Left Ventricular Diastolic Dysfunction Research Articles

Exploring the impact of coronary microvascular dysfunction on cardiac remodeling after st-elevation myocardial infarction

Abstract Background The complex interplay between Coronary Microvascular Dysfunction (CMD) and ST-segment Elevation Myocardial Infarction (STEMI) presents significant clinical hurdles. CMD, commonly seen as a complication following STEMI, is associated with adverse cardiovascular outcomes and persistent anginal symptoms. Despite its clinical relevance, the link between CMD post-STEMI and subsequent left ventricular (LV) diastolic dysfunction, along with functional LV remodelling (FLVR), is yet to be fully explored. Purpose Examine the link between CMD 3 months post-STEMI and its impact on FLVR and diastolic dysfunction. Methods This prospective, observational cohort study focused on STEMI patients. At 3-month post-STEMI, a comprehensive coronary physiology assessment of the culprit artery was conducted using the thermodilution method to measure fractional flow reserve (FFR), coronary flow reserve (CFR), and the index of microcirculatory resistance (IMR). CMD was identified with an IMR ≥ 25 or a CFR < 2.0, assuming an FFR > 0.80. Diastolic dysfunction was classified according to ASE/EACVI 2016 guidelines. FLVR was categorized as per Surenjav Chimed et al.'s criteria: Group I with no significant changes in LV size or function, Group II with a decrease in LV ejection fraction (LVEF) greater than 5% without LV dilatation, Group III with an increase in left ventricular end-diastolic volume (LVEDV) ≥ 20%, and Group IV showing both an increase in LVEDV ≥ 20% and a decrease in LVEF over 5%. The study aimed to elucidate the relationship between CMD and the progression of FLVR and diastolic dysfunction, tracked over a 12-month period. Results The study involved 210 patients, mostly men (59.5%), with a median age of 65 (IQR: 58–76). At the 3-month follow-up, CMD was observed in 57 (27.1%) patients. CMD patients had a higher female prevalence (63.2% vs. 32.0%; p < 0.001) and more diabetes (42.1% vs. 17.7%; p < 0.001) compared to non-CMD patients. Both groups shared similar body mass indices, medications, and other risk factors. Laboratory results were similar between groups, except brain natriuretic peptide levels were higher in CMD patients (70.0 vs. 37.0 ng/L; p < 0.001). After 12 months, CMD patients demonstrated significantly less recovery in LVEF (-10.00% vs. 8.00%; p < 0.001), higher prevalence of grade 2 LV diastolic dysfunction (73.08% vs. 1.32%; p < 0.001), and a higher incidence of advanced FLVR (notably in Groups 3 and 4) compared to non-CMD (11.32% vs. 7.28% and 22.64% vs. 1.99%, respectively; p < 0.001). In the adjusted multivariable logistic regression analysis, IMR values independently predicted more severe FLVR and diastolic dysfunction. Conclusions This study highlights that CMD 3 months after STEMI is linked to worse FLVR, diastolic dysfunction, and less recovery in LVEF, emphasizing the need for early CMD detection for better risk assessment. Further research is essential to explore underlying mechanisms and intervention opportunities.LVEF Changes at 12 Months by CMD StatusDiastolic Dysfunction and LV Remodeling

Relationship between changes in renal function after acute phase of tafamidis administration and left ventricular diastolic function at mid-term follow-up in transthyretin cardiac amyloidosis

Abstract Background A large number of heart failure (HF) patients present with various degrees of renal dysfunction, known as cardio-renal syndrome. Renal impairment in HF patients is also associated with an independent risk factor for morbidity and mortality. Transthyretin (TTR) amyloidosis (ATTR) is characterized by disintegrated liver-derived TTR that accumulates as amyloid fibrils in the myocardium, leading to initially presenting as left ventricular (LV) hypertrophy and LV diastolic dysfunction. Although there is no proven therapy for patients with ATTR cardiomyopathy (ATTR-CM), tafamidis meglumine, a TTR stabilizer, has been associated with favorable outcomes. Although the kidneys are also an important organ where amyloid deposition occurs, the effect of tafamidis on renal function and its relationship to LV diastolic function is unclear. Purpose The purpose of this study was to investigate the relationship between changes in renal function after the acute phase of tafamidis administration and LV diastolic function at mid-term follow-up in patients with ATTR-CM. Methods We studied 56 patients with biopsy-proven ATTR-CM who were treated with tafamidis. All patients underwent blood examinations before and 45.6 ± 23.0 days after the acute phase of tafamidis administration. Echocardiography was performed before and 15.6 ± 9.8 months after the mid-term of tafamidis administration. The primary endpoint was defined as a composite of cardiovascular death or HF hospitalization for 5.0 years. Results Twelve patients had improved renal function as assessed by estimated glomerular filtration rate in the acute phase after tafamidis administration, while 44 patients deteriorated. In the group with improved renal function in the acute phase after tafamidis administration, pulsed-wave Doppler-derived early diastolic velocity from the septal mitral annulus (E’) and left atrial volume index (LAVI) tended to improve at mid-term follow-up compared to the non-improved group. (E’: 0.8 ± 1.7 cm/s vs. 0.2 ± 1.1 cm/s, p=0.127, LAVI: -8.7 ± 12.0 mL/m2 vs. 0.2 ± 16.8 mL/m2, p=0.093). Furthermore, Kaplan-Meier curve indicated that the occurrence of cardiovascular events for patients with improved renal function in the acute phase after tafamidis administration tended to be lower than those without (log-rank P=0.137). Conclusions The improvement of renal function in the acute phase after tafamidis administration was associated with the improvement of LV diastolic function at mid-term follow-up, leading to favorable outcome. Our findings may provide new insights for the management of patients with ATTR-CM.

Prognostic stratification of patients with mitral regurgitation using artificial intelligence-enhanced electrocardiogram for left ventricular diastolic function assessment

Abstract Background The determination of left ventricular diastolic dysfunction (LVDD) and filling pressure in patients with significant (>moderate) mitral regurgitation (MR) poses a complex challenge. We recently validated an artificial intelligence-enabled electrocardiogram (AI-ECG) algorithm to detect LVDD and estimate LV filling pressures. Methods This retrospective study sought to examine the risk of all-cause mortality across AI-ECG LVDD grades. Patients from the AI-ECG LVDD study test cohort who underwent transthoracic echocardiography confirming significant MR and an ECG within fourteen days of each other at Mayo Clinic between 09/2001 and 06/2022 were included. LVDD status was determined based on the index ECG, and patients were categorized into groups representing normal diastolic function (NDF) or LVDD grades 1 (G1), 2 (G2), or 3 (G3). Results Of 4,019 patients with significant MR (mean age 69.8, 49.0% women), 1,175 (29.2%), 1,881 (46.8%), and 963 (24.0%) were classified by AI-ECG as NDF/G1-LVDD, G2-LVDD, and G3-LVDD, respectively. The median mitral effective regurgitant orifice area was 26 mm² (interquartile range 20-36 mm²). Over a median follow-up of 3.5 years, 1,636 (40.7%) patients died. In multivariable survival analysis adjusted for multiple risk factors, a worse AI-ECG LVDD grade was independently associated with an increased death risk [G2DD: adjusted hazard ratio (aHR) 1.98 (95% confidence interval (95% CI) 1.63-2.40), G3DD: aHR 2.59 (95% CI 2.09-3.20)]. These findings were consistent when accounting for mitral valve intervention and among patients with >moderate MR or after mitral valve intervention. Conclusion In patients with significant MR, the grading of LVDD by AI-ECG is independently associated with all-cause mortality.

Impact of microvascular resistance reserve on post-STEMI cardiac remodelling and diastolic function

Abstract Background Coronary microvascular dysfunction (CMD) is a common sequelae of ST-segment elevation myocardial infarction (STEMI), preventing adequate recovery of left ventricular (LV) perfusion. The interferences of con-commitment epicardial stenosis or hyperemic hemodynamic alterations limit traditional physiologic metrics. The microvascular resistance reserve (MRR) was developed to overcome these shortcomings. Purpose We aim to investigate the association between post-STEMI MRR, and the ensuing left ventricle (LV) diastolic dysfunction, and functional remodeling. Methods In this prospective, observational study, we enrolled STEMI patients with multivessel disease who successfully underwent primary percutaneous coronary intervention (PCI). At three months post-PCI, all patients received complete revascularization followed by coronary physiology assessment using the bolus thermodilution method to measure the fractional flow reserve (FFR), coronary flow reserve (CFR), and the index of microcirculatory resistance (IMR). MRR was calculated using the formula: MRR = (CFR/FFR) × (Pa rest/Pa hyper), where Pa rest and Pa hyper represent resting and hyperemic aortic pressure, respectively(1). CMD was defined as an MRR < 3.0 based on Boerhout et al(2). Diastolic dysfunction was defined according to the ASE 2016 guidelines. Functional LV remodelling (FLVR) was categorized according to Chimed et al(3). The relationship between CMD and the stages of FLVR and diastolic dysfunction was scrutinized over a 12-month follow-up period. Results We enrolled 210 patients, of whom 125 (59.5%) were men with a median age of 65 (IQR: 58–76). At the 3-month follow-up, the MRR was 3.46 (IQR 3.00, 3.92), with 56 (26.7%) patients having CMD (MRR<3.0). MRR is significantly correlated with the change of LVEF between primary PCI and 12 months (r=0.48, p<0.001, Fig1A). CMD patients have lower LVEF at 12 months (50.00% vs. 40.00%; p < 0.001) and demonstrated significantly less recovery in LV systolic function (-10.00% vs. 8.00%; p < 0.001, Fig 1B, 1C). CMD patients had a higher prevalence of grade 2 or 3 LV diastolic dysfunction (65.38% vs. 3.95%; p < 0.001, Fig 2A) and a higher incidence of advanced FLVR (Groups 3 and 4) compared to those without CMD (30.77% vs. vs. 10.53%; p < 0.001, Fig 2B). In multivariable logistic regression analysis, MRR was independently associated with LV diastolic dysfunction (0.17, 95%CI 0.08-0.33, p<0.001). Conclusions The novel parameter MRR is significantly related to LVEF recovery in STEMI patients and is an independent predictor for advanced LV diastolic dysfunction and FLVR. CMD patients, as diagnosed with MRR, showed a higher prevalence of advanced FLVR and diastolic dysfunction. These results suggest that MRR is a useful parameter for the identification and management of CMD in STEMI patients.

Autonomous cortisol secretion in patients with primary aldosteronism is associated with left ventricular hypertrophy and diastolic dysfunction

Abstract Background and Aims: Autonomous cortisol secretion (ACS) constitutes a significant portion of patients diagnosed with primary aldosteronism (PA) and is potentially linked to adverse cardiovascular outcomes. This study aimed to explore the impact of ACS on cardiac remodeling and diastolic dysfunction in PA patients. Methods We prospectively enrolled 567 PA patients from March 2000 to March 2023. ACS was defined as a cortisol level >1.8 μg/dL after a 1 mg dexamethasone suppression test (DST). Clinical, biochemical, and echocardiographic data were collected at baseline and during one-year follow-up after targeted treatments including adrenalectomy and mineralocorticoid receptor antagonist administration. Results In this prospective cohort, 21.5% of PA patients had concurrent ACS. PA patients with ACS were older and had a higher prevalence of diabetes. They also exhibited significantly higher left ventricular mass index (LVMI) and worse diastolic function (E/e'). Baseline post-1 mg DST cortisol levels positively correlated with baseline LVMI and E/e' in restricted cubic spline analysis. Multivariable linear regression analysis showed that ACS presence was significantly associated with higher LVMI and worse E/e' after adjusting for significant variables. Among patients who underwent adrenalectomy, both those with and without ACS showed significant improvements in LVMI and E/e'. Patients who received mineralocorticoid receptor antagonist treatment also showed significant improvement in E/e', irrespective of ACS presence. However, significant LVMI improvement was observed only in PA patients without ACS who received mineralocorticoid receptor antagonist treatment. Conclusions The presence of ACS in PA patients was associated with worse left ventricular hypertrophy and diastolic dysfunction. Adrenalectomy and mineralocorticoid receptor antagonist treatment partially reversed cardiac remodeling in PA patients with ACS.

The impact of cardiovascular risk factors on longitudinal changes in cardiac structure and function in an older population of hypertensive patients

Abstract Background Hypertension is associated with cardiac structural and functional changes, with left ventricular hypertrophy and diastolic dysfunction as strong predictors of adverse cardiac events. Limited data exist on how cardiovascular (CV) risk factors accelerate left ventricular (LV) mass and diastolic dysfunction over time in older hypertensive patients. Purpose To investigate the association between CV risk factors and accelerated deterioration of LV mass, left atrial volume (LAV), global longitudinal strain (GLS), and tissue Doppler E/e’ ratio in an older population of hypertensive patients. Methods Post-hoc analysis of a randomized clinical trial that investigated whether atrial fibrillation screening, using an implantable loop recorder, and subsequent initiation of anticoagulation, could prevent stroke in high-risk individuals. Only individuals with hypertension who had transthoracic echocardiography performed on two occasions, with a median of 5 years between echocardiograms, were included in this sub-study (n = 570). Multivariable linear regression analysis was performed to investigate the association between risk factors and changes in LV mass, LAV, GLS and E/e’. ß-values were calculated per 1 SD change for all variables. Results Mean age was 74±3 years, and 55% were men. Mean body mass index (BMI) was 27.8±4.3 kg/m2, 26% had diabetes, 58% used statins, 12% had a history of ischemic heart disease, and 4% had heart failure. The median use of antihypertensive drugs was 2 (IQR: 1,2), mean systolic blood pressure was 148.6±18.2 mmHg. During a median follow-up of 5 years, the mean increase in LV mass was 6.5±38.3g. Male sex (ß 0.24, p < 0.001) and increasing BMI (ß 0.29, p <0.001) were significantly associated with an accelerated increase in LV mass (Fig. 1). The mean increase in LAV was 14.6±15.7ml. Diabetes (ß -0.16, p = 0.006) and high sensitivity C-reactive protein (hsCRP) (ß 0.14, p = 0.007) were significantly associated with changes in LAV (Fig. 2). The absolute decline in mean GLS was 0.27%. Increasing age (ß -0.09, p = 0.027), heart failure (ß -0.10, p = 0.020), ischemic heart disease (ß -0.16, p < 0.001), hsCRP (ß -0.12, p = 0.003) and s-creatinine (ß -0.09, p = 0.033) were all significantly associated with an accelerated decline in GLS (Fig. 1). E/e’ declined with an average 0.96±2.89. Increasing age (ß 0.12, p = 0.001), female sex (ß 0.09, p = 0.049), and increasing systolic blood pressure (ß 0.13, p = 0.004) were associated with an increase in E/e’ (Fig. 2). Conclusion Male sex and increasing BMI were independently associated with an accelerated increase in LV mass. Diabetes was independently associated with LAV decline, while hsCRP was significantly associated with increasing LAV. Increasing age, heart failure, ischemic heart disease, hsCRP, and s-creatinine were independently associated with an accelerated decline in GLS. Increasing age, systolic blood pressure and female sex were independently associated with increasing E/e’.

Left atrioventricular coupling index: association with diastolic dysfunction and prognostic implications in heart failure patients

Abstract Background Left atrioventricular coupling index (LACI), an index coupling left atrial (LA) to left ventricular (LV) volume at end-diastole (Figure 1), showed to be associated with prognosis in different clinical settings. However, the relation between LACI and LV diastolic dysfunction (DD) remains to be established. Purpose The present study aimed to investigate the association between LACI and LV DD and to assess its prognostic value in patients with heart failure (HF). Methods We retrospectively analyzed 1158 stable HF patients (mean age 66±12 years, 75% men) on optimal medical therapy (derivation cohort). Clinical and echocardiographic features were characterized across LACI tertiles. The independent prognostic value of LACI (endpoint: all-cause death/HF-hospitalization) was assessed by Cox regression and spline curve analyses. Results were validated in an external cohort of 242 HF patients. Results In the derivation cohort, the median LACI value was 0.29 (IQR:0.19-0.42). Patients in the third tertile (LACI>0.36) were older and presented with more advanced HF symptoms. While prevalence of grade-1 DD (ASE/EACVI classification) progressively decreased across LACI tertiles, the prevalence of grade-3 DD significantly increased (8%,23%, and 46% respectively, P<0.0001). A cut-off value ³0.26 identified moderate-to-severe DD with an area-under the-curve of 0.75. During follow-up (median 28 months, IQR:11-53), 407 (35%) patients reached the endpoint. On multivariable analysis, LACI was independently associated with outcomes (HR for 1-unit-increase 2.34; 95%CI 1.35-4.03; P=0.002 – Figure 2), showing incremental predictive value over the DD grading system (net reclassification improvement=0.150, P<0.0001). The prognostic value of LACI was consistent in the external validation cohort. Conclusions LACI is associated with DD severity and is an independent predictor of outcomes in HF patients.How to assess LACIPrognostic value of LACI in HF

Sex-specific association of NT-proBNP with clinically inapparent structural heart disease in the general population: results from the STAAB study

Abstract Background Guidelines recommend echocardiography in subjects beyond defined levels of natriuretic peptides. The ACC/AHA guidelines on heart failure (HF) state echocardiographic signs of structural heart disease (SHD) that define the precursor stage B of heart failure. Purpose To study the age- and sex-specific association between echocardiographically assessed structural heart disease (echoSHD) and NT-proBNP levels in the general population. Methods The STAAB study investigates precursor stages of HF in the general population of a medium-sized city in Germany (source population 124,297 inhabitants as of 2011 census). Study participants were recruited between 12/2013 and 10/2017 from the source population without preceding HF diagnosis, stratified for sex and age (30-79 years). For this analysis, we excluded participants with previously diagnosed coronary artery disease. EchoSHD was accepted if one of the following criteria, diagnosed according to current echo guidelines, was detectable at echocardiography: left ventricular (LV) hypertrophy, LV dilation, reduced LV ejection fraction, moderate-to-severe LV valve disease, and LV diastolic dysfunction. Results Of 4,649 subjects analysed (93.6% of STAAB participants, age 30-79 years, 53.5% women), 863 (18.6%) had echoSHD. NT-proBNP depended strongly on age and sex (figure). Frequencies of echoSHD varied between women (23.0%) and men (13.5%; P<0.001). EchoSHD was associated with increased NT-proBNP levels in both women (geometric mean ratio 1.18, 95%CI 1.09–1.27, P<0.001; figure) and men (ratio 1.62, 1.46–1.79, P<0.001); P<0.001 for different ratios in both sexes. Of note, age did not influence these ratios as well as their difference (P=0.34 and P=0.95, resp.). Conclusion Clinically inapparent echoSHD was associated with higher levels of NT-proBNP, of a magnitude that was relevant in men. The sex difference in the strength of this relationship might be due to different pathophysiological processes leading to SHD and ultimately HF in women and men. It might also indicate the need for adopted definitions of echoSHD in women. Our results further point towards the need of age- and sex-specific NT-proBNP thresholds.NTproBNP according to sex, age, and SHD

Cardiac structure and function in patients with chronic obstructive pulmonary disease

Abstract Background Chronic obstructive pulmonary disease (COPD) is common and strongly associated with cardiovascular disease, but the pathophysiology has not been fully elucidated. Purpose We aimed to investigate cardiac structure and function in patients with COPD compared to a matched general population. Methods In a prospective cohort study, 796 patients with COPD were included and matched 1:2 on age and sex with controls from a general population study. All participants underwent an examination program including echocardiography. Standardized linear regression coefficients were used to compare cardiac structure and function in patients with COPD vs. controls. Impaired left ventricular (LV) function was defined as a left ventricular ejection fraction (LVEF) <50%, or global longitudinal strain (GLS) <16% (numerical). Impaired right ventricular (RV) function was defined as tricuspid annular plane systolic excursion (TAPSE) <1.7 cm. Diastolic dysfunction was defined as having at least two of the following parameters: E/e’ >14, septal e’ velocity <7cm/s, or lateral e’ velocity <10 cm/s, left atrial volume index (LAVi) >34 mL/m2, or tricuspid regurgitation velocity (TRV) >2.8 m/s. Logistic regression was used to assess associations between having COPD and systolic and diastolic dysfunction. Results Mean age was 70.2 ± 8.3 years and 52% were females. COPD patients had a mean forced expiratory volume in 1 second (FEV1) of 49.4 ± 18.8% predicted. At baseline, 43% of the patients with COPD had hypertension and 10% had diabetes (DM). Additionally, 57% with COPD had cardiovascular disease at baseline, including 12% with ischemic heart disease (IHD), 15% with atrial fibrillation (AF), 6% with heart failure, and 5% with a previous ischemic stroke. Patients with COPD had impaired measures of cardiac structure and function including a lower GLS (COPD vs. controls: 16.3 vs. 19.2%), lower TAPSE (2.3 vs. 2.6 cm), larger LAVi (29.0 vs. 24.7 mL/m2), and higher TRV (2.7 vs. 2.3 m/s), p for all associations <0.001. (See figure). Patients with COPD had a significantly higher prevalence of impaired LV systolic function (OR for GLS <16%: 8.18, 95% CI(6.04; 11.1), p <0.001), impaired RV systolic function (OR for TAPSE <1.7 cm: 2.77, 95% CI(1.63; 4.69), p <0.001), and LV diastolic dysfunction (OR for diastolic dysfunction grade I or higher: 4.00, 95% CI(3.12; 5.13), p <0.001) after adjustment for age, sex, hypertension, smoking, DM, IHD, AF, and lower density lipoprotein. (See figure). Conclusion Patients with COPD had significantly impaired LV and RV systolic function as well as impaired diastolic function compared with individuals from the general population. These findings underscore the importance of recognizing and addressing cardiovascular comorbidities in COPD.

Intact DNA repair in differentiated cardiomyocytes is essential for maintaining cardiac function in response to pressure overload in mice

Abstract Introduction DNA in every cell is continuously damaged and DNA repair mechanisms are essential for protection against DNA damage-induced aging-related diseases. For example, deficient repair of endogenously generated DNA damage in mice with cardiomyocyte-restricted inactivation of Xpg, is associated with progressive heart failure. Purpose Here we tested the hypothesis that unrepaired DNA damage in differentiated cardiomyocytes increases cardiac vulnerability in response to hemodynamic overload. Methods To increase the burden of spontaneous DNA damage, we generated mice with cardiomyocyte-restricted inactivation of DNA repair endonuclease XPG. At 8 weeks of age, αMHC-Xpgc/- and control (Ctrl) mice were subjected to pressure overload by transverse aortic constriction (TAC). Eight weeks after TAC, left ventricular (LV) function was assessed using echocardiography and hemodynamic measurements, followed by molecular and histological analyses. Results Cardiomyocyte-restricted inactivation of Xpg resulted in systolic as well as diastolic LV dysfunction (Table). TAC-induced LV hypertrophy is similar in both groups (Ctrl 38%; αMHC-Xpgc/- 34%). In Ctrl mice, LV hypertrophy was accompanied by minimal LV dilation and modest changes in systolic and diastolic LV function. Conversely, TAC in αMHC-Xpgc/- produced severe LV dysfunction and resulted in overt congestive heart failure, demonstrated by aggravation of LV dilation, and marked increases in LV end-diastolic pressure, left atrial weight and lung fluid weight, which was accompanied by further increases in the expression levels of the hypertrophic marker genes atrial natriuretic peptide and beta-myosin heavy chain (Table). Moreover, lectin staining revealed a decrease in capillary density and TUNEL staining revealed further elevated levels of myocardial apoptosis. In addition, a significant increase of myocardial collagen content was observed. Conclusion Cardiomyocyte-restricted loss of DNA repair protein XPG increases cardiac vulnerability to develop heart failure in response to pressure overload. These findings underscore the importance of genomic stability for maintenance of cardiac function, not only during basal conditions, but also in response to a pathological stimulus.

Three dimensional biatrial expansion index as an independent predictor of outcome in dilated cardiomyopathy

Abstract Background Left atrial expansion index (LAEI) is a marker of left ventricular (LV) diastolic dysfunction and an outcome predictor in heart failure (HF). However, the role of the right atrial expansion index (RAEI) in the setting of left-sided HF is incompletely understood. Purpose We sought to evaluate the left, right and combined bi-atrial expansion index (BAEI) with three-dimensional (3D) echocardiography in a cohort of patients with dilated cardiomyopathy (DCM) and to assess their prognostic role. Methods We enrolled 121 consecutive patients (mean age 59±14 years, 74% men) with DCM in sinus rhythm, who underwent 3D echocardiography and were prospectively followed for 19±11 months for an endpoint of death, nonfatal cardiac arrest and HF hospitalization. As previously described, for the left atrium (LA), LAEI was measured as (3D LA Vmax – 3D LA Vmin) x 100/3D LA Vmin, where Vmax was the maximal end-systolic atrial volume and Vmin was the minimal end-diastolic atrial volume. For the right atrium (RA), RAEI was calculated as (3D RA Vmax – 3D RA Vmin) x 100/3D RA Vmin. BAEI was defined as the sum of LAEI and RAEI. Results 55 patients (46%) reached the endpoint: there were 27 deaths, 5 nonfatal cardiac arrests and 23 readmissions for HF. Patients with adverse outcome had lower LAEI (52±25 vs. 63±36, p=0.047), lower RAEI (57±29 vs. 70±32, p=0.02), lower BAEI (108±46 vs. 133±55, p=0.008). In univariate Cox regression, all three expansion indices were predictors of adverse events: HR=3.23 [95% CI, 1.45-7.20], p=0.004 for LAEI, HR=2.12 [95% CI, 1.24-3.61], p=0.006 for RAEI, HR=3.99 [95% CI, 1.70-9.36], p=0.001 for BAEI. We constructed a multivariable model with well-established event predictors in DCM and one expansion index at a time. After adjustment for age, left ventricular ejection fraction, mitral regurgitation severity and pulmonary artery systolic pressure, all three expansion indices remained independent predictors of the composite endpoint: HR=2.75 [95% CI, 1.18-6.38], p=0.02 for LAEI, HR=1.86 [95% CI, 1.04-3.31], p=0.04 for RAEI, HR=3.53 [95% CI, 1.46-8.51], p=0.005 for BAEI. BAEI yielded the highest incremental prognostic power (likelihood ratio chi2 test=14, p=0.03) on top of the baseline model consisting of age, left ventricular ejection fraction, mitral regurgitation severity and pulmonary artery systolic pressure (likelihood ratio chi2 test=9). Conclusion In DCM, 3D atrial expansion indices are significantly lower in patients with major adverse events, reflecting a more impaired atrial reservoir dysfunction. Both LAEI, RAEI and BAEI were independent outcome predictors in patients with DCM. Combining the left and right atrial expansion indices might improve risk stratification, since BAEI had the highest predictive value after adjustment for confounders.

Prognostic implications and alterations in left atrial deformation following transcatheter aortic valve implantation for severe aortic stenosis

Abstract Background Left atrial reservoir strain (LARS) as a single parameter estimate of left ventricular (LV) diastolic dysfunction (DD), may provide important prognostic insights into patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI). Purpose To evaluate the prognostic implications of pre- and post TAVI LARS-defined DD (LARS-DD) grade in patients undergoing TAVI for severe AS and its association with new-onset atrial fibrillation. Methods Pre-TAVI LARS-DD was evaluated by speckle-tracking echocardiography and was assigned as grade 0 to 1 (LARS ≥24%), grade 2 (LARS ≥19 to <24%) and grade 3 (LARS <19%). Patients were followed-up for the primary endpoint of all-cause mortality from the date of TAVI. For the secondary endpoint, patients with pre- and post-TAVI LARS measurements, no history of atrial fibrillation and with clinical/ECG follow-up following the post-TAVI follow-up echocardiogram were evaluated for the occurrence of new-onset atrial fibrillation. Results A total of 601 patients (median age 81 [76-85] years, 53% male) undergoing TAVI for severe AS were included. Overall, 169 patients (28%) were LARS-DD grade 0/1, 96 patients (16%) were LARS-DD grade 2 and 336 (56%) were LARS-DD grade 3. Over a median follow-up of 40 (IQR 26 to 58) months, a total of 258 (43%) patients died (Figure 1). In a comprehensive multivariable Cox regression model adjusted for age, sex, EuroSCORE II, New York Heart Association class III to IV symptoms, LV ejection fraction, atrial fibrillation, LA volume index and LV stroke volume index, LARS-DD grade was independently associated with all-cause mortality (adjusted HR 1.28 per one grade increase above LARS-DD grade 0/1, 95% CI 1.07 to 1.53, P=0.007). For the secondary endpoint of new-onset atrial fibrillation, a total of 285 patients were evaluated (Figure 2). On multivariable Fine and Gray regression analyses adjusting for age and LA volume index, post-TAVI LARS (SDHR 1.14 per 1% <20%, 95% CI 1.05 to 1.23, P=0.0009), rather than pre-TAVI LARS (SDHR 1.00 per 1% <20%, 95% CI 0.91 to 1.11, P=0.93) was associated with the occurrence of new-onset atrial fibrillation. Conclusions Increasing LARS-DD grade was independently associated with long-term post-TAVI survival in patients with severe AS and may enhance risk stratification. In addition, post-TAVI LARS, but not pre-TAVI LARS, was closely related to the occurrence of new-onset atrial fibrillation, likely better reflecting intrinsic LA dysfunction.Figure 1:All-Cause MortalityFigure 2:New-Onset Atrial Fibrillation

Effects of empagliflozin on cardio-renal interaction in heart failure with reduced ejection fraction: results from in-vivo experiments and the CINNAMON-study

Abstract Background Heart failure is often accompanied by renal dysfunction, which indicates a pathophysiological connection between the heart and kidneys. Empagliflozin, a SGLT2 inhibitor, showed beneficial effects on both cardiovascular and renal endpoints. Mechanistically, however, it is unclear whether the empagliflozin-dependent renal protection is mediated via the inhibition of renal SGLT2 or rather indirectly via improved cardiac function. Interestingly, in the EMPEROR trials, there was a significant interaction of empagliflozin-dependent kidney protection with systolic contractile dysfunction. We hypothesized that Empagliflozin treatment ameliorates heart failure in response to chronic pressure overload in mice leading to improved renal function. We correlated these findings with data from our prospective, single-armed trial. Methods Transverse aortic constriction (TAC) or sham surgery was performed in C57BL/6J (wildtype, WT) and SGLT2 deficient mice (SGLT2-/-). Animals received either Empagliflozin (10 mg/kg bodyweight) or vehicle by daily oral gavage. Cardiac function was evaluated by echocardiography and kidney function by transdermal FITC-Sinistrin measurement (GFR), urinary albumin/creatinine ratio (UACR) and Siriusred fibrosis staining. Results After 10 weeks, echocardiography confirmed TAC induced pressure-overload, leading to reduced left ventricular ejection fraction (LVEF) and diastolic dysfunction. Empagliflozin attenuated changes in LVEF (Fig. A) and improved diastolic dysfunction (data not shown). Interestingly, at 10 weeks, TAC reduced GFR, increased UACR and tended to increase renal fibrosis, which was attenuated by empagliflozin (Fig. B, C and D). To test if direct inhibition of SGLT2 in the heart and kidney is mechanistically involved, TAC surgery was repeated in SGLT2-deficient mice (SGLT2-/-). In fact, exposure to TAC resulted in comparable reduction of LVEF in SGLT2-/- mice and Empagliflozin prevented this deterioration similar to WT mice (Fig. E vs. A). Surprisingly, Empagliflozin also prevented GFR deterioration 10 weeks after TAC in mice lacking SGLT2 (SGLT2-/-) with comparable magnitude as in WT mice (Fig. F), suggesting that the reno-protective effect of Empagliflozin was independent from renal SGLT2 inhibition. The effect of empagliflozin on the heart and kidney was also investigated in patients with HF (prospective, single-arm CINNAMON-study, DRKS00031101). After 180 days of Empagliflozin treatment (10 mg), there was a significant improvement in LVEF, NT-proBNP levels and KCCQ-12 Scores (Fig. G-I) and the effects on UACR and GFR are subject of investigation. Conclusion This is the first study investigating the role of SGLT2 in Empagliflozin-dependent kidney protection of mice that develop heart failure after TAC. Importantly, empagliflozin treatment prevented deterioration of LVEF and GFR independent of the presence of SGLT2 in mice and improved cardiac markers and quality of life in patients.

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.

Proteomic biomarkers and pathway analysis for progression to heart failure in three epidemiological representative cohorts.

Biomarkers associated with asymptomatic ventricular dysfunction might improve risk stratification and identify pathways leading to heart failure (HF). We explored the association between proteomic biomarkers and left ventricular hypertrophy (LVH), diastolic dysfunction (DD) and incident HF in three population-based cohorts. A chip was used to measure 92 protein biomarkers in blood samples from >1500 Malmö Preventive Project (MPP) participants, of whom 514 had LVH (34%), 462 had DD (32.4%) and, over a median follow-up of 13 (11-14) years, 130 developed HF (7.7%). Findings were confirmed in the STANISLAS (n > 1500, 238 participants with LVH, 76 with DD) and HOMAGE case-control (562 cases of incident HF, 871 controls) cohorts. In multivariable logistic or Cox regression analyses adjusted for age, sex and cardiovascular risk factors, N-terminal pro-B-type natriuretic peptide (NT-proBNP) was associated with LVH, DD and incident HF in all cohorts: MPP (LVH odds ratio [OR] [95% confidence interval] 1.48 [1.28-1.71]; DD OR 1.71 [1.53-1.92]; HF HR 1.98 [1.66-2.36]); STANISLAS (LVH OR 1.20 [1.02-1.41]; DD OR 1.46 [1.12-1.90]); HOMAGE (HF HR 1.85 [1.62-2.12]). Galectin-4, growth differentiation factor 15 and suppression of tumorigenicity-2 were associated with incident HF in MPP and HOMAGE. A pathway enrichment analysis suggested that inflammation and viral infection were related to incident HF. In conclusion, our study reinforces the role of NT-proBNP as a key biomarker for asymptomatic cardiac dysfunction and incident HF, consistent with its established use in clinical practice. This underscores the value of NT-proBNP for identifying patients at high risk for HF, and provides insights into pathways leading to HF and potential therapeutic targets.

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

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.

Exaggerated blood pressure response to submaximal exercise must be considered relative to fitness: strong associations with hypertensive target organ damage

Abstract Exaggerated systolic blood pressure (SBP) during submaximal exercise is associated with increased cardiovascular (CV) risk. However, findings are mixed and new evidence indicates that cardiorespiratory fitness should be considered for proper clinical interpretation of exercise SBP responses. This study aimed to determine the relationship between SBP response to submaximal effort corrected for fitness and abnormalities of cardiac structure and function. Methods Each of 231 participants (age 54±12 years; 53% females) with controlled clinic BP, no evidence for ischemic heart disease, valvular heart disease or heart failure underwent cardiopulmonary exercise testing (Bruce protocol), resting and exercise echocardiography and 24h ABPM. Submaximal exercise SBP (measured at the 2nd stage of Bruce protocol) was corrected for two fitness variables: 1) peak VO2 and 2) maximal workload in METs (SBP/peakVO2 and SBP/METs). Results There were no, or weak, associations with exercise SBP and target organ damage. However, there was a progressive deterioration of cardiac function and structure parameters across the exercise SBP tertiles corrected for fitness (Table 1). Both SBP/peakVO2 and SBP/METs significantly correlated with left ventricular (LV) mass, LV diastolic and systolic, and left atrial parameters (Table 2). ROC analysis revealed good performance of corrected SBP response to submaximal exercise in detection of LV hypertrophy and diastolic dysfunction (AUC 0.792 and 0.808, and 0.771 and 0.802 for SBP/peakVO2 and SBP/METs, respectively; Figure). Conclusions Fitness-corrected SBP responses to submaximal exercise can identify more profound target organ damage with respect to cardiac function and structure even among patients with controlled clinic BP. Exaggerated BP response to exercise must be considered relative to fitness for proper clinical interpretation of BP responses to exercise testing.Figure

The BET inhibitor Apabetalone protects against heart failure with preserved ejection fraction by suppressing myocardial inflammation

Abstract Background Posttranslational histone modifications, play a major role in cardiac hypertrophy and dysfunction. Apabetalone (APA), a selective inhibitor of bromodomain and extraterminal containing protein family (BET) proteins, prevents bromodomain-containing protein 4 (BRD4) interactions with chromatin thus modulating transcriptional programs in different organs. Purpose We sought to investigate whether APA could be beneficial in cardiometabolic heart failure with preserved ejection fraction (cHFpEF). Methods Mice were subjected to high fat diet feeding and L-NAME treatment for 15 weeks to induce cHFpEF. Histology, mouse echocardiography (Vevo3100) and Treadmill exhaustion test were performed. Unbiased gene expression profiling by PCR array and proteomics analysis (Olink) was employed in left ventricular (LV) myocardial specimens from HFpEF mice and control animals. Cultured cardiomyocytes (CMs) treated with palmitic acid (PA) were used as an in vitro model of metabolic stress. cHFpEF mice were chronically treated with the BET inhibitor APA (150mg/kg/day) or vehicle (DMSO). In order to translate our findings to the human setting, passive stiffness of skinned CMs collected from cHFpEF patients was assessed before and after APA treatment. Results HFpEF mice displayed LV hypertrophy, diastolic dysfunction, myocardial fibrosis, lung congestion and impaired exercise tolerance as compared to controls. Interestingly, diastolic dysfunction - assessed by E/A ratio and isovolumic relaxation time (IVRT) - and lung congestion were significantly reduced in HFpEF mice treated with APA, while exercise tolerance was improved. Transcriptomic analysis in PA-treated CMs and LV mouse specimens from cHFpEF mice showed a profound deregulation of genes controlling inflammation, namely IL-6, TNF-alpha, and IL-1beta. ChIP assays showed BRD4 occupancy on the promoter of several inflammatory genes, including IL6. Treatment with APA suppressed most of inflammatory genes, with a pronounced effect on IL6 expression. Moreover, APA reduced circulating levels of several inflammatory chemokines. The beneficial effects of APA were explained by modulation of IL-6/CaMKII/STAT3 pathway both in cHFpEF hearts and PA-treated CMs. In skinned CMs from cHFpEF patients, both APA and IL6 blockade were able to attenuate passive stiffness. Conclusions Our findings set the stage for preclinical studies and exploratory clinical trials testing APA in patients with cHFpEF.

Development of machine learning models for prediction of left ventricular systolic dysfunction in patients with isolated left ventricular dilation

Abstract Background/Introduction Isolated left ventricular dilation (ILVD), in the absence of concomitant LV systolic dysfunction, is a risk factor for new reduction in LV ejection fraction (LVEF) and adverse clinical outcomes. We assessed the performance of different machine learning (ML) models in predicting new reduction in LVEF in patients with ILVD. Methods A retrospective analysis of de-identified patient records in the Tempus Database with at least two transthoracic echocardiograms (TTE) conducted between January 2019 and December 2022 were retrospectively analyzed, with the follow up period ending in January 2023. Inclusion/exclusion criteria are shown in Figure 1A. Briefly, patients with ILVD were defined based on echocardiographic parameters as those with LVEF > 50% and LV end diastolic volume indexed (LVEDVi) > 62 mL/m2 for females and > 75 mL/m2 for males, without prior LVEF < 50% and/or grade 2/3 diastolic dysfunction. The endpoint was LVEF < 40% on future (≥90 days) TTE. Five hard voting ML models and one soft voting ensemble model were trained with data parsed from TTE reports (Figure 1B). Feature importance (SHAP) was calculated, and receiver operating characteristic (ROC) and Kaplan Meier curves evaluated the final model (Figure 1C-E). Results A total of 2,962 patients met the inclusion criteria. The median time from index to last TTE was 578 (IQR = 500) days. LVEF < 40% on follow up TTE was noted in 6% of patients (177 patients, median 478 days to endpoint, IQR = 535 days). Of the six models developed, the ensemble model had the highest ROC area under the curve (0.791, Figure 1D), precision (0.163), F1-score (0.266), and specificity (0.773). The ensemble model also had the lowest predicted prevalence (25.5%), although this was higher than the observed prevalence in the test set (5.7%). Patients predicted to develop LVEF < 40% had a 8.2x higher risk of developing LVEF < 40% within five years of index (p<0.001, Figure 1E). Feature importance showed that male gender, higher heart rate, lower LVEF at index TTE, higher LVEDVi, and lower tricuspid annular plane systolic excursion had the highest mean absolute impact on the model’s output probability (Figure 1C). Conclusion Using only data parsed from the index TTE, ensembling a model for the prediction of developing LVEF < 40% in patients with ILVD and without a history of LV diastolic or systolic dysfunction performed the best. Additional analyses including clinical variables such as comorbidities, symptoms, and medications may improve the model’s performance.