Role of arrhythmic phenotype in prognostic stratification and management of dilated cardiomyopathy.

AIMS: Dilated cardiomyopathy (DCM) with arrhythmic phenotype combines phenotypical aspects of DCM and predisposition to ventricular arrhythmias, typical of arrhythmogenic cardiomyopathy. The definition of DCM with arrhythmic phenotype is not universally accepted, leading to uncertainty in the identification of high-risk patients. This study aimed to assess the prognostic impact of arrhythmic phenotype in risk stratification and the correlation of arrhythmic markers with high-risk arrhythmogenic gene variants in DCM patients. METHODS AND RESULTS: In this multicentre study, DCM patients with available genetic testing were analysed. The following arrhythmic markers, present at baseline or within 1 year of enrolment, were tested: unexplained syncope, rapid non-sustained ventricular tachycardia (NSVT), ≥1000 premature ventricular contractions/24 h or ≥50 ventricular couplets/24 h. LMNA, FLNC, RBM20, and desmosomal pathogenic or likely pathogenic gene variants were considered high-risk arrhythmogenic genes. The study endpoint was a composite of sudden cardiac death and major ventricular arrhythmias (SCD/MVA). We studied 742 DCM patients (45 ± 14 years, 34% female, 410 [55%] with left ventricular ejection fraction [LVEF] <35%). During a median follow-up of 6 years (interquartile range 1.6-12.1), unexplained syncope and NSVT were the only arrhythmic markers associated with SCD/MVA, and the combination of the two markers carried a significant additive risk of SCD/MVA, incremental to LVEF and New York Heart Association class. The probability of identifying an arrhythmogenic genotype rose from 8% to 30% if both early syncope and NSVT were present. CONCLUSION: In DCM patients, the combination of early detected NSVT and unexplained syncope increases the risk of life-threatening arrhythmic outcomes and can aid the identification of carriers of malignant arrhythmogenic genotypes.

Apoptosis, a useful marker in the management of hot-phase cardiomyopathy?

AIMS: 'Hot phases', characterized by chest pain and troponin release, may represent the first clinical presentation of arrhythmogenic cardiomyopathies. Differential diagnosis with acute myocarditis is an unmet challenge for the clinicians. We sought to investigate histological and genetic features in patients with cardiomyopathy presenting with hot phases. METHODS AND RESULTS: We evaluated a case series of consecutive patients hospitalized for suspected 'hot-phase cardiomyopathy' in two Italian centres from June 2017 to March 2022 (median follow-up 18 months) that underwent both endomyocardial biopsy (EMB) and genetic testing. Apoptosis was confirmed with TUNEL assay. Among the 17 enrolled patients (mean age 34 ± 15 years, 76% male), only six patients (35%) presented standard histological and immunohistochemical markers for significant cardiac inflammation at EMB. Conversely, apoptosis was found in 13 patients (77%). Genetic testing was positive for a pathogenic/likely pathogenic (P/LP) variant in genes involved in cardiomyopathies (most frequently in DSP) in eight patients (48%), rising to 62% among patients with apoptosis on EMB. Notably, all patients without apoptosis tested negative for P/LP disease-related variants. Left ventricular ejection fraction was lower in patients showing apoptosis at EMB compared to those without (p = 0.003). CONCLUSIONS: Apoptosis, rather than significant inflammation, was mostly prevalent in this case series of patients with 'hot-phase' presentation, especially in carriers of variants in cardiomyopathy-related genes. Detecting apoptosis on EMB might guide clinicians in performing genetic testing and in more tailored therapeutic choices in 'hot-phase cardiomyopathy'.

New echocardiographic indices of shift to biventricular failure to optimize risk stratification of chronic heart failure.

AIMS: The present study investigated the prognostic impact of either isolated left atrial (LA) impairment, or its association with right ventricular (RV) failure, in heart failure (HF) with reduced ejection fraction (HFrEF), using basic and speckle tracking echocardiography (STE). METHODS AND RESULTS: One hundred and six outpatients with HFrEF were enrolled in this prospective observational study. Patients with primary lung diseases, non-sinus rhythm, previous cardiac surgery, and poor acoustic window were excluded. After clinical examination and basic echocardiography, STE was used to measure peak atrial longitudinal strain (PALS) and a new marker of RV performance and pulmonary circulation relation: free-wall RV longitudinal strain (fwRVLS)/systolic pulmonary artery pressure (sPAP). Patients were followed for all-cause/cardiovascular death and HF hospitalization. Of 84 eligible patients (60.1 ± 11.5 years; 82% male patients), 48 reached the combined endpoint (cardiovascular death and/or HF hospitalization). Population was divided into three groups: Group 1 (PALS ≥ 15 and fwRVLS/sPAP ≤ -0.5), Group 2 (PALS ≤ 15 and fwRVLS/sPAP ≤ -0.5), and Group 3 (PALS ≤ 15 and fwRVLS/sPAP > -0.5). Mean follow up was 3.5 ± 0.3 years. The higher severity groups were associated with higher LA volume index (P < 0.0001), New York Heart Association class (P = 0.02), mitral regurgitation (P = 0.0004) and tricuspid regurgitation grades (P < 0.0001), lower left ventricular (LV) ejection fraction (P = 0.0003), LV global longitudinal strain (P < 0.0001), PALS (P < 0.0001), tricuspid annular plane systolic excursion (P < 0.007), sPAP (P < 0.0001), and RV strain (P < 0.0001). Reduced PALS and fwRVLS/sPAP were independent predictors of the combined endpoint with adjusted Cox models (hazard ratio = 9.54; 95% confidence interval = 2.95-30.92; P = 0.0002 for Group 3 vs. Group 1). Kaplan-Meier curves showed early and persistent divergence between the three groups for the prediction of the combined endpoint and of all-cause death (P < 0.0001). CONCLUSIONS: The combination of LA and right heart damage entails worse prognosis in patients with HFrEF. The evaluation of PALS and fwRVLS/sPAP could aid risk stratification of HFrEF patients to provide them early treatment.