Dilated Cardiomyopathy Patients Research Articles

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.

Prognostic impact of the concept of late gadolinium enhancement granularity in non-ischaemic dilated cardiomyopathy

Abstract Background The prognostic stratification of non-ischaemic dilated cardiomyopathy (DCM) to predict the risk of death is mainly driven by the left ventricular ejection fraction (LVEF). Indeed, LVEF<35% is currently the only indication for primary prevention with implantable cardioverter-defibrillator (ICD) in these patients. Beyond LVEF, several cardiac magnetic resonance imaging (MRI) studies have suggested the strong prgnostic impact of late gadolinium enhancement (LGE), and particularly its extent and location. Therefore, we assumed that a more granular approach combining detailed LGE findings including extent, location and pattern could improve risk stratification in this population. Purpose To assess the additional prognostic value of the concept of "Late Gadolinium Enhancement (LGE) Granularity" that includes extent, location, and pattern in non-ischaemic dilated cardiomyopathy (DCM) patients to predict all-cause death. Methods Between 2008-2021, all consecutive patients with DCM without ICD or history of sustained ventricular arrythmia referred for cardiac MRI were included in two French centres. In line with the current ESC and AHA guidelines, DCM was defined by the LV dilation and LVEF< 50% using cardiac MRI. All patients with history of coronary artery disease or clinical history of myocarditis were excluded. The primary outcome was all-cause death using the French National Registry of Death. Cox regressions were performed to determine the prognostic value of each LGE findings. The additional prognostic value of the LGE granularity was assessed by the C-statistic increment, the continuous net reclassification improvement (NRI), and the integrative discrimination index (IDI). Results Of 1,668 DCM patients (age 52±8 years, 54% males), 268 (16%) died after a median (interquartile range) follow-up of 9 (7-12) years. With a median LVEF value of 39% (30-46), 472 (28%) patients had non-ischemic LGE. Using survival curves, patients with LVEF>35% but the LGE septal location showed a higher risk of death compared to all patients with LVEF≤35% with or without LGE (except for the septal location, all p<0.001). In DCM patients with LGE (N=472), LGE extent (adjusted HR: 4.27, 95% CI: 2.22-8.22), septal location (HR: 5.74, 95% CI: 3.35-9.85) and multiple areas of LGE (HR: 4.38, 95% CI: 2.08-9.22; all p<0.001) were all independently associated with death after adjustment for prognosticators. The concept of "LGE granularity" combining all these LGE features showed the best improvement in model discrimination and reclassification over traditional prognosticators including LVEF (C-statistic improvement: 0.14; net reclassification improvement=64.3%; integrative discrimination index=29.0%; all p<0.05). Conclusion In a large cohort of DCM patients, the concept of "LGE granularity" combining LGE extent, location and the presence of multiple areas had an additional prognostic value above traditional prognosticators including LVEF to predict all-cause death.

The added value of advanced echocardiography in dilated cardiomyopathy: looking at the right heart

Abstract Introduction and aims Right ventricular (RV) dilation and dysfunction significantly impact the prognosis of dilated cardiomyopathy (DCM) patients, and early detection of subclinical changes is mandatory. Furthermore, right atrial (RA) size and function are still often neglected in DCM patients. Accordingly, our aims were to evaluate (i) right heart chambers and tricuspid annulus (TA) subclinical remodeling, and (ii) the prognostic value of RA compared to left atrial (LA) size and function in patients with DCM without clinical RV involvement, RV pressure/volume overload or sustained atrial tachyarrhythmias by advanced echocardiography techniques. Materials and methods Sixty-eight patients out of a cohort of 106 patients with DCM (mean age 60 years, 35 men) were evaluated by comprehensive transthoracic two- (2DE) and three-dimensional (3DE) and speckle-tracking (2DSTE) echocardiography, were compared to 62 age- and sex-matched healthy controls (mean age 61 years, 32 men), and were followed-up for 37 ± 16.6 months. Results DCM patients have RV and RA global longitudinal dysfunction by 2DSTE, and higher RA minimum volumes (Vmin) and TA areas despite having normal RV volumes and ejection fraction (EF) and RA maximum volumes (Vmax) by 3DE compared to controls (Table). RA and RV strain correlate with each other (r=0.360, p=0.013 for RA reservoir and r=0.347, p=0.017 for conduit strain). TA area correlates with RA contractile strain (r=-.293, p=0.046) and RV free-wall strain (r=0.373, p=0.008), RA Vmax (r=0.513, p<0.001), RV (r=0.404, p=0.004 for end-diastolic and r=0.444, p=0.001 for end-systolic) and left ventricular (LV) volumes (r=0.394, p=0.016) and LV EF (r=-.361, p=0.028). RA reservoir strain (AUC=0.769) has higher value for outcome prediction compared to LA strain (p=0.02 between them). Conclusion Patients with DCM have RV longitudinal dysfunction and decreased RA function, in the absence of clinical RV involvement or atrial arrhythmias, and decreased RA strain is associated with an increased risk of hospitalization and cardiac death.Comparison of right heart parametersPrognostic value of atrial function

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

Health-related quality of life disparity in cardiac sarcoidosis versus other myocardial diseases

Abstract Background Sarcoidosis, a systemic inflammatory disorder, can manifest as progressive inflammatory heart disease, termed cardiac sarcoidosis (CS). Despite advances in treatment, the impact of CS on health-related quality of life (HRQoL) remains incompletely understood. This study aimed to compare HRQoL between patients with CS and those with non-inflammatory cardiomyopathies, namely dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Purpose To assess and compare HRQoL across patients with cardiac sarcoidosis and non-inflammatory cardiomyopathies. Methods A total of 240 CS patients (86% response rate), 96 DCM patients (55% response rate), and 81 HCM patients (65% response rate) completed the RAND-36 general health-related questionnaire, comprising eight dimensions. Patients listed for transplantation were excluded. Clinical data were obtained from the Finnish myocardial inflammatory diseases registry for CS patients and from medical records in hospitals for HCM and DCM patients. Results Median age ranged from 56 to 59 years across the groups. Unlike DCM, which typically presents with heart failure symptoms, a substantial proportion (82%) of CS patients presented with advanced atrioventricular block or ventricular arrhythmias, while HCM cases were often incidentally detected or identified through family screening. Most CS patients (94%) had implanted pacemakers or ICDs, compared to a lower proportion in HCM (26%) and DCM (63%). DCM patients exhibited a higher prevalence of impaired LVEF (<50%) compared to CS and HCM patients. Functional impairment, as measured by NYHA class, was most pronounced in DCM patients. CS patients experienced more adverse events between diagnosis and the study entry, particularly sustained ventricular tachycardia/ventricular fibrillation. However, heart failure hospitalizations did not significantly differ between groups. Table 1 presents a comparative analysis of patient-reported outcomes across four functional and mental dimensions to assess the relative burden of disease among patients with CS, HCM, and DCM. While the functional dimensions in CS exhibited disparities from both HCM and DCM, no significant differences were observed in the mental dimensions between CS and HCM. CS patients reported lower scores in the domains of role physical, and general health compared to either HCM or DCM counterparts. Conclusion Patients with CS demonstrated significantly poorer HRQoL compared to those with non-inflammatory cardiomyopathies. This underscores the substantial burden of disease associated with CS and highlights the importance of comprehensive management strategies to address both clinical and quality of life aspects in affected individuals.

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.

Coronary microvascular dysfunction as assessed by cardiac MRI and its association with aerobic exercise capacity in dilated cardiomyopathy

Abstract Background Dilated cardiomyopathy (DCM) has a poor prognosis. Aerobic exercise capacity (peak VO2) is an independent predictor of mortality but the central mechanisms contributing to exercise intolerance in DCM are unknown. Purpose To characterise myocardial perfusion reserve (MPR) and determine if cardiovascular magnetic resonance (CMR) measures of structure, function and microvascular function are associated with aerobic exercise capacity in DCM. Methods Single centre, prospective, case-control comparison of adults with DCM and matched controls. Adenosine-stress perfusion CMR to assess cardiac structure, function and quantitative perfusion, and cardiopulmonary exercise testing (CPET) to determine peak VO2, was performed. Controls were propensity matched based on age, sex, body mass index and diabetes status, and between group comparison was adjusted for other key clinical characteristics (CMR: ethnicity and systolic blood pressure; CPET: ethnicity, systolic blood pressure, smoking history and lung disease). Comparison of perfusion in segments with and without late gadolinium enhancement was performed using mixed effects linear regression taking into account individual patient segmental perfusion. Pre-specified multivariable linear regression, including key clinical and cardiac variables, was undertaken in patients with DCM to identify independent associations with percentage predicted peak VO2, which incorporates age, sex, height and weight. Results Sixty-six patients with DCM (median age 61 years, 71% male) were matched to 66 controls (median age 59 years, 71% male). The DCM group had greater left ventricular (LV) end-diastolic and end-systolic volumes, lower systolic and diastolic function, and had more focal and diffuse fibrosis compared to controls (Table 1). There was lower rest (0.58±0.14 versus 0.65±0.17 mL/min/g; P=0.033) and stress (1.53±0.49 versus 2.01±0.60 mL/g/min; P<0.001) myocardial blood flow, and lower MPR (2.69±0.84 versus 3.15±0.84 mL/g/min; P=0.002) in the DCM group. In DCM patients, mixed effects linear regression demonstrated lower rest (adjusted mean 0.54(95% CI 0.50-0.57) versus 0.58(0.55-0.62) mL/g/min; P<0.001) and stress MBF (1.38(1.25-1.51) versus 1.55(1.43-1.67) mL/g/min; P<0.001) in segments with LGE compared to segments without LGE, but there was no difference in MPR (2.71(2.47-2.96) versus 2.76(2.55-2.97) mL/g/min; P=0.496). DCM patients had markedly lower peak VO2 (19.8±5.5 versus 25.2±7.3 mL/kg/min; P<0.001). Multivariable linear regression demonstrated that LV ejection fraction, extracellular volume fraction and MPR, but not LV mass, were independently associated with percentage predicted peak VO2 in DCM (R squared=0.531, P<0.001; Table 2). Conclusions DCM patients have lower rest and stress myocardial blood flow and lower MPR compared to controls. In DCM, MPR, LV ejection fraction and fibrosis are independently associated with aerobic exercise capacity.

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.

Propensity score-matched analysis in isolated left ventricular dilation and non-ischaemic dilated cardiomyopathy

Abstract Background The presence and extent of late gadolinium enhancement (LGE) assessed by cardiac magnetic resonance imaging (CMR) are strong prognosticators of death in patients with non-ischaemic dilated cardiomyopathy (DCM), defined by the current guidelines as left ventricular (LV) dilation and left ventricular ejection fraction (LVEF)<50%. Although the current guidelines defined the concept of "isolated LV dilation" as LV dilation with preserved LVEF≥50%, the prognostic value of the LGE granularity including its extent, location and pattern is not established in this population. Purpose To assess the prognostic value of the concept of "LGE granularity" including its extent, location, and pattern for predicting all-cause death above traditional prognosticators in patients with LV dilation and reduced LVEF (i.e. DCM) or preserved LVEF (i.e. isolated LV dilation), separately. Methods Between 2008 and 2021, all consecutive patients with DCM and isolated LV dilation without ICD or history of sustained ventricular arrhythmia referred for CMR were included in two centres. All patients with history of coronary artery disease or myocarditis were excluded. The primary outcome was all-cause death using the French National Registry of Death. A 1:1 propensity score matching was performed to balance baseline characteristics in patients with DCM vs. those with isolated LV dilation. Cox regressions were performed to determine the prognostic value of each LGE findings. Results Of 2,752 patients analysed (age 52±8 years, 56% male), 408 (15%) patients died after a median (interquartile range) follow-up of 9 (7-12) years. A total of 737 (27%) patients had LGE. Patients with DCM had a higher rate of death than patients with isolated LV dilation (16% versus 13%, p=0.02). In the propensity-score matched population (N=1,084 in DCM subgroup and N=1,084 in isolated LV dilation), the LGE presence was associated with death (HR=2.98, 95%CI: 1.97-4.50, p<0.001). In isolated LV dilation patients with LGE (N=265), the LGE extent (HR=1.41, 95%CI:1.09-1.83, p=0.009), the presence of LGE in multiple areas (HR=3.86, 95%CI: 1.73-8.61, p<0.001) and the septal location (HR=2.97, 95%CI:1.37-6.46, p=0.006) were strong prognosticators of death after adjustment for traditional prognosticators. Similarly, in DCM patients with LGE (N=268), the LGE extent (HR=1.42, 95% CI:1.07-1.89, p=0.014), the presence of LGE in multiple areas (HR=8.41, 95%CI: 3.32-21.3, p<0.001) and the septal location (HR=6.65, 95% CI: 3.02-14.6, p<0.001) were strongly associated with death after adjustment. Conclusion In a large cohort of DCM and isolated LV dilation patients, the concept of "LGE granularity" was independently associated with all-cause death after adjustment for all traditional prognosticators in both DCM and isolated LV dilation. These results suggest the existence of a continuum between isolated LV dilation and DCM, and that CMR assessment could improve the risk stratification in this population.

Quantifying late gadolinium enhancement improved sudden cardiac death risk prediction in non-ischemic dilated cardiomyopathy

Abstract Background While previous studies have proved the late gadolinium enhancement (LGE) was associated with poor prognosis in non-ischemic dilated cardiomyopathy (DCM), the optimal method for LGE quantification and the ability of LGE extent in identifying sudden cardiac death (SCD) remain less clarified. Purpose This study sought to compare the reproducibility of LGE quantification methods and explore the asssociation between LGE extent and SCD endpoint in DCM patients. Methods In this prospective study, LGE was quantified by the 2-6 standard deviations (SD) above the remote myocardium and full-wide half-maximum (FWHM) methods. The primary endpoint was SCD and arrythmia endpoint included SCD and aborted SCD. Reproducibility of LGE quantification was measured by Bland-Altman analysis and intra-class correlation coefficients (ICC). Competing risk regression analysis, C-index and area under the curve (AUC) were performed to identify the prognostic value. Results Among the 770 patients, 336 (44%) patients had LGE. FWHM demonstrated the best reproducibility compared with other quantification methods (intraobserver variability: ICC = 0.94, mean bias: -0.43 ± 4.89%; interobserver variability: ICC = 0.90, mean bias: -2.65 ± 6.40%). After a median follow-up of 49 months, SCD occurred in 61 (8%) patients and arrythmia endpoint occurred in 87 (11%) patients. Among all quantification method, LGE extent measured by FWHM showed the highest predictive value of SCD (C index: 0.72) and arrythmia events (C index: 0.71) than other methods. In the competing risk analysis, LGE extent was independently association with SCD (Hazard ratio [HR] 1.05, 95% confidence interval [CI] 1.03 - 1.07, P < 0.001) and arrythmia endpoint (HR 1.05, 95% CI 1.03 - 1.06, P < 0.001). LGE extent >8% showed significantly higher risk of SCD and arrythmia endpoint than those with LGE extent ≤8% (P < 0.001). Incoporating LGE exent and 35% left ventricular ejection fraction (LVEF) significantly improved the SCD (C index: 0.74 vs 0.61, P < 0.001) and arrythmia endpoint (C index: 0.73 vs 0.59, P < 0.001) prediction compared with LVEF. Conclusions FWHM demonstrated best reproducibility and highest SCD prediction ability among LGE quantification methods. Adding LGE extent to LVEF significantly improved the predictive value of SCD and arrythmia endpoint.Figure 1

Improving the yield of genetic testing in dilated cardiomyopathy using late gadolinium enhancement

Abstract Background Genetic testing has become an important tool in the work-up of dilated cardiomyopathy (DCM), aiding in family screening and providing information about prognosis and arrhythmic risk. Nonetheless, a significant proportion of patients with DCM present negative genetic test results. The "Madrid Score" was created to evaluate the likelihood of positive genetic tests and increase their yield in DCM patients. Purpose To determine if late gadolinium enhancement (LGE) assessment can improve the Madrid Score accuracy and increase the yield of genetic tests for DCM. Methods A single-centre retrospective study of patients diagnosed with DCM who underwent cardiac magnetic resonance (CMR) and genetic test between January 2017 and October 2023. The CMR imaging included the assessment of LGE. Multivariate logistic regression was performed and the model’s change in performance was evaluated when adding LGE. Results A total of 90 patients with the diagnosis of DCM underwent CMR and genetic test during the study period. Patient’s mean age was 51.0±14.6 years, and 57.1% were male. The genetic test was positive (G+) in 42 (46.7%), and negative (G-) in 48 (53.3%) patients. A variant of uncertain significance was present in 31 (34.4%), and these were included in the G- group. Most of the known independent predictors of a G+ given by the Madrid Score were significant in our cohort: Family history of DCM (OR: 4.82; CI: 1.73-11.60; p < 0.001), absence of hypertension (OR: 0.19; CI: 0.06-0.58; p < 0.001), absence of left bundle branch block (OR: 0.22; CI: 0.05-0.98; p = 0.047), and low electrocardiogram voltage in peripheral leads (OR: 3.13; CI: 0.87-11.26; p = 0.081). When analyzing the effect of LGE in the regression model (R2 = 0.622, p < 0.001), we found that the number of LGE segments (OR: 2.54; CI: 1.10-5.90; p = 0.031), and the presence of LGE in the anterior wall (OR: 3.01; CI: 1.42-12.04; p = 0.041), were associated with a higher rate of positive genetic tests. When comparing both regression models, the incorporation of LGE increased the prediction power of the standard Madrid Score, correctly predicting 82.0% of the tests in our sample, with a probability of a G+ result ranging from 2% when all predictors were absent to 84% when ≥6 predictors, including LGE, were present. Conclusion Our study suggests that LGE assessment may enhance the Madrid Score performance and consequently improve genetic testing decisions in DCM, potentially leading to better use of the limited resources in our health care system.

Utility of polygenic risk score for prediction of dilated cardiomyopathy and modulation of severity of LV dysfunction among cases

Abstract Background Dilated cardiomyopathy (DCM) is a predominant cause of heart failure and a leading indication for cardiac transplantation. While rare genetic variants are established as causative factors in familial forms of the disease, recent genome-wide association studies (GWAS) have also underscored the significant contribution of common genetic variation to DCM. Polygenic scores (PGS) constructed from GWAS have demonstrated promise in risk stratification for a range of common diseases and may similarly have value for risk prediction in DCM. However, data regarding the clinical utility of PGS in DCM remains sparse. Purpose We aimed to evaluate the utility of PGS for prediction of DCM and its association with left ventricular ejection fraction (LVEF) and family history. We further aimed to assess the contribution of PGS in DCM patients with established causative rare variants (genotype-positive) and those without (genotype-negative). Methods We used a previously-constructed PGS, which was developed from a GWAS meta-analysis (8387 DCM cases and 939161 controls) and multi-trait analysis (MTAG) with cardiac MRI traits. In the present analysis, we calculated PGS for a newly assembled cohort of 978 DCM cases from a major university medical centre and 7207 controls from a national register. To evaluate the clinical utility of PGS, we built logistic regression models and assessed the association between PGS and DCM status. Subsequently, we performed subgroup analyses, including: i) individuals of European ancestry, ii) non-European ancestry, iii) males, iv) females, v) genotype-positive participants(n=193), and vi) genotype-negative participants (n=294). We then used linear and logistic regression models, respectively, to assess the associations of PGS with LVEF and documented family history of DCM. Results PGS demonstrated a significant enrichment among DCM cases compared to controls (OR per SD 1.93, P = 9.47E-68). This association persisted with consistent effect estimates - ranging from OR 1.5 to 2.2 - across all examined subgroups and demonstrated sufficient statistical significance (all P<1.58E-06) (Figure 1). Genotype-negative cases had a significantly higher PGS compared to genotype-positive individuals (P = 0.0015), although PGS was significantly enriched in both groups as compared to controls. Furthermore, among DCM cases, higher PGS was significantly associated with lower LVEF at first presentation (P=0.03, beta=-0.5% per SD) (Figure 2). There was no significant association found between PGS and family history. Conclusions PGS is strongly associated with risk of DCM, and may modulate the severity of LV dysfunction among DCM cases. Polygenic burden contributes to DCM risk in both genotype-positive and negative cases, although the contribution is stronger in patients without known causative rare variants. Overall, our results suggest a potential clinical applicability for PGS in DCM risk stratification.Figure 1.Association of PGS with DCMFigure 2.Association of PGS with LVEF

MicroRNA-145-5p restricts cardiac scar resolution during cardiac regeneration

Abstract Background Human hearts have a very limited capacity to renew cardiomyocytes following injury. The lost myocardium is permanently replaced with noncontractile fibrotic tissue, consequently leading to heart failure. In contrast, zebrafish retain cardiac regenerative capacity during their lifetime. After injury, zebrafish hearts undergo transient fibrotic scarring that subsequently resolves and is replaced with new cardiomyocytes over time. Thus, understanding the molecular mechanisms governing cardiac scar resolution in zebrafish could offer insights into enhancing the regenerative capacities of human hearts. Objective We aimed to decipher the molecular pathways associated with zebrafish cardiac scar resolution. Methods We investigated the mRNA and miRNA responses to injury at 14 days post-injury by high-throughput transcriptome profiling of RNAs isolated from healthy or cryoinjured hearts. The prediction of miRNA-mRNA interactions was performed to identify the most differentially expressed miRNAs and their target genes. These miRNAs and genes were validated in zebrafish regenerating hearts and in the left ventricles of ischemic cardiomyopathy or dilated cardiomyopathy patients. The potential role of identified miRNAs in cardiac scar resolution was investigated in human cardiac fibroblasts. Results Principal component analyses identify two distinct clusters in both the mRNAome and miRNAome corresponding to healthy and injured hearts, indicating significant changes in transcriptome profiles during zebrafish cardiac regeneration. Gene set enrichment analyses indicate that molecular pathways involved in extracellular matrix organization and inflammatory response are markedly activated whereas genes associated with mitochondrial organization and oxidative phosphorylation are downregulated in injured hearts. We observed the downregulation of miR-145-5p and the upregulation of procollagen V in the injured hearts. In contrast to zebrafish, in the left ventricles of ischemic cardiomyopathy patients, miR-145-5p is significantly upregulated and procollagen V α1 is downregulated. Theoretical prediction of miRNA-mRNA interactions indicates procollagen V α1 is negatively correlated with miR-145-5p. Overexpression of miR-145-5p in human cardiac fibroblasts downregulates collagen V α1 and alpha smooth muscle actin, upregulates procollagen I and matrix metalloproteinase 9, and inhibits cell proliferation and migration. In contrast, inhibition of miR-145-5p upregulates collagen V α1 and alpha smooth muscle actin, downregulates procollagen I and matrix metalloproteinase 9, and stimulates cell proliferation and migration. Conclusion Our study suggests that miR-145-5p may play a role in the suppression of myofibroblast transdifferentiation via collagen V α1, which restricts scar resolution and cardiac repair.

A systematic review and meta-analysis to determine the biological sex ratio in monogenic genetic and non-genetic dilated cardiomyopathy

Abstract Background Dilated cardiomyopathy (DCM) is characterised by left ventricular or biventricular systolic dysfunction and dilatation, in the absence of abnormal loading conditions or coronary artery disease (1). Up to 30% of cases have an identified monogenic cause, usually with autosomal dominant (AD) inheritance (2). The disease appears to be twice as common in males, suggesting either a sex specific penetrance or a potential difference in expressivity. This sex ratio has not been systematically evaluated for genetic forms of DCM. Purpose To assess the sex ratio in patients with all-cause DCM compared to genetic (monogenic) and gene-elusive subtypes, defined by the presence or absence of a pathogenic variant in DCM-associated genes. Methods A literature search was conducted to identify cohorts of DCM patients with identifiable sex ratios. Exclusion criteria were patients with syndromic, X-linked, mitochondrial, or autosomal recessive (AR) DCM. Studies with a small cohort size (n<100), a paediatric population, unidentifiable sex ratio, or ischaemic and peripartum DCM were excluded. 98 studies with a total of 36,662 participants were included in this study. A random-effects meta-analysis generated a pooled proportion of female participants with a 95% confidence interval (95% CI) for an overall DCM cohort as well as for the subtypes – all genetic DCM, individual gene level for 10 key DCM genes (including titin, TTN, and lamin, LMNA), and gene elusive DCM. Results The overall DCM cohort had a 0.30 female proportion (95% CI: 0.28-0.32; Figure 1). This corresponds to a male:female (M:F) ratio of 2.38:1. This ratio did not significantly change in patients with an identified causative DCM variant (0.31 [95% CI 0.26-0.36]; M:F ratio of 2.22:1; p=0.563). There was also no significant difference when compared to patients who had been genetically tested with no identified variant (0.30 [95% CI 0.24-0.37]; M:F ratio of 2.29:1; p=0.814). Furthermore, the ratio within participants with AD gene variants was not significantly different for the specific genes of TTN (0.28 [95% CI 0.22-0.36]; M:F ratio of 2.51:1) and LMNA (0.35 [95% CI 0.27-0.44]; M:F ratio of 1.84:1). Overall, the sex ratio amongst patients with these AD gene variants was similar to the all-cause group (0.34 [95% CI 0.28-0.40]; M:F ratio of 1.98:1; p=0.18); Figure 2. Conclusions This meta-analysis suggests that DCM is twice as prevalent in males than females, even in pooled monogenic genetic subtypes with an equally prevalent genetic risk factor, indicating a difference in penetrance between the sexes. Further studies are required to determine the drivers of this sex specific penetrance.Forest plots: overall DCM cohortForest plots: gene-specific DCM cohort

Cardiovascular magnetic resonance to differentiate veteran athlete's heart with cavity dilatation and mild dilated cardiomyopathy

Abstract Introduction Endurance athletic training may lead to left ventricular (LV) dilatation and mildly reduced resting LV function which can be difficult to differentiate from dilated cardiomyopathy (DCM). Myocardial fibrosis is increasingly recognised in lifelong athletes and is also prevalent in DCM where it confers adverse prognosis.(1,2) However, it is unknown whether the pattern and prevalence of fibrosis in athletes with cavity dilatation differs from DCM. In this study, we compared the CMR fibrosis distribution and tissue characteristics between athletic LV dilatation and mild DCM patients. Methods We prospectively recruited 113 males; 64 endurance athletes and 49 mild DCM patients. Inclusion criteria Age 50-80 years, LVEF 45-54% and LV end-diastolic volume indexed to body surface area (LVEDVi)≥110ml/m2. Athletes trained≥10 weekly hrs for≥15 yrs. Exclusion criteria; Chest pain, prior coronary revascularisation, severe valvular disease, myocarditis, hypertrophic cardiomyopathy, inducible ischaemia or myocardial infarction on CMR. CMR protocol included volumetric assessment, T1 mapping, quantitative stress perfusion and quantitative late gadolinium enhancement. Statistical analysis between groups was performed using unpaired t-test and receiver-operator curve (ROC) analysis. Results LVEDVi was not significantly different between athletes and mild DCM patients (123.3±12.6 vs 129.8±23.1ml/m2, P=0.057). However, LVEF (52.0±6.1 vs 47.6±5.2%, P<0.001) and right ventricular (RV) EDVi (121.0±14.3 vs 97.6±25.2ml/m2, P<0.001) were both greater in athletes. There was no difference in non-ischaemic fibrosis prevalence between both groups (50.0 vs 49.0%, P=0.915) nor the burden of fibrosis (3.5±2.9 vs 7.4±12.0g, P=0.087). However, the distribution of fibrosis varied with a significantly greater prevalence of basal mid-myocardial inferolateral fibrosis amongst athletes (87.5 vs 50.0%, P=0.002) whereas basal mid-myocardial inferoseptal fibrosis was significantly more common in mild DCM (45.8 vs 9.4%, P=0.002). Native T1 (1249.0±38.1 vs 1308.3±47.1ms, P<0.001) and extracellular volume (ECV) (22.0±2.1 vs 25.9±3.5%, P<0.001) were both lower in athletes than mild DCM patients. Furthermore, athletes had higher myocardial perfusion reserve (MPR) (3.65±1.30 vs 2.76±0.92, P<0.001) and stress myocardial blood flow (MBF) (2.09±0.70 vs 1.62±0.66, P<0.001). On ROC analysis, native T1 (area under curve (AUC) 0.89, P<0.001), ECV (AUC 0.85, P<0.001) and stress MBF (AUC 0.68, P<0.001) were able to differentiate athletes and mild DCM. Native T1 and ECV were significantly better at discriminating than MPR (P<0.001). Conclusion Myocardial fibrosis was highly prevalent in both veteran endurance athlete's heart and mild DCM whilst its distribution was distinctive between the groups. Native T1 and ECV were the best discriminators. Recognition of fibrosis patterns and associated tissue characteristics may be clinically useful to differentiate these two overlapping phenotypes.Figure 1; LGE distribution in athletes cFigure 2; CMR tissue characteristics to

Integrated plasma proteomics and myocardial tissue transcriptomics reveal elevated fibrosis markers in arrhythmogenic cardiomyopathy patients

Abstract Background Arrhythmogenic cardiomyopathy (ACM) is characterized by myocardial fibrofatty replacement and ventricular arrhythmias, with potential progression to heart failure. This study aims to identify ACM-specific biomarkers for improved prognosis and possible treatment strategies. Methods RNA sequencing and transcriptome analyses were performed in cardiomyocytes of 10 ACM patients, 10 dilated cardiomyopathy patients and 10 healthy controls. Analyses were performed using liquid chromatography and mass spectrometry. Additionally, plasma protein expression was assessed in 38 ACM patients and 24 healthy controls using the Proximity Extension Assay (Olink®). A standardized bicycle exercise test was performed in 11 ACM patients and controls and blood was obtained before and after exercise. Results Myocardial tissue transcriptomics identified several upregulated molecules associated with extracellular matrix formation and immune response in ACM. Plasma protein sequencing revealed upregulation of proteins involved in metabolic pathways, inflammation, and fibrosis. Integration of these analyses identified key soluble profibrotic markers such as Fibulin-3, Endostatin and C-X-C motif chemokine 10 (CXCL10) in plasma of ACM patients. After exercise, Fibulin-3 levels increased in ACM patients compared to controls. These findings were further validated using enzyme-linked immunosorbent assay (ELISA). Conclusion This comprehensive analysis revealed distinct proteomic and transcriptomic signatures in ACM patients' plasma and cardiomyocytes. The integrative analysis identified several upregulated profibrotic markers in ACM. Our Findings may advance diagnostic and prognostic strategies and offer potential therapeutic targets.

Association Between Coronary Microvascular Dysfunction and Exercise Capacity in Dilated Cardiomyopathy.

Aerobic exercise capacity is an independent predictor of mortality in dilated cardiomyopathy (DCM), but the central mechanisms contributing to exercise intolerance in DCM are unknown. Characterize coronary microvascular function in DCM and determine if cardiovascular magnetic resonance (CMR) measures are associated with aerobic exercise capacity. Prospective case-control comparison of adults with DCM and matched controls. Adenosine-stress perfusion CMR to assess cardiac structure, function and automated inline myocardial blood flow quantification, and cardiopulmonary exercise testing (CPET) to determine peak VO2, were performed. Pre-specified multivariable linear regression, including key clinical and cardiac variables, was undertaken to identify independent associations with peak VO2. Sixty-six patients with DCM (mean age 61 years, 71% male) were propensity-matched to 66 controls (mean age 59 years, 71% male) based on age, sex, body mass index and diabetes. DCM patients had markedly lower peak VO2 (19.8±5.5 versus 25.2±7.3mL/kg/min; P<0.001). The DCM group had greater left ventricular (LV) volumes, lower systolic function, and had more fibrosis compared to controls. In the DCM group, there was similar rest but lower stress myocardial blood flow (1.53±0.49 versus 2.01±0.60mL/g/min; P<0.001) and lower MPR (2.69±0.84 versus 3.15±0.84; P=0.002). Multivariable linear regression demonstrated that LV ejection fraction, extracellular volume fraction and MPR, were independently associated with percentage predicted peak VO2 in DCM (R2=0.531, P<0.001). In comparison to controls, DCM patients have lower stress myocardial blood flow and MPR. In DCM, MPR, LV ejection fraction and fibrosis are independently associated with aerobic exercise capacity.

SnRNA-seq reveals differential functional transcriptional pathway alterations in three mutant types of dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a leading cause of heart failure, characterized by ventricular dilation, thinning of the ventricular walls, and systolic dysfunction in either the left or both ventricles, often accompanied by fibrosis. Human cardiac tissue is composed of various cell types, including cardiomyocytes (CMs), fibroblasts (FBs), endothelial cells (ECs), macrophages, lymphocytes and so on. In DCM patients, these cells frequently undergo functional and phenotypic changes, contributing to contractile dysfunction, inflammation, fibrosis, and cell death, thereby increasing the risk of heart failure. This study focuses on DCM patients with mutations (LMNA, RBM20, and TTN) and analyzes functional changes in subpopulations of four cardiac cell types. The study involves functional annotation of subpopulations within each cell type and explores the association between gene mutations and specific functions and pathways. Additionally, the SCENIC method is employed of a particular cell subpopulation with significant functional importance, aiming to identify key transcriptional regulators in specific cell states. By analyzing the expression levels of ligand-receptor pairs in vCM4, vFB2, EC5.0, T cells, and NK cells across the DCM mutant genotypes, we predicted their signaling pathways and communications. This research provides insights into the molecular mechanisms of DCM and potential therapeutic targets.

Usefulness of tissue tracking to differentiate tachycardia-induced cardiomyopathy from dilated cardiomyopathy in patients admitted for heart failure.

Differentiation of tachycardia-induced cardiomyopathy (TIC) from dilated cardiomyopathy (DCM) in patients admitted for heart failure (HF) with left ventricular dysfunction and supraventricular tachyarrhythmia (SVT) remains challenging. The role of tissue tracking (TT) in this setting remains unknown. Forty-three consecutive patients admitted for HF due to SVT with left ventricular ejection fraction (LVEF) < 50% undergoing CMR were retrospectively included. Those eventually evolving to LVEF > 50% at follow-up were classified as TIC and those maintaining a LVEF < 50% were classified as DCM. Clinical, echocardiography, and CMR findings, including TT, were analyzed to predict LVEF recovery. Twenty-five (58%) patients were classified as TIC. Late gadolinium enhancement (LGE) was more frequent in DCM group (61% vs 16%, p = 0.004). Left ventricle (LV) peak systolic radial velocity and peak diastolic radial strain rate were lower in DCM group (7.24 ± 4.44mm/s vs 10.8 ± 4.5mm/s; p = 0.015 and -0.12 ± 0.33 1/s vs -0.48 ± 0.51 1/s; p = 0.016, respectively). Right ventricle (RV) peak circumferential displacement was lower in patients with TIC (0.2 ± 1.3 vs 1.3 ± 0.9°; p = 0.009). In the multivariate analysis, diabetes (p = 0.046), presence of LGE (p = 0.028), LV peak systolic radial velocity < 7.5mm/s (p = 0.034), and RV peak circumferential displacement > 0.5° (p = 0.028) were independent predictors of lack of LVEF recovery. In the setting of acute HF with LV dysfunction related to SVT, diabetes, LGE, LV peak systolic velocity, and RV peak circumferential displacement are independent predictors of lack of LVEF recovery and, therefore, represent clinically useful parameters to differentiate TIC from DCM.

Prognostic value of enhanced cine cardiac MRI-based radiomics in dilated cardiomyopathy

BackgroundEarly precise identification of high-risk dilated cardiomyopathy (DCM) phenotype is essential for clinical decision-making and patient surveillance. The aim of the study was to assess the prognostic value of enhanced cine cardiac magnetic resonance (CMR)-based radiomics in DCM. MethodsWe prospectively enrolled 401 (training set: 281; test set: 120) DCM patients. Radiomic features were extracted from enhanced cine images of entire left ventricular wall and selected by the least absolute shrinkage and selection operator. Different predictive models were built using logistic regression classifier to predict all-cause mortality and heart transplantation. Model performances were compared with the area under the receiver operating characteristic curves (AUCs). Kaplan-Meier curves, log-rank test, and Cox regression were used for survival analysis. ResultsEndpoint events occurred in 65 patients over a median follow-up period of 25.4 months. 13 radiomic features were finally selected. The Rad_Combined model integrating clinical characteristics, CMR parameters and radiomics features achieved the best performance with an AUC of 0.836 and 0.835 in the training and test sets, respectively. High-risk groups with endpoint events defined by the Rad_Combined model had significantly shorter survival time than low-risk group in both the training [Hazard Ratio (HR) = 7.74, P < 0.001] and test sets (HR = 4.84, P < 0.001). ConclusionThe Rad_Combined model might serve as an effective tool to help risk stratification and clinical decision-making for patients with DCM. Trial registrationChinese Clinical Trial Registry, ChiCTR1800017058 by the ethics committee of West China hospital,Sichuan University.