Original Investigation
Association of Genetic Variants With Outcomes in Patients With Nonischemic Dilated Cardiomyopathy

https://doi.org/10.1016/j.jacc.2021.08.039Get rights and content
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Abstract

Background

The clinical relevance of genetic variants in nonischemic dilated cardiomyopathy (DCM) is unsettled.

Objectives

The study sought to assess the prognostic impact of disease-causing genetic variants in DCM.

Methods

Baseline and longitudinal clinical data from 1,005 genotyped DCM probands were retrospectively collected at 20 centers. A total of 372 (37%) patients had pathogenic or likely pathogenic variants (genotype positive) and 633 (63%) were genotype negative. The primary endpoint was a composite of major adverse cardiovascular events. Secondary endpoints were end-stage heart failure (ESHF), malignant ventricular arrhythmia (MVA), and left ventricular reverse remodeling (LVRR).

Results

After a median follow-up of 4.04 years (interquartile range: 1.70-7.50 years), the primary endpoint had occurred in 118 (31.7%) patients in the genotype-positive group and in 125 (19.8%) patients in the genotype-negative group (hazard ratio [HR]: 1.51; 95% confidence interval [CI]: 1.17-1.94; P = 0.001). ESHF occurred in 60 (16.1%) genotype-positive patients and in 55 (8.7%) genotype-negative patients (HR: 1.67; 95% CI: 1.16-2.41; P = 0.006). MVA occurred in 73 (19.6%) genotype-positive patients and in 77 (12.2%) genotype-negative patients (HR: 1.50; 95% CI: 1.09-2.07; P = 0.013). LVRR occurred in 39.6% in the genotype-positive group and in 46.2% in the genotype-negative group (P = 0.047). Among individuals with baseline left ventricular ejection fraction ≤35%, genotype-positive patients exhibited more major adverse cardiovascular events, ESHF, and MVA than their genotype-negative peers (all P < 0.02). LVRR and clinical outcomes varied depending on the underlying affected gene.

Conclusions

In this study, DCM patients with pathogenic or likely pathogenic variants had worse prognosis than genotype-negative individuals. Clinical course differed depending on the underlying affected gene.

Key Words

dilated cardiomyopathy
genetics
heart failure
left ventricular reverse remodeling
mutation
prognosis
sudden cardiac death
ventricular arrhythmia

Abbreviations and Acronyms

DCM
dilated cardiomyopathy
ESHF
end-stage heart failure
ICD
implantable cardioverter-defibrillator
LVEF
left ventricular ejection fraction
LVRR
left ventricular reverse remodeling
MACE
major adverse cardiovascular event
MVA
malignant ventricular arrhythmia
NGS
next-generation sequencing
SCD
sudden cardiac death
TTE
transthoracic echocardiogram

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Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.

Jeffrey A. Towbin, MD, served as the Guest Associate Editor for this paper. Christie Ballantyne, MD, served as the Guest Editor-in-Chief for this paper.

The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.

Drs Escobar-Lopez and Ochoa contributed equally to this work.