New Study Elucidates Causes and Genetic Drivers of Sudden Cardiac Death in Young Adults: IHJ October 2025

The Clinical Challenge of Sudden Young Death

Sudden cardiac death in young adults (SCDY, defined here as ages 18–45 years) is a rare but paramount public health concern, often representing the first and last clinical manifestation of underlying heart disease. SCD is defined as an unexpected death from cardiac causes in an individual previously observed to be well within 24 hours of being found dead. Unlike the elderly population where atherosclerotic Coronary Artery Disease (CAD) is the single most common cause, SCD in the young is complex, frequently stemming from congenital or structural heart diseases. This prospective study aimed to identify the varied cardiovascular causes and genetic factors driving SCDY.

Study Overview

Conducted at a tertiary referral hospital in New Delhi over four years (October 2019–November 2023), the study included 59 suspected SCD cases aged 18 to 45 years who were previously healthy. The core methodology involved a thorough conventional and verbal autopsy, meticulous gross and microscopic cardiac examination by an expert cardiac pathologist, and whole-exome genetic sequencing (WEGS). This comprehensive approach aimed to provide a definitive diagnosis, even for cases that appeared structurally normal.

Key Clinical Findings

• Of the 59 cases analyzed (mean age 33.7 years, predominantly male), nearly two-thirds showed identifiable cardiac abnormalities.

• The leading observation was Sudden Unexplained Death (SUD)/negative autopsy (35.6%). In these cases, WES identified genetic variants in 42.8%. Sarcomeric genes (30.4 %) and Z-disk protein genes (21.7 %) constituted the most significant proportion, followed by genes associated with channelopathies and junctional proteins.

• Importantly, concealed cardiomyopathy-associated genes (77.8%) were far more common than channelopathy-related genes (22.2%) in SUD cases, suggesting that many unexplained deaths are caused by undiagnosed structural issues at the molecular level.

• The second most common cause was Atherosclerotic Coronary Artery Disease (CAD) with Myocardial Infarction (MI) (28.8%). CAD was most frequent in the older cohort (41–45 years). In 47.6% of CAD cases, occlusion involved the Left Anterior Descending artery (LAD).

• The third major category was Structural Cardiomyopathies (25.4%). Hypertrophic Cardiomyopathy (HCM) was the most common structural diagnosis, accounting for 66% of cardiomyopathy cases. Other identified structural causes included Dilated Cardiomyopathy (DCM), Arrhythmogenic Cardiomyopathy (ACM), and isolated cases of Postpartum Cardiomyopathy (PPCM).

Clinical Relevance for Practice

The findings underscore that SCDY is rarely truly random; a significant structural or genetic substrate is often present. Physicians should note the high prevalence of non-diagnostic autopsies (as seen in SUD), which, when coupled with WES, reveal a high frequency of genetic variants, particularly in sarcomeric genes and Z-disc protein genes. For clinical management, this indicates the necessity of post-mortem genetic testing, yielding a definitive diagnosis in 14.3% of SUD cases, often identifying genes linked to concealed cardiomyopathies.

Furthermore, the high incidence of CAD, particularly among young individuals with reported lifestyle risk factors such as smoking and alcohol use, highlights the urgent public health need to address these contributors to premature cardiovascular mortality. Family history remains a critical tool, as a positive history of sudden death may identify nearly two-thirds of patients with inherited genetic heart diseases, facilitating screening in surviving relatives.

Reference: Arava S, Goswami A, Pandit JN, Jain S, Dagar S, Mallick SK, Harisha K, Alam N, Srinivasamurthy A, Rijal R, Behera C. Sudden cardiac death in young: a cardiac-focused autopsy and molecular study to identify the cause. Indian Heart Journal. 2025 Jul 3.