Patients with heart failure (HF) of mostly ischemic etiology were found to have increased burden of mendelian cardiomyopathy variants compared with control individuals, according to a study published in JAMA Cardiology.

In this retrospective study, researchers evaluated whole-exome sequencing data of patients with HF from the Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity (CHARM) and Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) trials.

A total of 5942 patients with HF and 13,156 controls were included in this retrospective study (mean age, 68.9 years; 70.9% men).

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A significant enrichment of protein-truncating variants in the TTN gene were found (odds ratio [OR], 2.54; 95% CI, 1.96-3.31; P =3.35×10−13). This enrichment was found to be further increased when only taking account of exon variants expressed in heart tissues (OR, 4.52; 95% CI, 3.10-6.68). There was a similar enrichment in a validation set using data from the UK Biobank (OR, 4.97; 95% CI, 3.94-6.19).

Of the patients with HF, 3.4% had a documented pathogenic or likely pathogenic cardiomyopathy variants in 21 different genes, and 60.2% of those patients had HF with ischemic heart disease as the clinically identified etiology. There was a lower yield in patients with HF and preserved ejection fraction vs patients with either midrange or reduced ejection fraction (2.6% vs 3.8% vs 3.5%, respectively). The investigators note that this difference could be explained by different rates of truncating TTN variants.

A limitation of this retrospective analysis was the inclusion of relatively small patient subgroups, particularly subgroups that included patients who carried a diagnostic variant.

The researchers concluded that their findings “show that rare genetic variants provide complementary information to the clinical phenotypes in patients with HF.”

Disclosure: This clinical trial was supported by AstraZeneca. Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Povysil G, Chazara O, Carss KJ, et al. Assessing the role of rare genetic variation in patients with heart failure. Published online December 16, 2020. JAMA Cardiol. doi:10.1001/jamacardio.2020.6500

This article originally appeared on The Cardiology Advisor