Genetic Dilated Cardiomyopathy and Response to Contemporary Heart Failure Therapy

Abstract

Introduction and Objectives: Since 2021, four therapeutic pillars-angiotensin receptor neprilysin inhibitor (ARNI) or ACE inhibitors /angiotensin receptor antagonists (ACEi/ARA), beta-blocker (BB), aldosterone receptor antagonist (ARM), and SGLT2 inhibitor (SGLT2i)-have been recommended for the treatment of patients with heart failure (HF) with reduced left ventricular ejection fraction (LVEF). The guidelines do not differentiate among etiologies of left ventricular dysfunction, however, the effects of these therapies specifically on genetic dilated cardiomyopathies remain unclear. In this retrospective study, we aimed to investigate the clinical response to the four pillars of therapy in a cohort of patients with familial dilated cardiomyopathy (fDCM) Methods: Patients diagnosed with fDCM were selected from heart failure and cardiomyopathy consultations at a tertiary hospital. The diagnostic criteria included the identification of pathogenic genetic variants in both sporadic and familial cases, as well as familial cases even if a conclusive genetic test was either not available or negative for VP. The analysis focused on patients who underwent serial echocardiograms after 2018. Echocardiographic changes from baseline to the last examination were determined, and only LVEF variation ≥10 percentage points were considered significant. The last visit recorded ongoing HF therapies, including the initiation date and dosage. Results: A total of 56 patients were included, 50% male, with a median age of 53 [range:20-79]. Pathogenic variants were identified in 32,1 % of patients. Initial LVEF was 40,5% [range: 17- 55], 10,7% of patients had atrial fibrillation, and 3,6% left bundle branch block. Fifty patients performed cardiac magnetic resonance, with late gadolinium enhancement present in 55,4%. During a follow-up period of 2,5 years, 96% of patients were treated with BB, 85,7% with ACEI/ARA, 59% ARNI, 79 % ARMs, and 93% with SGLT2i. The median LVEF at the last echocardiogram was 39,6% [range: 21- 57]. Six patients had an improvement in LVEF ≥ 10 points, and of these, only 3 reached a final LVEF >50%. In seven patients there was a reduction in LVEF in the same proportion, with a final value of 32% [range: 22- 41]. Most fDCM patients did not obtain a significant variation of LVEF despite optimized HF therapy. Conclusions: This study demonstrates that while the therapy using the four pillars is beneficial for patients with HF and reduced LVEF, the response may be insufficient for those with hereditary dilated cardiomyopathies. This highlights the need for clinical trials in these specific set of DCM patients.