Dilated Cardiomyopathy Research Articles

Prognostic impact of myocarditis as aetiology compared with dilated cardiomyopathy and ischaemic heart disease in heart failure

Abstract Background A subgroup of myocarditis can lead to heart failure. However, whether prognosis of myocarditis-induced heart failure differs from other heart failure remains largely unknown. Aim This study aimed to investigate the prognostic impact of myocarditis induced heart failure compared with heart failure with dilated cardiomyopathy and ischaemic heart disease as causes respectively in the overall population and a propensity score-matched cohort, based on patient-level data from the Swedish Heart Failure Registry (SwedeHF). Methods Patients with heart failure (HF) were enrolled from the SwedeHF (2003-2020) linked with the National Patient Register, and the Swedish Cause of Death Register. Endpoints were all-cause mortality, cardiovascular death, and hospital re-admissions, followed up from the index date until censoring or event. Results Of 54416 patients identified through the SwedeHF with HF, 418 hade myocarditis as aetiology (MC-HF), 6,871 with dilated cardiomyopathy (DCM-HF) and 47127 with ischemic heart diseases (IHD-HF). In general patients with MC-HF have shorter disease duration and less comorbidities compared with DCM-HF and IHD-HF, but older than DCM-HF and younger than IHD-HF. Compared with DCM-HF, MC-HF are associated with 29% higher risk for all cause mortality [(1.29 (1.07 - 1.55), p=0.0079] and 40% higher risk for cardiovascular death [ 1.40 (1.09 - 1.80), p=0.0088], and 19 % higher risk for heart failure rehospitalization [1.19 (1.03 - 1.37), p=0.018] and even higher risk by censoring within one-year . However, compared with IHD-HF, patients with MC-HF have similar risk for all cause mortality [0.95 (0.80 - 1.13), p=0.54], cardiovascular death [0.95 (0.75 - 1.20), p=0.65], and heart failure rehospitalization [0.93 (0.81 - 1.06), p=0.29]. Similar results were obtained from a propensity 1:2 matched cohort. No significant interactions were found regardless of age (< and < 70 years) , sex, LVEF (≥50%, 40-49%, 30-39% and < 30%) for all cause mortality comparing MC-HF vs DCM-HF, and MC-HF vs IHD-HF. Conclusion Patients with myocarditis-induced heart failure have worse outcome than heart failure due to dilated cardiomyopathy, with even higher risk during one year. This finding highlights the importance of early and more effective customized management of patients with myocarditis in particular those with high risk to develope heart failure.

Long-term follow-up of the TRED-HF trial

Abstract Background The TRED-HF trial (1) found that 44% of patients with recovered dilated cardiomyopathy (DCM) relapsed in the short term after withdrawal of medical therapy. The longer-term risk of relapse is uncertain. Purpose This follow-up aims to investigate the longer-term risk of relapse in patients with recovered DCM and any possible predictive factors. Methods TRED-HF trial participants were followed until May 2023. The primary outcome was DCM relapse defined as >10% reduction in left ventricular (LV) ejection fraction to <50%, doubling in N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) to >400ng/L, or clinical recurrence of heart failure (HF). Therapy intensity for HF was calculated using QUAD scores. The incidence of relapse was calculated using Kaplan-Meier estimates. Predictors of relapse were investigated using Cox proportional hazard modelling. Results For all fifty-one patients, median follow-up from enrolment was 6 (IQR: 6-7) years. Overall, thirty-three patients (65%) relapsed with an estimated 5-year relapse rate of 61% (95% CI 45-73). Twenty patients relapsed during the randomised trial, nine of whom had a recurrent relapse during follow-up (Figure 1). Thirteen patients relapsed for the first time after completion of the trial; of those, one patient did not have therapy withdrawn during the trial, 8 had restarted low intensity HF therapy and 4 patients stayed on no therapy. Five patients stayed off HF therapy and did not relapse. The overall mean intensity of HF therapy was lower after the trial compared to enrolment (mean difference in QUAD score -6 [-8 to -4]; p<0.001). A mean reduction in medication intensity was also seen at the point of relapse during the trial and during follow-up (Figure 2). Of relapses during follow-up, seven had identifiable triggers (arrhythmia (n=4), pregnancy (n=1), hypertension (n=1), infection (n=1)). Patients taking more HF medications at baseline or with higher baseline NT-pro-BNP were more likely to relapse. Corrected atrial fibrillation was associated with reduced future risk of relapse. Conclusions In patients with recovered DCM, the risk of relapse after therapy withdrawal increased with longer follow-up. Lower doses of HF medications and recurrent external triggers contributed to relapse. Few patients who stopped medications had sustained remission. Recovery of DCM after correction of AF was associated with a low risk of relapse provided atrial fibrillation did not recur.

Comparison of different non-invasive estimates of right ventriculo-arterial coupling as outcome predictors in dilated cardiomyopathy

Abstract Right ventriculo-arterial coupling (RVAC) has emerged as an outcome predictor in pulmonary hypertension, but its role in left-sided HF remains to be clarified. Different non-invasive estimates for RVAC have been proposed, but a direct comparison of their prognostic ability is lacking. We sought to evaluate RVAC non-invasively using five different methods in a cohort of patients with dilated cardiomyopathy (DCM) and to assess their prognostic role. We enrolled 121 consecutive patients with non-ischemic DCM in sinus rhythm, who underwent comprehensive echocardiography, including speckle-tracking and 3D analysis. They were prospectively followed for 19±11 months for a composite endpoint of death, nonfatal cardiac arrest and hospitalization. RVAC was measured using five non-invasive estimates: (1) as the tricuspid annular plane systolic excursion (TAPSE)/pulmonary artery systolic pressure (PASP) ratio; (2) as the right ventricular (RV) global longitudinal strain (RV-GLS)/PASP ratio; (3) as the longitudinal strain of the RV free wall (LS-RVFW)/PASP ratio; (4) as the 3D RV ejection fraction (RVEF)/PASP ratio; and (5) as the 3D RV stroke volume (SV)/3D RV end-systolic volume (ESV) ratio. Mean age in the study cohort was 59±14 years and the majority (74%) were men. 55 patients (46%) reached the endpoint: there were 27 deaths, 5 nonfatal cardiac arrests and 23 readmissions for heart failure. Patients with adverse outcome had lower TAPSE/PASP (0.42±0.23 vs. 0.62±0.33, p<0.001), lower RVEF/PASP (0.96±0.49 vs. 1.47±0.67, p<0.001), lower RV SV/ESV (0.57±0.20 vs. 0.93±0.29, p<0.001) and higher RV-GLS/PASP (-0.25±0.20 vs. -0.38±0.23, p=0.002) and LS-RVFW/PASP (-0.28±0.30 vs. -0.51±0.33, p<0.001), reflecting greater ventriculo-vascular decoupling. In univariate Cox regression, all three RVAC indices were outcome predictors: HR=0.09 [95% CI, 0.02-0.37], p=0.001 for TAPSE/PASP, HR=13.67 [95% CI, 2.77-67.48], p=0.001 for RV-GLS/PASP, HR=8.72 [95% CI, 3.24-23.45], p<0.001 for LS-RVFW/PASP, HR=0.27 [95% CI, 0.14-0.50], p<0.001 for RVEF/PASP, HR=0.004 [95% CI, 0.001-0.019], p<0.001 for RV SV/ESV. In ROC analysis, the SV/ESV ratio had the highest AUC (AUC=0.88, p<0.001), a value lower than 0.74 having 86% sensitivity and 77% specificity for event prediction. After adjustment for age, NYHA class, left ventricular ejection fraction, and maximal left atrial volume, all coupling indices remained independent predictors of outcome: HR=1.90 [95% CI, 1.01-3.57], p=0.047 for TAPSE/PASP, HR=2.15 [95% CI, 1.17-3.96], p=0.01 for RV-GLS/PASP, HR=2.48 [95% CI, 1.34-4.60], p=0.004 for LS-RVFW/PASP, HR=3.19 [95% CI, 1.19-8.52], p=0.02 for RVEF/PASP, HR=7.50 [95% CI, 3.47-16.22], p<0.001 for RV SV/ESV. In DCM, RVAC is significantly more impaired in patients with major adverse events. Non-invasive RVAC was an independent predictor of adverse outcome irrespective of the formula used for estimation, but 3D RV SV/ESV ratio had the greatest prognostic power.

Relationships between 18-month kinetics and functional capacity and left ventricular remodeling and cardiac fibrosis in dilated cardiomyopathy

Abstract Introduction Myocardial fibrosis is a primary pathogenetic process in dilated cardiomyopathy (DCM) that is responsible for progressive cardiac remodeling and functional capacity impairment. We sought to verify whether there were differences between 18-month kinetics of functional capacity and left ventricular remodeling in DCM patients with different types and advancement of fibrosis who were up-titrated with guideline directed pharmacotherapy (GDMT). Methods Between May 2019 and September 2020, 99 DCM patients (88 male, mean age 45.2 ± 11.8 years, mean EF 29.7 ± 10%) underwent cardiac magnetic resonance with assessment of replacement fibrosis via late gadolinium enhancement (LGE) and interstitial fibrosis via extracellular volume (ECV). Each patient had serial (baseline, 6-, 12-, 18 month) functional assessment: NYHA class and 6- minute walking test (6-MWT) and follow-up echocardiography, including measurement of left ventricular end-diastolic volume (LVEDvol) and ejection fraction (EF). Patients were divided into LGE-negative and LGE-positive groups, whereas based on median ECV – they were divided into those with ECV below and above median values. Results Overall, LGE was identified in 44 (44%) of patients, whereas median ECV was 27.7%. NYHA class was significantly worse in patients with LGE (1.5±0.5 vs. 1.9±0.6) and with higher ECV (1.93±0.6 vs. 1.6±0.5) in comparison to those without LGE and lower ECV. However, NYHA class improved during observational period in all groups. There were no differences in 6-MWT distance in LGE positive and negative groups at all time points. Baseline 6-MWT distance in LGE positive group was 494.2±88.2 vs. 453.9±98.8 meters in LGE negative group. Baseline 6-MWT distance in upper median ECV group was (408.8±103.5 vs. 492.4±92.9 meter) was significantly lower ECV group (p=0.03). During 18 months 6-MWT distance increased only in LGE negative group but in both ECV groups (Figure 1 A-D). There were no differences in EF between patients with and without LGE and also with higher and lower ECV. Baseline EF in LGE positive group was 27.4±11.2% and 31.7±10.6% in LGE negative. Baseline indexed LVEDvol in LGE positive group was 107.7±40.7 vs. 91.8±37.8 ml/m2 (p=0.09) in LGE negative group. EF increased significantly in both groups, whereas indexed LVEDvol decreased only in LGE negative group (Figure 2 A-D). Conclusions Regardless of the presence of replacement and to some extent of interstitial fibrosis, functional and cardiac morphological improvement was observed during 18 months observation in DCM patients on GDMT. The greatest improvement occurred during the first 3 (occasionally 6) months which was associated with the greatest escalation of GDMT. Further dose escalation was not associated with a significant improvement in both functional and morphological parameters.

The essential role of the miRNA-208a/TARBP2/Sox6 axis in myosin expression in the end stage human heart failure

Abstract Despite diverse aetiologies, failing human hearts (HF) of various origins (coronary artery disease (CAD), dilated cardiomyopathy (DCM), restrictive cardiomyopathy, and hypertrophic cardiomyopathy (HCM)) exhibit impaired contractility and share alterations in MYH6, MYH7, and MYH7B gene expression. Here, we explore the miRNA-208a/TARBP2/Sox6 axis in regulating myosin expression within left ventricles of explanted human hearts. Methods Samples of left ventricles were obtained from explanted hearts of patients with terminal HF (NYHA III-IV) and reduced left ventricle ejection fraction (LVEF <25%) due to CAD (n=10), DCM (n=10), HCM (n=6), and controls (n=5). We analysed the expression of cardiac myosin heavy chains (MYH6, MYH7, MYH7B), cardiac damage markers (ANP, BNP), and heart-related MyoMiRs using quantitative real-time PCR. Results Pre-transplant data for the 31 subjects (25 male, 3 female) included: age 54.4±8.2y, BP 112±18/67±11 mmHg, HR 79±16 min-1, LVEF 27±14%, LVEDD 8.8±15.8mm, RVEDD 32.8±5.1mm, QRS 0.140±0.05s, QT 0.42±0.04s, NT-proBNP 5551±4259 ng/l. In all diseased groups, MYH6 mRNA was downregulated, while MYH7 and MHRT ncRNA were upregulated. We observed strong positive correlations between MYH7, MYH7B, and MHRT transcription, suggesting coordinated expression. The miRNA-208a/miRNA-208b ratio shifted heavily towards miRNA-208b in controls, with a similar effect for miRNA-499 and MYH7B. A strong negative correlation existed between miRNA-499 and MYH7B expression across HF samples. TARBP2 expression decreased slightly in all pathological groups, while Sox6 mRNA increased. Conclusion Elevated Sox6 expression may contribute to MYH6 downregulation and MYH7/MYH7B upregulation. Altered TARBP2 expression could promote cardiomyopathy via Sox6-mediated repression of cardiac slow-twitch myofiber proteins. Changes in miRNA-208a processing leading to Sox6 upregulation may inhibit Sox6-dependent myosin transcript expression.

Pathogenic cardiomyopathy gene variants inform prognosis in atrial fibrillation: results from exome sequencing in over 17,000 patients in TIMI trials

Abstract Background Rare genetic variants in cardiomyopathy genes are associated with risk of atrial fibrillation (AF), even in the absence of overt ventricular dysfunction. Data on clinical outcomes for rare genetic variant carriers among patients with AF remain sparse. Purpose We aimed to study the prognostic implication of rare pathogenic/likely pathogenic (PLP) variants for dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) in patients with AF from large, well-phenotyped randomized clinical trials. Methods and results Rare variants were called using exome sequencing data in 5 large clinical trials from the TIMI study group (ENGAGE-AF, FOURIER, SAVOR, PEGASUS, DECLARE). PLP variants for cardiomyopathy were identified using phenotype- and gene-specific curation of protein-truncating variants and high-confidence variant classifications from the ClinVar database. In 17,190 patients with a history of AF, we identified 421 (2.4%) PLP variant carriers (age 67±10, 35% women) and 16,769 (97.6%) pts without PLP variants (age 70±9, 36% women). Among these individuals, we identified 265 DCM carriers (1.5%), 106 (0.6%) HCM carriers and 54 (0.3%) ARVC carriers. In this cohort, 9,275 (54%) had a history of heart failure (HF) and 2,991 (17.4%) prior ischemic stroke. Over 2.5 years median follow-up, 1,365 pts (7.9%) were hospitalized for HF, 599 (3.5%) had an ischemic stroke, and 1147 (6.7%) died of cardiovascular causes. In logistic regression analyses adjusting for age, sex, trial, and principal components of ancestry, PLP variants were significantly associated with a history of HF (OR 1.66, p<0.0001), most notably for DCM variants (OR 1.97, 1.48-2.62, p<0.0001). PLP variants were independently associated with incident HF admissions (adj HR 1.75, 1.39-2.29, p<0.0001), most notably for HCM (adj HR 2.59, 1.68-3.99, p<0.0001) and ARVC variants (adj HR 2.50, 1.34-4.66, p=0.004). The increased risk of HF admissions remained consistent in patients with (adj HR 1.49, 1.11-2.00, p=0.009) and those without (adj HR 1.88, 1.00-3.54, p=0.049) a history of HF. PLP variants were also associated with higher risk of cardiovascular death (adj HR 1.46, 1.06-2.02, p=0.02), most notably for DCM variants (adj HR 1.77, 1.21-2.58, p=0.003). In contrast, PLP variants were not associated with history of ischemic stroke at baseline (adj OR 0.99, p=0.96) nor with incident ischemic stroke (adj HR 0.95, p=0.84). Conclusion In patients with AF, rare cardiomyopathy gene variants are associated with increased risks of HF and of cardiovascular death, but not stroke. These results, collected from large well-phenotyped randomized clinical trials, demonstrate an important prognostic implication for rare genetic variants for CMP in pts with AF.

Subclinical myocardial phenotype in genotype-positive relatives attending clinical and genetic screening for familial dilated cardiomyopathy

Abstract Aim To investigate if asymptomatic relatives carrying genetic variants associated with familial dilated cardiomyopathy (DCM) show early signs of myocardial disease assessed by echocardiography. Methods and Results Asymptomatic relatives without a DCM-phenotype (n=176, 46% males, mean age 39 years ± 16) of 111 DCM index patients carrying likely pathogenic or pathogenetic variants in TTN, RBM20, and FLNC genes were recruited from two tertiary referral centers for inherited cardiac diseases. All participants underwent echocardiographic examinations focusing on left ventricular (LV) ejection fraction (LVEF), LV global longitudinal strain (LVGLS), and LV end-diastolic diameter (LVEDD), with operators blinded to genetic results. The participants were grouped into genotype positive ([G+], n=82) or genotype negative relatives ([G-], n=94) carrying or not carrying the disease-causing variant. The G+ group had significantly lower systolic LV parameters compared to G- individuals with a mean LVGLS of -18.7% ± 2.4 versus -20.1% ± 2.8, p: 0.0029; and a mean ejection fraction of 57.8% ± 3.7 versus 59.7% ± 2.4, p: <0.0001. The proportion of G+ individuals with an abnormal LVGLS (defined as less than -18%) was 46% compared to 18% in the G- group. 26 % of G+ individuals had an LVEF in the interval between 50 - 55% compared to of 5% G- individuals[MOU1] . Mean LVEDD did not differ significantly between G+ and G-groups (49.7 mm ± 4.9 versus 48.8 mm ± 4.7). However, LVEDD indexed to BSA were significantly increased in G+ individuals (26.7 mm/m2 ± 2.8 versus 25.4 mm/m2 ± 2.5, p-value 0.001). Conclusion Overall, the absolute mean values of LVGLS, LVEF, and LVEDD were within normal ranges in both G+ and G- groups of individuals. However, compared to non-carrier relatives, almost half of the asymptomatic G+ DCM relatives had signs of subclinical myocardial dysfunction with significantly lower values of LVGLS, LVEF, and larger left ventricular dimensions.

Dynamic changes of excessive trabeculation in dilated cardiomyopathy: a longitudinal cardiovascular magnetic resonance study

Abstract Background A portion of dilated cardiomyopathy (DCM) patients present with left ventricular (LV) excessive trabeculation at diagnosis. It remains unknown if the extent of trabeculation would be reduced after guideline-directed medical therapy (GDMT). Purpose To investigate the dynamic change of excessive trabeculation after GDMT in patients with DCM, and its relationship with that in LV structure and function. Methods A group of DCM patients with baseline and follow-up cardiovascular magnetic resonance (CMR) examination after 1-2 years of GDMT were enrolled. Trabeculation was assessed by Petersen method as measuring the thickness of the most prominent non-compacted (NC) layer and the corresponding compacted (C) segment at the apical long-axis view at end-diastole. Excessive trabeculation was defined as the NC/C ratio > 2.3, and a regression was reached if it decreased to ≤ 2.3. Major adverse cardiovascular events (MACE) consisted of cardiovascular death, heart transplantation, and heart failure readmission. Results Among 218 DCM patients (45 ± 14 years, 67.4% male), 58 (26.6%) met the excessive trabeculation criteria at baseline. Despite a similar LV ejection fraction (LVEF), patients with excessive trabeculation had a higher LV end-diastolic dimension (73.3 ± 9.0 vs. 70.5 ± 8.0mm) and native T1 (1325.3 ± 71.2 vs. 1305.5 ± 65.9mm) (both p<0.05) with a trend of more late gadolinium enhancement (51.7% vs. 39.4% of patients). After 15 months of GDMT, patients with excessive trabeculation (n=58) showed a decreased NC layer (12.7 ± 3.4 vs. 11.3 ± 3.0 mm) and NC/C ratio (3.1 ± 0.9 vs. 2.7 ± 0.9) (both p < 0.05), 25.9% of whom showed a regression of trabeculation. Patients with the regression had a lower NC/C ratio (1.8 ± 0.4 vs. 3.0 ± 0.8, p < 0.001) and LV end-diastolic volume index (LVEDVi) (121.5 ± 40.5 ml/m2 vs. 165.9 ± 67.8ml/m2, p=0.004) compared with those without. The change of (△) NC/C ratio was associated with that of LVEDVi (r = 0.323), and LVEF as well (r = -0.254) (both p < 0.001). Excessive trabeculation at baseline did not differentiate patients with a higher risk of MACE by Kaplan-Meier survival curve (p= 0.208), but its persistent presence at follow-up did (p= 0.004). However, when put △NC/C ratio, △LVEDVi, △LVEF and In NT-proBNP into multivariate cox regression model, only the △LVEDVi (HR, 0.963; 95% CI: 0.942, 0.985; P = 0.001) and In NT-proBNP (HR, 2.016; 95% CI: 1.288, 3.157; P = 0.002) were independent predictors of MACE. Conclusions Regression of excessive trabeculation occurred after GDMT in DCM patients that was related somewhat to LV reverse remodeling and not an independent predictor of MACE. It may also indicate the interconnection between LV remodeling and trabeculation.

Cardiac sympathetic innervation, assessed with 123I-MIBG SPECT, predicts left ventricular function improvement in patients with newly diagnosed dilated cardiomyopathy

Abstract Introduction Beta-blockers (BB) are commonly prescribed medications for heart failure (HF) due to their ability to counteract the increased sympathetic nervous system (SNS) activity seen in HF, resulting in downregulation and desensitization of β-receptors. In patients with dilated cardiomyopathy (DCM), the introduction of BB therapy can lead to left ventricular ejection fraction (LVEF) improvement in 30-50% of cases. Single-photon emission computed tomography (SPECT) with 123I-meta-iodobenzylguanidine (MIBG) is a useful tool for assessing cardiac SNS activity. Healthy individuals typically exhibit high SPECT-MIBG uptake and low washout rate (WR) due to normal β-receptor levels and low norepinephrine (NE) levels, respectively (Fig 1A). While better SPECT-MIBG results have been associated with LVEF improvement in the general HF population, less data is available for DCM patients. Purpose This study aimed to evaluate the predictive value of MIBG-SPECT for LVEF improvement in newly diagnosed DCM patients. Methods Twenty-one DCM patients (mean age 47 ± 10 years, 90% male, baseline LVEF 29.5 ± 8.7%, left ventricular end-diastolic volume (LVEDV) 114 ± 36 ml/m2) with stable HF symptoms (NYHA class 1.8 ± 0.6) and newly diagnosed DCM underwent baseline MIBG-SPECT and echocardiography. HF therapy was initiated and up-titrated, and echocardiography was repeated at 6 months. Semi-quantitative parameters from MIBG-SPECT, including the MIBG uptake ratio from the heart and mediastinum (H/M) at 15 minutes (-15) and 4 hours (-4), as well as the WR [WR = (H/M-15 - H/M-4) / H/M-15], were evaluated. Patients were stratified based on median WR - 8.79 (IQR 5.17-12.90). Results After 6-months of HF therapy up-titration, 18 patients improved LVEF, and the mean LVEF increase was 7.7 ± 10.4%. Although, patients with WR > median did not differ in terms of baseline LVEF (30.2 ± 7.0 vs. 27.7 ± 9.6, p=0.52), they had worse LVEF at 6 months (32.0 ± 11.0 vs. 40.6 ± 9.2%, p=0.04). Moreover, WR at baseline strongly correlated with 6-month LVEF (R=-0.51, p=0.01) and was a significant predictor of 6-month LVEF (β=-0.55 ± 0.19, p=0.009). Moreover, WR could successfully predict LVEF improvement ≥ 10% (OR 1.27 [95%CI 1.01-1.61], p=0.03; AUC 0.82 [95%CI 0.63-0.99], p<0.001) with a cut-off point of 8.0 (sensitivity 88%, specificity 77%) (Fig 1B). Conclusion Most DCM patients demonstrated LVEF improvement during 6 months of HF therapy up-titration. Baseline WR from MIBG-SPECT was found to be a reliable predictor of significant LVEF improvement in this patient population.Fig1.A-SPECT-MIBG results. B-ROC curve.

The dynamic increment of epicardial adipose tissue is associated with reverse remodeling after guideline-directed medical treatment in dilated cardiomyopathy patients

Abstract Background/Introduction Epicardial adipose tissue (EAT) accumulation is associated with adverse prognosis in patients with HFpEF and a better prognosis in HFrEF patients. Whether EAT is playing a protective role in dilated cardiomyopathy (DCM) patients have been described sparingly. Purpose Aim to explore whether the epicardial fat would change along with the dynamic changes in cardiac function and volumes after receiving guideline-directed medical therapy (GDMT) in patients with DCM. Methods We prospectively enrolled 232 DCM patients who underwent complete baseline and follow-up Cardiac magnetic resonance (CMR) examinations. The measurement of the epicardial fat composition includes epicardial fat thickness, paracardial fat thickness, and paracardial fat volume, while the measurement of body fat composition includes subcutaneous and visceral abdominal fat, while We used univariable and multivariable logistic regression to evaluate the association between different body and cardiac fat depots with the changes in bi-ventricular structure (delta indexed EDV) and function (delta EF). Results The study included 232 patients (mean age 46.1±14.1 years, 157 (67.7%) males). After GDMT, we found that the visceral fat thickness and EAT (thickness and volume) tend to significantly increase. The increase in the (left ventricular reverse remodeling) LVRR group was significantly higher compared with the non-LVRR group. Independently with the changes of BMI and body fat depots, the increment of EAT was associated with the improvement in bi-ventricular function and volumes (significantly positively correlated with the improvement of LVEF (r = 0.499, p < 0.001), and RVEF (r = 0.482, p < 0.001), negatively correlated with delta LVEDVi (r = -0.407, p < 0.001), delta RVEDVi (r = -0.305, p < 0.001)). Conclusions After GDMT, the increment of EAT was positively correlated with the improvement of bi-ventricular structure and function, independent of the changes in BMI and body fat depots.Graphic Abstract

Exome sequencing in over 63,000 patients in TIMI trials uncovers pathogenic cardiomyopathy variant carriers with high risk for heart failure and cardiovascular death

Abstract Background Rare genetic variants predisposing to cardiomyopathy (CMP) confer increased risk for adverse events. The prevalence of CMP variants in contemporary cardiovascular (CV) trials and their association with prevalent heart failure (HF) and incident HF hospitalizations (HHF) is not established. Purpose We aimed to identify carriers of rare pathogenic/likely pathogenic (PLP) variants for dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) in well-phenotyped clinical trial cohorts and to evaluate their prognostic significance. Methods Rare variants were identified from high-quality exome sequencing data from 5 large clinical trials (ENGAGE AF-TIMI 48, SAVOR-TIMI 53, PEGASUS-TIMI 54, DECLARE-TIMI 58, FOURIER (TIMI 59)). Putatively pathogenic variants for cardiomyopathy were identified using phenotype- and gene-specific curation of protein-truncating variants and high-confidence variant classifications from ClinVar. We conducted logistic regression for prevalent disease and Cox proportional hazard models for incident HHF, both adjusted by age, sex, trial, and first 10 principal components and using those without CMP variants as the reference. Sensitivity analysis by history of HF at baseline was performed for prospective outcomes. Results In 63,700 participants, we identified 866 CMP variant carriers of which 518 identified as DCM carriers (age 65±9 yrs, male 66%), 194 HCM carriers (65.5±9 yrs, male 69%), and 125 ARVC carriers (66±9 yrs, male 77%). Out of the 518 DCM variant carriers, 402 had a PLP variant in TTN. DCM variant carriers had higher odds of history of HF (Odds ratio [OR] 1.94, 1.57-2.39, p<0.0001) whereas this was not observed for HCM variant carriers (OR 1.18, 0.85-1.65, p=0.33) or ARVC variant carriers (OR 1.23, 0.80-1.90, p=0.35). Over a mean follow-up of 2.5 years, the rate of HHF was significantly higher for DCM variant carriers (Hazard ratio [HR] 1.58, 1.14-2.20, p=0.006), HCM variant carriers (HR 2.78, 1.87-4.13, p<0.001), and ARVC variant carriers (HR 1.89, 1.02-3.53, p=0.04). These associations were, if anything, stronger in patients without HF at baseline (HR 2.06, 1.30-3.25) than in patients with HF at baseline (HR 1.48, 1.12-1.95). DCM variant carriers also had a higher rate of CV death (HR 1.50, 1.05-2.12, p=0.02), which was not observed for HCM (HR 1.10, 0.57-2.11, p=0.78) or ARVC (HR 0.35, 0.09-1.41, p=0.14) variant carriers. Conclusion In 5 contemporary CV trials, CMP variant carriers have an increased rate of HHF, while DCM variant carriers also have a higher rate of CV death. These findings motivate better identification of these high-risk individuals and the incorporation of genetic testing in CV trials.

Larger QRS but better hemodynamic function after high output His bundle pacing in patients with heart failure and narrow QRS. A paradox or a new concept?

Abstract Background QRS duration is an important factor in determining Cardiac Resynchronisation Therapy (CRT) response and a useful surrogate for electromechanical dyssynchrony. However, we don’t have studies confirming this concept in conduction system pacing. Purpose We performed His Bundle Pacing (HBP) with high output (3.5V/1msec) in HF patients with dilated or ischemic cardiomyopathy and narrow QRS to evaluate hemodynamic benefit independent of the QRS duration or AV delay shortening. Methods 14 patients with dilated (7 patients) or ischemic (7 patients) cardiomyopathy (EF<35%) and narrow QRS (<120ms) were referred for implantation of a defibrillator. We implanted an ICD- HBP system, and we collected clinical, echocardiographic, and electrocardiographic data. Results We obtained HBP in all 14 patients successfully. PQ after implantation was shorter from 172±48 to 143±16 (P=0.048) so as to pace the ventricle. Baseline QRS duration increased after pacing from 110±15 to 123±16ms (P=0.008) as measured by ECG analyzer. Despite this increase in QRS duration basal mean EF increased from 30±4% to 46±10% (P<0.001) after a median follow-up of 17 months. Left ventricular end-diastolic diameter and left ventricular end-diastolic volume decreased from 62±5 to 57±5mm (P=0.013) and from 195±69 to 126±27ml (P<0.001), respectively. Left ventricular end-systolic volume decreased from 139±58 to 69±27 (P<0.001). TAPSE increased from 19±4 to 27±4. NYHA class decreased by one class in every patient after only one month. HBP threshold was 1.05V±0.7/1msec and raised to 1.33±0.93/1msec (due mainly to 2 patients with very high threshold). The impedance was 588±109 and decreased to 484±69 Ohms. R-wave at implant was 3.2±1.8mV. In 2 out of 14 patients, threshold increased but was still less than 3.5V/1msec. Conclusions HBP in HF patients with dilated or ischemic cardiomyopathy and narrow QRS improves hemodynamic function in right and left ventricle and decreases NYHA class. This benefit appears to be produced by a higher stimulation output despite a larger QRS after pacing. We exclude that a very short AV delay could be favorable, by measuring acute EF changes only after increasing the pacing output without AV delay modifications. To our knowledge these are the first cases of beneficial HBP in HF patients with narrow QRS. Interestingly, larger QRS corresponds to higher EF in patients with high output HIs Bundle Pacing.

The myocardium of human dilated nonischemic cardiomyopathy harbors unique tissue-resident lymphocyte subsets

Abstract Purpose The etiology of dilated nonischemic cardiomyopathy (NICM) is often unclear, but thought to be multifactorial, involving an interplay between genetic factors and direct myocardial damage caused by infection, autoimmunity, or toxins. Tissue-resident lymphocytes are non-circulating immune cells which are retained within various tissues and play integral roles in maintaining homeostasis, responding to infection, regulating inflammation, and mediating tissue repair. Despite their likely involvement in various cardiac pathologies, the presence of tissue-resident lymphocytes in the human heart has not yet been well-characterized, neither in health nor in disease. Methods Human left ventricular tissue and paired peripheral blood samples were obtained from six adult organ donors with normal heart function who died of noncardiac causes and from the explants of six adult patients with end-stage nonischemic cardiomyopathy. Heart tissue was processed using mechanical and enzymatic digestion. Mononuclear cells were isolated from both heart and paired blood by density centrifugation. Isolated mononuclear cells were surface stained with an antibody cocktail and interrogated using multidimensional flow cytometry. Results The adult human heart contains a diverse immune cell population (Fig 1A). Both healthy and NICM cardiac lymphocytes express distinct phenotypic profiles which resemble those of resident lymphocytes found across various tissues, distinct from those isolated from paired blood. Frequencies of effector memory T (Tem) cells (CD45RA- CCR7-) were higher in heart than in blood among both CD4+ and CD8+ T-cells. In heart compared to blood, significantly more Tem expressed CD69, a canonical marker of tissue-resident memory T (Trm) cells (Fig 1B). Cardiac Trm, especially CD8+ Trm, expressed classical Trm signature markers including integrins CD103 (epithelial binding) and CD49a (collagen binding). NICM Trm expressed more CD49a than healthy heart Trm (Fig 1C). NK-cells also demonstrated higher CD69 expression (trNK) in heart than in blood, with associated expression of CD103, CD49a, and CXCR6 (Fig 1D). Compared to healthy hearts, NICM trNK were predominantly CD56bright/CD16- (Fig 1E and 1F) and expressed less CD57 (Fig 1D), overall indicating a less mature state with lower cytotoxic potential. Confocal imaging of cardiac tissue revealed CD69-expressing tissue-resident lymphocytes within the cardiac interstitium. Conclusions The adult human heart contains diverse populations of lymphocytes which express canonical markers of tissue residency, similar to lymphocytes resident in other tissues. Compared to healthy hearts, NICM hearts have more CD49a+ Trm, perhaps related to greater fibrosis, and also harbor a distinct subset of immature tissue-resident NK cells which may shed light on pathophysiology. Future work is focused on better exploring the functional phenotypes of these resident cells and better localizing them within the myocardium.FA - Figure 1

Proteogenomic analysis in population biobanks identifies new therapeutic targets across heart failure subtypes

Abstract Background Heart failure (HF) represents a multifactorial clinical syndrome with differential response to existing therapies across its subtypes. Proteogenomic analysis of genetic variants associated with changes in circulating protein level and risk of heart failure subtypes provides an opportunity for a systematic identification of proteins with subtype-specific causal effects as novel therapeutic targets. Purpose To identify proteins as potential therapeutic targets for specific heart failure subtypes by leveraging proteomics and genomics data in population biobanks. Methods We evaluated the causal effects of 2,773 proteins on 5 HF-related outcomes, including overall HF, non-ischaemic HF (ni-HF), ni-HF with reduced / preserved ejection fraction (ni-HFrEF / ni-HFpEF), and dilated cardiomyopathy (DCM). For each protein-phenotype pair, we performed a two-sample Mendelian randomisation (MR) analysis using protein-specific genetic association estimates derived from protein quantitative trait locus (pQTL) studies in 114,145 individuals from deCODE, UK Biobank, Fenland study, and SCALLOP consortium and genome-wide association studies (GWAS) of HF outcomes in 145,795 individuals by HERMES Consortium. We further prioritised candidate protein targets based on replication of results across datasets, model parameters, assays, and colocalization of causal genetic variants. Finally, we profiled the causal effects of identified proteins on 32 related cardiac traits and risk factors to explore potential mechanisms of actions and on-target side effects. Results We identified 493 proteins associated with at least one HF outcome at a false discovery rate (FDR) < 1% in the primary MR analysis. We further prioritised 44 proteins with concordant effect direction across datasets, model parameters, and assays or colocalization in at least one dataset. All 44 identified proteins showed cross association with at least one of 35 tested traits other than HF or cardiomyopathies at FDR <1%, including coronary artery disease (18 proteins), body mass index (11 proteins), type 2 diabetes (6 proteins), systolic / diastolic blood pressure (13 proteins), and chronic kidney disease (9 proteins). Conclusion We characterised the causal associations of 2,773 circulating proteins across HF-related outcomes and prioritised 44 proteins by integrating proteomics and genomics data in population biobanks. These findings extend our understanding of the molecular mechanism underlying different forms of HF and may inform the development of new therapeutic strategies.Study design

Unraveling anesthetic challenges of a patient with dilated cardiomyopathy posted for lower limb amputation surgery -A case report

This case report details the anesthetic management of a 64-year-old male with dilated cardiomyopathy (DCM) and a significantly reduced ejection fraction, undergoing lower limb amputation for peripheral arterial disease. Managing anesthesia in such patients poses considerable challenges due to the complexities associated with congestive heart failure. The successful administration of general anesthesia in this case can be attributed to a rigorous preoperative assessment and a meticulously devised anesthetic plan. The systematic approach included careful monitoring, fluid management, and the use of specific anesthetic agents that minimize cardiovascular stress, thereby ensuring an uneventful anesthetic course. This report emphasizes the importance of strategic planning and expert execution in the anesthesia management of patients with severe cardiomyopathy undergoing major surgical procedures.

Locally increased dysferlin expression improves left-ventricular function by stabilizing membrane nanodomains of cardiomyocytes in the myocardial infarction border zone

Abstract Introduction Dysferlin, a transmembrane protein with multiple Ca2+-binding C2-domains, is expressed in the sarcolemma and vesicle membranes of striated muscle cells. Upon Ca2+ entry, Dysferlin is thought to mediate vesicle fusion and membrane repair events in order to rapidly seal sarcolemmal lesions. Dysferlin mutations are associated with progressive muscular dystrophies and dilated cardiomyopathy. However, the precise role of Dysferlin in protection of membrane nanodomains in ventricular myocytes (VMs) after myocardial infarction (MI) remains elusive. Purpose We hypothesized that Dysferlin is crucial to prevent VMs from loss-of-function and cell death by stabilizing membrane nanodomains like the transverse-axial tubule (TAT) system and the intercalated disc (ICD) cell-cell contact sites post-MI. Methods and Results 1 week post-MI induced by LAD artery ligation, investigator-blinded echocardiography revealed increased infarct sizes and decreased left-ventricular (LV) ejection fraction of Dysferlin-knockout (KO) vs. WT mice (mean±SEM: 21±2 vs. 28±2%, n=20/30 mice, P<0.05). Immunoblotting of WT LV tissue lysates showed an upregulated Dysferlin expression to 148% compared to sham-operated controls. Importantly, immunohistology identified a maximal Dysferlin expression of 230% in the MI border zone that faces a high ischemic and mechanical stress. Hence, we used data-independent mass spectrometry (DIA-MS) to analyse the proteomic profile of the infarction zone, border zone and remote zone from WT vs. KO hearts 1 week post-MI (each n = 5 mice). Overall, we reproducibly quantified 4360 proteins across all LV samples, identifying local genotype-specific proteotypes post-MI. In WT vs. KO samples, DIA-MS revealed 725 differentially abundant proteins in the zone pairwise comparison, highlighting a vital role of Dysferlin for LV remodelling post-MI. In addition, superresolution stimulated emission depletion (STED) microscopy was applied to study the subcellular localization and function of Dysferlin in the MI border zone. Here, we observed VMs with disrupted TAT endomembrane networks and significantly extended ICD regions. Interestingly, STED imaging revealed Dysferlin clusters that highly decorated residual TAT structures and interdigitated ICD membrane folds in the MI border zone. DIA-MS analysis of anti-Dysferlin co-imunoprecipitation experiments from WT vs. KO LV tissues characterized the cardiac interactome of Dysferlin, confirming interactions with proteins of the TAT system and the gap junction hemichannel Connexin-43. Conclusions Our data demonstrate Dysferlin as an endogenous membrane repair protein necessary to stabilize sarcolemmal nanodomains in the MI border zone. Dysferlin not only prevents from loss of TAT structures, but also compensates for increased mechanical stress at the ICDs. Hence, Dysferlin emerges as a novel therapeutic target to control membrane integrity in VMs to prevent from loss-of-function and cell death post-MI.

Changes in blood metabolomes as potential biomarkers for severity and prognosis in doxorubicin-induced heart failure: a study in HER2-positive and HER2-negative breast cancer patients

Abstract Background The use of doxorubicin for breast cancer treatment is often limited due to cardiotoxicity. Doxorubicin was shown to cause the alterations of cardiac metabolome levels in doxorubicin-treated rats. Interestingly, these changes were robustly associated with the development of doxorubicin-induced heart failure. Unfortunately, measurements of cardiac metabolome levels are rarely possible in humans. Hence, non-invasive biomarkers as representatives of doxorubicin-induced heart failure are required in clinical research and practice. Human epidermal growth factor receptor 2 (HER2) is a point of interest in breast cancer treatment. HER2 is associated with tumor aggressiveness. However, it was observed that HER2 protected against systemic oxidative stress and dilated cardiomyopathy. Therefore, we hypothesized that the alterations of blood metabolome levels and cardiac functions following doxorubicin treatment were different between HER2-positive and HER2-negative breast cancer patients. Purpose We determined the potential roles of changes in blood metabolomes as severity and prognostic markers of doxorubicin-induced heart failure. In addition, the changes in blood metabolomes and cardiac parameters following doxorubicin treatment in HER2-positive and HER2-negative breast cancer patients were compared. Methods HER2-positive (n=37) and HER2-negative (n=37) breast cancer patients were enrolled. Echocardiography, heart rate variability, and blood collection were performed at baseline and 2 weeks after completion of doxorubicin treatment in all patients, as well as at 3 months after completion of doxorubicin treatment in HER2-negative breast cancer patients. Blood obtained at all 3 time points was processed for measuring cardiac injury markers. Blood obtained at baseline and 2 weeks after completion of doxorubicin treatment was also processed for measuring oxidative stress in peripheral blood mononuclear cells using flow cytometry and 85 metabolome levels in plasma using mass spectrometry-based targeted metabolomics. Results Cardiac injury and systolic dysfunction at 2 weeks after completion of doxorubicin treatment were comparable between HER2-positive and HER2-negative breast cancer patients. However, only HER2-negative breast cancer patients exhibited increased systemic oxidative stress and cardiac autonomic dysfunction at this time point. Moreover, 33 and 29 blood metabolomes were altered at 2 weeks after completion of doxorubicin treatment in HER2-positive and HER2-negative breast cancer patients, respectively (Figure). Interestingly, the changes in most of these metabolomes were correlated with the changes in cardiac parameters, both at 2 weeks and 3 months after completion of doxorubicin treatment (Figure). Conclusions The changes in blood metabolomes following doxorubicin treatment were dependent on HER2 status, which might be served as severity and prognostic markers of doxorubicin-induced heart failure.

Identification and validation of circulating microRNAs as biomarkers for heart failure with preserved ejection fraction

Abstract Background Heart failure (HF) is a syndrome due to cardiac insufficiency, manifested by excessive volume overload, increased sympathetic activity, and circulatory redistribution [1]. Heart failure with preserved ejection fraction (HFpEF) accounts for approximately 40%-50% of the total HF events, and its development is often accompanied by various complications, including hypertension, obesity, and metabolic syndrome. Biomarker associations in heart failure with reduced ejection fraction were mostly cardiac stretch based, while many biomarkers of HFpEF are also associated with inflammation [2]. To date, treatments that effectively improve the clinical prognosis of HFpEF are relatively limited, thus HFpEF remains one of the challenges that needs to be further explored. A full understanding of the molecular mechanisms of HFpEF is essential to improve the early diagnosis, treatment and prognosis of these patients. Purpose The study aims to explore key circulating miRNAs and related molecular pathways in HFpEF patients through bioinformatics analysis and machine learning, and to further validate them using a double-hit HFpEF mouse model. Methods We downloaded HF datasets including circulating miRNA expression profiles from the GEO database. LASSO regression, SVM-RFE, Random Forest and XGboost algorithm were conducted to identify key miRNAs for diagnostic model construction. We used R software, GO, KEGG and Cytoscape to better understand the functions of key miRNA targets. Besides, the mRNA-miRNA interaction networks were predicted by starbase. We also constructed a HFpEF mouse model subjected to high fat diet and L-NAME (0.5 g/L) in drinking water to discover the correlation between the screened circulating miRNA and HFpEF. Results After differential expression analysis of the combined HFpEF dataset, we identified 37 differentially circulating miRNAs, of which 15 were down-regulated and 22 were up-regulated. Subsequently, we screened by machine learning and identified 4 key miRNAs that may be involved in the progression of HFpEF, including hsa-miR-645, hsa-miR-296-5p, hsa-miR-199b-5p, and hsa-miR-509-3-5p. We validated these miRNAs based on their expression, and the ROC plots suggest that these miRNAs may have diagnostic capability in HFpEF. The results of GO and KEGG enrichment analyses showed that the target genes of the differentiated miRNAs were mainly enriched in the MAPK signaling pathway, mTOR signaling pathway, protein processing in endoplasmic reticulum, hippo signaling pathway, cell cycle, Foxo signaling pathway, hypertrophic cardiomyopathy, dilated cardiomyopathy, and circadian rhythm. The mRNA-miRNA interaction networks suggested that TMEM135 was regulated by both has-miR-199b-5p and hsa-miR-296-5p. The RT-PCR results also suggested that miR-199b-5p was upregulated in the HFpEF mice. Conclusion We validated 4 circulating miRNAs with strong correlation to HFpEF, which provide a more reliable basis for pre-symptomatic diagnosis.

Who should be prioritized for screening for adult onset dilated cardiomyopathy among first degree relatives?

Abstract Introduction Familial genetic and cardiovascular screening is highly recommended to detect dilated cardiomyopathy (DCM) in first-degree relatives (FDRs). Consequently, questions arise regarding the prioritization of screening among FDRs especially in Asian populations. Purpose To investigate prevalence and proportion of FDRs of DCM patients presenting with DCM. Methods Patients with DCM and their FDRs who underwent genetic counseling between April 2017 and March 2023 at a single tertiary center were retrospectively enrolled. The study collected baseline demographics and conducted sequential echocardiograms, along with genetic cascade sequencing for 36 genes clinically relevant to DCM. A positive DCM phenotype in FDRs was determined based on the presence of a decreased left ventricular ejection fraction (LVEF) with left ventricular enlargement, with a full phenotype containing both criteria and a partial phenotype containing either of them. Results A total of 122 probands (median age 59 years) and 241 FDRs (median age 43 years) participated in the study. Out of 72 FDRs (29.9%) with P/LP proband variants, only 18.6% of FDRs showed a positive DCM-phenotype. Overall, 29 individuals (15.5%) exhibited a positive DCM-phenotype, with 2.7% displaying a full DCM-phenotype and 12.8% displaying a partial DCM-phenotype. Among them, 69% exhibited heart failure (HF) with preserved EF, 20.7% had HF with mildly reduced EF, and 10.3% had HF with reduced EF. Siblings tended to be older compared to offspring (52.1 years vs. 35.5 years), aligning with the tendency shown in the more fulminant manifestation of the positive phenotype. Accordingly, a higher prevalence was observed among siblings (n=4, 80%) with a full phenotype and in those with a partial phenotype. Conclusion This study demonstrated higher prevalence of phenotype-positive DCM among siblings of probands. Given disease’s manifestation in adulthood, it is essential to prioritize the screening of all FDRs with emphasis on the siblings.

Epi-Allele: CRISPR-mediated allele-specific epigenetic editing alleviates hypertrophic cardiomyopathy

Abstract Background Hypertrophic cardiomyopathy (HCM) is a prevalent genetic heart disease caused by variants in sarcomere genes like MYH7, which accounts for 40% of cases with 75% being heterozygous. HCM shows incomplete penetrance, where mutant allele expression correlates with severity. Thus, allele-specific suppression is a potential therapy. While allele-specific RNAi or CRISPR/Cas9 showed moderate efficacy, low expression level of MYH7 is associated with the risk of heart failure and dilated cardiomyopathy. We hypothesized CRISPR-based epigenetic editing（dCas9 fused with DNA methylation and histone regulation elements） may potently achieve phenotypic modification without impacting overall gene expression. Objective We investigated allele-specific CRISPR epigenetic editing (Epi-Allele) to selectively suppress mutant Myh6 allele expression without affecting total expression, as a novel HCM therapy in a mouse model. Results We first generated C57R403Q/DBA mice to simulate heterozygous HCM patients. Allele-specific Myh6 gRNAs reduced C57 allele expression and increased DBA expression without impacting total Myh6 expression in primary cardiomyocytes, effects sustained for one year in report cells. HCM mice with Epigenetic editor and allele-specific gRNAs (Epi-Allele) showed reduced left ventricular wall thickness, normalized ECG, and less cardiac fibrosis. Similar therapeutic effects were observed in HCM mice treated by a dual AAV delivery system of Epi-Allele. We further found that Epi-Allele could reverse established disease in the inducible transgene mice. We’ve also seen similar surprising therapeutic effects from Epi-Alleles in patient-derived pluripotent stem cell-induced cardiomyocytes (iPSC-CMs). Conclusion We suggest that Epi-Allele may be a novel therapy for HCM and other dominant diseases where the mutant gene plays a vital role, overcoming the limitations of previous allele-specific suppression strategy.Figure abstract of Epi-AlleleThe universality of Epi-Alleles