartile range of 3 to 105 days). The proportion of patients that reached the primary endpoint in the first 30 days was 67%. Conclusion According to our study, the risk of stroke in the year following the diagnosis of TCM is significantly higher than what is currently described in the literature. The fact that 10 of the 15 events occurred in the first 30 days may suggest a therappy design to lower the risk during that critical period could be explored. However, further studies are needed to address this issue.

Leadless pacemaker - lead parameters stability and battery longevity in the mid-term follow-up

Abstract Background A leadless pacemaker (L-PM) has been designed to avoid the need for a pacemaker pocket and transvenous lead. Long-term safety will largely depend on the need for replacements, mainly due to battery depletion (end-of-life). While the mean L-PM battery longevity predicted by the manufacturer is 12 years, real-world longevity data are still scarce. We aimed to describe L-PM parameters’ stability and battery longevity during the mid-term follow-up. Methods Single-center registry of consecutive patients undergoing L-PM implantation from May 2015 to November 2023. Procedural characteristics, lead parameters and battery longevity were collected immediately after implantation and during the most recent follow-up visit. Results Overall, 261 consecutive patients had a transcatheter L-PM implanted through a femoral vein (mean age 78±10 years; 66% male). Mean procedural duration was 44±28min and fluoroscopy time was 4,4±3,9min. The device was successfully implanted in all but one patient. The main indications for permanent pacing were high-degree atrioventricular block [N=130 (50%)], atrial fibrillation with pauses [N=78 (30%)], and sinus node disease [N=28 (11%)]. Immediately after implantation, three cases (1,2%) of pericardial effusion (one with tamponade) were reported. In one case (0,4%), a conventional pacemaker was implanted due to L-PM acute dysfunction. No other procedure-related complications, including dislodgment, were reported at discharge. After a mean follow-up of 2,8±1,7years, the pacing threshold and R-wave amplitude remained stable [0,67mV vs. 0,62mV (p=0,9); and 10,3mV vs. 16,1mV (p<0,001), respectively] and mean ventricular pacing was 54±38%. Expected battery longevity was >8 years (maximum value) in 84% of the patients. In the subgroup of patients with >5 years of follow-up (N=20; mean follow up of 6,3±1,8years), the expected battery longevity was >8 years in 85% (N=17) of the patients. In three cases, the L-PM was upgraded to cardiac resynchronization therapy or left bundle branch area pacing due to pacing-induced left ventricular dysfunction. There was one case of L-PM end-of-life 6 years after implant (pacing threshold 0,5mV; ventricular pacing 100%), in which a second L-PM was successfully implanted. Overall, 78 (31%) patients died, a mean of 2,2±1,9 years after L-PM implantation, none related to the device. Conclusion In this real-world cohort, L-PM maintained stable pacing parameters and, in the mid-term follow-up, only one battery depletion was observed while expected longevity remained above 8 years in the large majority of patients. Longer follow up will allow better understanding of both technical and clinical aspects relevant to manage end-of-life devices.Table 1Figure 1

New onset of left ventricular dysfunction and diastolic dysfunction are uncommon in patients with her2+ breast cancer after completion of cancer therapy

Abstract Background Cardiotoxicity from anthracyclines and trastuzumab is common among patients with breast cancer during therapy. However, there are limited data on new onset of cardiotoxicity (systolic or diastolic dysfunction) after completion of therapy. This knowledge has implications to guide long-term follow-up. Purpose The aim of this study was to evaluate the incidence of cancer therapy related cardiac systolic dysfunction (CTRCD) and diastolic dysfunction (DD) in women with HER2+ breast cancer after completion of cancer therapy and compare to incidence during cancer therapy. Methods We conducted a prospective cohort study of women with HER2+ breast cancer who were treated with sequential anthracycline and trastuzumab therapy, with or without radiation therapy (The EMBRACE-MRI trial, NCT02306538). Comprehensive surveillance echocardiograms were performed at baseline and every 3 months during treatment, early post-trastuzumab, then at years 1, 2, and 3 post trastuzumab completion. CTRCD was defined as a reduction in 3D-left ventricular ejection fraction (LVEF) by ≥ 10% from baseline to < 55%. Diastolic dysfunction was defined as per the American Society of Echocardiography guidelines. Results A total of 136 female patients, with a mean age of 51.1 ± 9.2 years were recruited. Among them, 15.4% had hypertension, 3.7% had diabetes mellitus, and 10.3% had dyslipidemia. The mean cumulative doxorubicin equivalent dose was 203.9 ± 12.5 mg/m2, 120 patients received radiation therapy with the mean heart dose of 170.8 ± 75.9 cGy. During cancer treatment, 27 out of 136 patients (19.9%) developed CTRCD. In long-term follow-up, due to death or interruption due to the COVID-19 pandemic, follow-up was available in 128 patients at 1 year, 117 at 2 years and 111 at 3 years. 5 of the 27 patients still had persistent LV dysfunction (3 at 1 year, 1 at 2 year and 1 at 3 year), however, there were no new diagnosis of CTRCD post completion of therapy. Of 129 patients with baseline normal or indeterminate diastolic function, new DD was identified in 25/129 patients (19.4%) during cancer treatment (17 grade I, 2 grade II, 6 unable to grade). After completion of cancer therapy, 5 patients had persistent DD. In patients with no DD during therapy and completed 3 year follow-up, 5 patients developed new DD after therapy (2 grade I, 3 unable to grade). Figure 1 illustrates the percentage of patients with new CTRCD or new diastolic dysfunction at each timepoint. None of the patients developed clinical heart failure. Conclusion Although both CTRCD and diastolic dysfunction are common during sequential therapy with anthracyclines and trastuzumab in women with HER2+ breast cancer, new onset after treatment completion is rare during a careful follow-up. These findings have implications for long-term surveillance.

Subclinical left ventricular dysfunction detected by speckle tracking echocardiography predicts mortality in COVID-19 patients

Abstract In COVID-19 patients, both preexisting cardiovascular disease and cardiac injury resulting from SARS-CoV-2 infection are associated with increased mortality. In this patient population the value of speckle tracking echocardiography (STE) for detecting high-risk patients has not been evaluated thoroughly. Aim The aim of study was to determine the prevalence of subclinical myocardial dysfunction revealed by STE and its association with in-hospital and two-year mortality in patients with COVID-19 and preserved left ventricular ejection fraction (LVEF). Methods The study group comprised 163 consecutive patients with preserved LVEF(>/=50%) and maintained right ventricular function evaluated by assessment of tricuspid annular plane systolic excursion (TAPSE >14 mm) hospitalized in the cardiology department due to COVID-19 in 2020 and 2021. All patients underwent transthoracic echocardiographic examination with off-line analysis using STE. Left ventricular global longitudinal strain(GLS), right ventricular global longitudinal strain (RV-GLS), right ventricular free wall strain(RV-FWS) and myocardial work parameters: global work index(GWI), global wasted work(GWW), global constructive work(GCW) and global work efficiency(GWE) were measured. The primary outcome was in-hospital and two-year mortality. Results 96 patients (mean age 66 years, 59 [61%] male) had adequate image quality to evaluate deformation-derived parameters.19 patients (19.8%) died during hospitalization and 9 (9,4%) patients died within two years after discharge. In-hospital non-survivors were older, had lower baseline oxygen saturation(SpO2) and had higher NTproBNP. In non-survivors STE revealed significant impairment of LV and RV function compared to the group of survivors(Table 1). The independent predictors of in-hospital death were: age (OR 1.1 [95% CI 1.01 – 1.19]), SpO2 on admission (OR 0.83 [95% CI 0.75 – 0.93]), NTproBNP (OR 1.0003 [95% CI 1.0001 – 1.0006]) and LV-GLS (OR 1.45 (1.06 – 1.99)]. Based on the analysis of the ROC curves, the cut-off points optimal for predicting in-hospital death were identified: age >71 years (sensitivity [sens.] 74%, specificity [spec.] 68%) , baseline SpO2 value ≤ 89% (sens. 89%, spec. 74%,) NTproBNP >951 pg/ml (sens. 79%, spec. 58%) and GLS >-16% (sens. 63%, spec. 89%). The independent predictors of two-year mortality were: age (OR 1.10 [95% CI 1.02 – 1.19]), Sp02 on admission (OR 0.82 [95% CI 0.73 – 0.91]) and NTproBNP (OR 1.0006 [95% CI 1.0001 – 1.0011]).Based on the ROC curve analysis, the cut-off points optimal for predicting death within 24 months after COVID-19 were also identified: age>71 years (sens. 71%; spec. 72%), Sp02 <89% (sens. 69%, spec. 73%), NTproBNP >520 pg/ml (sens. 89%, spec. 48%). Conclusions STE allows for the detection of subclinical myocardial dysfunction in COVID-19 patients with preserved LVEF. However, LV GLS is the only independent STE-based predictor of in-hospital mortality in this patient population.

Cancer-specific Heart Failure (HF) risk score - a new risk score developed specifically to predict HF among cancer survivors

Abstract Background Heart failure (HF) is an important long-term complication in cancer survivors, especially in breast and haematological malignancies treated with anthracylines. However, screening for left ventricular dysfunction in all survivors is impractical due to potential low cost-efficiency. So we sought to develop a cancer-specific risk scoring system for HF (CRS-HF). Methods Cancer survivors (n=43,720) participating in the UK-Biobank were evaluated in this study (age 59.9 ± 7.4 years, 62.4% female). Participants were randomized into training and testing dataset with a 7:3 split. A Random Forest algorithm was applied to identify key variables that are predictive for HF incidence among cancer survivors. Results Incident HF developed in 4.3% over a median of 12.9 years. The random forest algorithm identified demographic (age, sex and body mass index), clinical (heart rate, blood pressure and cardiac history), pathology (lipids) results and other patient reported outcome measures (PROMS) that predicted HF with an accuracy of 0.872 (95%CI: 0.867-0.877) in the training set. In the testing set, the accuracy was 0.840 (95%CI: 0.832-0.848) and a reported sensitivity and specificity of 62.42% and 84.93% respectively. Our study also demonstrated that the CRS-HF performed better in ruling out non-HF incidence among survivors from breast cancer and lymphoma (accuracy: 0.858) than other cancer types (accuracy: 0.836). Conclusion The CRS-HF score is a prove-of-concept that appears to be an effective means of identifying HF risk in cancer survivors. Although initial findings demonstrate promising accuracy in forecasting HF occurrences among cancer survivors, comprehensive validation and potential refinements are warranted across diverse population cohorts.

Spermidine attenuates left ventricular dysfunction in estrogen deprived aging rats through mitigating lipid peroxidation and mitochondrial dysfunction

Abstract Background Aging women with postmenopause are particularly susceptible to cardiovascular diseases (CVDs), which are associated with the elevation of oxidative stress and mitochondrial dysfunction. Although hormone replacement therapy (HRT) has been reported to provide cardiometabolic protection, long-term HRT could be linked to CVD consequences. A novel organic therapy with spermidine has shown promise as cardioprotection in several CVDs. However, the effects of spermidine on left ventricular (LV) function, mitochondrial function and oxidative stress in estrogen-deprived aging rats have not been investigated. Purpose To evaluate the effects of spermidine on LV function, mitochondrial function and oxidative stress in estrogen-deprived and D-galactose-induced aging rats Methods Twenty female Wistar rats were randomly assigned to the sham and the ovariectomy (OVX) along with D-galactose (150 mg/kg/day, s.c.) administration throughout the experiment for 12 weeks. OVX with D-galactose-treated rats were divided into three interventional groups: vehicle (ODV), spermidine (20 mg/kg/day, p.o., ODS), and estradiol (50 ug/kg/day, s.c., ODE) (n=5/group) for 8 weeks. The sham group received a vehicle (SVV, n=5). At the end, all rats underwent echocardiography, followed by euthanasia. The hearts were removed for measuring mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential (MMP) changes (ΔΨm), and malondialdehyde (MDA) levels. Results Rats with OVX-induced estrogen deprivation with D-galactose-induced aging had LV impairments indicated by decreased LV ejection fraction, reduced ratio of peak velocity blood flow from left ventricular relaxation in early diastole (E) to peak velocity flow by atrial contraction (A), and increased sympathovagal imbalance (elevated low/high frequency (LF/HF) ratio) (Fig. 1A-C). These estrogen-deprived aging rats also had an increase in cardiac tissue MDA levels, mitochondrial ROS production, and MMP depolarization (Fig. 1D-F). Both spermidine and estrogen similarly demonstrated a significant reduction in all of those detrimental effects, leading to improved LV function (Fig. 1A-F). Conclusion Spermidine exerted cardioprotection comparable to estrogen supplement through mitigating oxidative stress and mitochondrial impairments in cardiac tissue, resulting in improved LV dysfunction and cardiac autonomic balance due to estrogen deprived aging conditions in rats. These findings suggest that spermidine administration could be a promising strategy for cardioprotection in postmenopausal women with aging.

Bnip3 promotes the release of mitochondria-derived extracellular vesicles in cardiac fibroblasts to exacerbate inflammation response after myocardial infarction

Abstract Background Cardiac fibroblasts (CFs) play a crucial role in tissue repair and remodeling following myocardial infarction (MI). Furthermore, CFs possess the ability to sense signals of myocardial injury and secrete cytokines, thereby eliciting a pro-inflammatory response during the early post-MI phase. Our previous studies have demonstrated that CFs located in the infarcted region release small extracellular vesicles (sEVs) abundant in damaged mitochondria, termed "mt-sEVs". These mt-sEVs are internalized by macrophages, prompting the secretion of IL-6 and IL-1β via NLRP3/Caspase-1 pathway. Nonetheless, the precise mechanisms underlying the promotion of mt-sEVs release remain elusive. Objective This study aimed to investigate the pivotal genes involved in mediating the release of CFs-derived mt-sEVs, with potential implications for post-MI therapeutic strategies. Methods Primary CFs were cultured for 24 hours in sugar-free medium with 1% oxygen (OGD) in vitro. Conditioned medium was subjected to ultracentrifugation to isolate sEVs. The presence of damaged mitochondrial components within the sEVs was confirmed using Mito-tracker and nanoflowmetry. Subcellular structures were visualized via transmission electron microscopy (TEM). Protein interactions were validated through co-immunoprecipitation (co-IP) assays. CF-specific gene knockout mice were generated and subjected to MI surgery. The proportion of F4/80+/CD86+ cells was quantified using flow cytometry. Cardiac function was evaluated using echocardiography, and the extent of cardiac fibrosis was assessed via Masson staining. Results Re-analysis of single-cell RNA sequencing data (GSE153480) unveiled a significant upregulation of the mitophagy receptor Bnip3 in CF sub-populations following MI, and the up-regulated trend was also observed in OGD-CFs. Deletion of Bnip3 hindered the expression of LC3 and its co-localization with mitochondria. TEM observed extensive fusion of mitophagosomes with multivesicular bodies in OGD-CFs. Fluorescence signal detected by nano flowmetry significantly decreased in Bnip3 knockdown sEVs incubated with Mito-tracker. Bnip3 deletion in CFs resulted in a significant downregulation of the sEVs release key factor Rab27a, concomitant with a striking increase in Rab27a ubiquitination. Predicted binding sites of both Bnip3 and Rab27a with the deubiquitinase Usp7 were validated through co-IP assays. Immunofluorescence staining demonstrated the co-localization of Usp7 with Bnip3 in OGD-CFs. CF-specific deletion of Bnip3 reduced the proportion of M1 macrophages, reversed left ventricular dysfunction, and mitigated myocardial fibrosis in post-MI hearts. Conclusion Collectively, our study reveals that Bnip3-mediated mitochondrial secretory autophagy in CFs was significantly activated to drive the release of mt-sEVs. Additionally, Bnip3 interacts with Usp7 to deubiquitinate Rab27a, promoting the release of mt-sEVs in CFs, exacerbating the inflammatory response after MI.Graphical abstract

Mechanisms of atrial-fibrillation-induced ventricular dysfunction and recovery in the human left ventricular myocardium

Abstract Background Atrial fibrillation (AF) frequently occurs alongside heart failure (HF). Clinical studies indicate improved left ventricular (LV) function following rhythm restoration but the underlying myocardial processes remain unclear. Purpose This study investigated effects of AF and its termination on human LV myocardium as well as potential molecular mechanisms involved in the AF-induced LV dysfunction. Methods Human LV tissue slices obtained from HF patients were long-term cultivated in-vitro. AF was simulated by tachy-arrhythmic culture pacing at 100 bpm with 30% irregularity for 7 days and contractile LV function was compared to slices undergoing sinus rhythm (SR)-simulation (60 bpm/0%). After 7 days, rhythm restoration was simulated by switching to SR-simulation. To elucidate cellular mechanisms involved in AF-induced LV dysfunction, human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) were subjected to AF-simulation and examined via epifluorescence microscopy (FURA-2) and confocal microscopy (Fluo-4). Additionally, to investigate the impact of reactive oxygen species (ROS) on cardiomyocytes, iPSC-CM were subjected to treatment with the ROS-scavenger N-acetylcysteine (NAC). Results AF-simulation caused a progressive decline in systolic force of human LV myocardium (n=14 slices) with significantly reduced twitch amplitudes compared to SR-simulation (n=11). Within just 5 days of AF-termination, a significant recovery in LV function was observed, indicated by improved systolic contraction amplitudes. IPSC-CM measurements revealed a significant reduction in systolic Ca2+-transient amplitudes as well as an increased diastolic Ca2+ leak after AF-simulation (n=41) compared to SR-simulation (n=44). However, 5 days after SR-restoration, iPSC-CM exhibited no significant differences anymore, indicating a fast recovery of systolic Ca2+-cycling. We further investigated the impact of ROS on LV function and could show that Ca2+-transient amplitude was preserved after AF-simulation in iPSC-CM when treated with NAC (n=35), suggesting an interplay of ROS with the Ca2+-homeostasis of cardiomyocytes. Conclusions This study demonstrates that AF impairs LV function in human HF myocardium. However, the involved changes in contractility and cardiomyocyte Ca2+ handling are reversible upon AF termination leading to improved LV function already within few days after AF cessation. Moreover, we provided an indication for an interplay of ROS with the Ca2+ homeostasis, endorsing an AF-induced LV-dysfunction, which merits further investigation.

Prognostic impact of echocardiographic predictors of subclinical systolic dysfunction in patients with moderate aortic stenosis

Abstract Introduction Moderate aortic stenosis (AS) marks a critical point in AS severity spectrum, paralleled by significant cardiac structural changes. Concentric left ventricular (LV) hypertrophy, in response to the increased afterload, enables the preservation of a normal ejection fraction (EF) despite significant underlying myocardial dysfunction. Reductions in LVEF may serve as early indicators of the LV's diminished capacity to withstand this increased afterload, potentially leading to LV fibrosis and irreversible myocardial damage. Research has shown that LVEF may not recover in some patients following aortic valve replacement (AVR). Consequently, there is a growing debate concerning higher LVEF thresholds for triggering AVR in patients with severe AS, aiming to intervene before clinical systolic dysfunction ensues and irreversible damage occurs. Meanwhile, a combination of objective indicators may help to identify those patients AS at high risk before a decline in LVEF occurs. Aim To explore the role of baseline left ventricle global longitudinal strain (GLS) and strain rate (SR) as markers of subclinical LV dysfunction, as predictors of LVEF depression, and their impact on survival of patients with moderate AS. Methods Patients with moderate AS and LVEF ≥ 50% at least in 2 echocardiograms were retrospectively identified. Prosthetic and bicuspid valves were excluded. Baseline LV GLS and SR were used as covariates in cox regression models to predict the cumulative incidence of LVEF depression over 5 years and overall survival after multivariable adjustment including time-dependent AVR. Results 574 patients were included (age 76 ± 9 years; 51% female; median follow-up time of 8.97 years). The average baseline aortic peak velocity was 3.4±0.8 m/s, mean pressure gradient was 25±9 mmHg, aortic valve area was 1.1± 0.3 cm2, and LVEF 60±5%. The average GLS was -17±7 % while the peak systolic SR was 1.2 ± 0.5/s. Both baseline GLS (HR= 0.88 for each -1%; 95% CI= 079-0.99; p= 0.04) and SR (HR= 0.89 for each +0.1/s; 95% CI= 0.80-0.99; p=0.03) were associated with 5-year incidence of LVEF depression (<50%). Risk discrimination improved by incorporating SR on top of GLS (increase in area under curve from 0.78 to 0.84; 95% CI= 0.01-0.10; p= 0.04). Furthermore, a nonlinear relation was found between GLS (optimal boundary <-15.8%; p=0.35) and SR (optimal boundary >0.96/s; p=0.34) and overall survival. Conclusions This study identifies baseline GLS and SR as predictors of LVEF depression in moderate AS underscoring their importance in detecting subclinical LV dysfunction. The combination of GLS and SR may enhance the prediction of cardiac function decline, suggesting their potential utility in guiding early intervention strategies. Although their direct relationship with survival needs further exploration, these findings advocate for incorporating GLS and SR in AS management to inform timely AVR decisions and improve patient outcomes.