Arrhythmic Risk in Nonischemic Cardiomyopathy: Key Points

Chrispin J, Merchant FM, Lakdawala NK, et al.
Risk of Arrhythmic Death in Patients With Nonischemic Cardiomyopathy: JACC Review Topic of the Week. J Am Coll Cardiol 2023;82:735-747.

The following are key points to remember from a review about the risk of arrhythmic death in patients with nonischemic cardiomyopathy (NICM):

  1. Mechanisms of ventricular arrhythmias (VAs) in patients with NICM mainly involve re-entry, and triggered activity may also play a role. Diffuse and patchy fibrosis causes electrophysiologic remodeling resulting in slowed conduction and functional block. Prolongation and dispersion of the action potential duration related to dysregulation of multiple types of ion channels and gap junctions increase the risk of arrhythmias and sudden cardiac death (SCD).
  2. In the SCD-HeFT (Sudden Cardiac Death in Heart Failure trial) study, implantable cardioverter-defibrillators (ICDs) were associated with a similar reduction in mortality in both the ischemic and nonischemic cohorts. The DEFINITE (Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation) study raised questions regarding the role for primary prevention ICDs in NICM. The DANISH (Danish Study to Assess the Efficacy of ICDs in Patients With Nonischemic Systolic Heart Failure on Mortality) trial failed to demonstrate a mortality benefit with ICD. In this study, almost 60% of patients in both arms had cardiac resynchronization therapy (CRT) devices, and the benefit of ICD therapy on top of CRT may be negligible. A follow-up analysis of the DANISH study noted a linear inverse relationship between age and the likelihood of survival benefit associated with ICDs, such that ICDs significantly reduced mortality in patients ≤70 years old, whereas no benefit was observed over age 70 years due to a higher proportion of nonarrhythmic causes of death.
  3. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor-neprilysin inhibitors, beta-blockers, spironolactone, and sodium-glucose cotransporter-2 inhibitors reduce VA and SCD in NICM, and their use carries a Class Ia recommendation in the 2017 American College of Cardiology/American Heart Association/Heart Rhythm Society guidelines to reduce SCD.
  4. A significant number of SCD events occur in patients who do not meet criteria for primary prevention ICD therapy based on left ventricular ejection fraction (LVEF). Biomarkers of heart failure and fibrosis such as N-terminal pro–B-type natriuretic peptide, galectin-3, and soluble suppression of tumorigenicity 2 (sST2) in combination with clinical risk factors may be useful in predicting SCD. A novel clinical risk assessment tool (VFRisk) employs 13 widely available clinical markers to augment risk stratification for patients with NICM, focusing on shockable rhythms as opposed to nonshockable rhythms.
  5. Consensus statements advise genetic testing for patients with NICM, especially with a suggestive family history. Rare cardiomyopathy causing variants in LMNA, DSP, PLN, FLNC, and RBM20 have been associated with an increased risk of VA that often presents with mildly reduced or preserved systolic function. A VA risk score ( ) in LMNA heart disease improves VA risk assessment using five variables routinely captured in practice: gender, non-missense mutation, atrioventricular block, nonsustained ventricular tachycardia, and LVEF.
  6. The presence of late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging increases VA risk regardless of LVEF or New York Heart Association class. The sensitivity of LGE is reduced in diffuse myocardial fibrosis. Specific sequences such as longer native T1 and shorter post-contrast T1 times may signify diffuse fibrosis and provide a more robust marker of the percent of interstitial space occupied by fibrosis.
  7. Improved phenotyping of genetic cardiomyopathies may allow for more targeted risk stratification. The authors propose several paths for future investigative work: 1) mode of sudden arrhythmic death, 2) risk stratification in NICM patients with mid-range LVEF or normal EF, 3) novel myocardial imaging methodologies, 4) genetic and genomic markers, and 5) assessment of competing risks of mortality. Personalized computational modeling is a promising tool for investigating arrhythmogenic propensity and SCD risk.

Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Prevention, Implantable Devices, EP Basic Science, Genetic Arrhythmic Conditions, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Magnetic Resonance Imaging

Keywords: Anti-Arrhythmia Agents, Arrhythmias, Cardiac, Cardiomyopathies, Cardiac Resynchronization Therapy, Death, Sudden, Cardiac, Defibrillators, Implantable, Diagnostic Imaging, Electrophysiology, Fibrosis, Heart Failure, Genetics, Magnetic Resonance Imaging, Natriuretic Peptide, Brain, Primary Prevention, Risk Assessment, Stroke Volume, Ventricular Function, Left

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