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Rare Genetic Variants Can Contribute to Ischemic Heart Failure

NEW YORK – Patients with heart failure, even if linked to ischemic disease, have increased numbers of rare variants in genes typically linked to dilated cardiomyopathy, a new analysis has found.

Heart failure affects about 40 million people globally, and most cases are due to ischemic heart disease, hypertension, or cardiomyopathies. Cardiomyopathies have been traced to rare variants in genes that encode sarcomere or cytoskeletal proteins, channels, or desmosomes, while genome-wide association studies have underscored common variants linked to heart failure. But as Columbia University Medical Center's David Goldstein and his colleagues from AstraZeneca and elsewhere noted in their new study, the role of rare variants in heart failure has been little explored. 

Using whole-exome sequencing data from nearly 6,000 heart failure patients, the researchers uncovered an enrichment of variants typically associated with dilated cardiomyopathy among patients with ischemic disease-linked heart failure, in particular rare, protein-truncating variants in the TTN gene. As they reported in JAMA Cardiology on Wednesday, the findings suggest genes linked to Mendelian conditions could also influence complex, late-onset diseases.

According to Goldstein, the results also support the idea that the cardiomyopathy-linked genes could represent therapeutic targets. "We see the results as making the genes responsible for cardiomyopathies potentially more attractive targets for intervention, given their broad relevance," he wrote in an email. "There remains significant clinical need in particular for [heart failure with preserved ejection fraction]," where the heart pumps well but is too stiff to fill normally. 

For their study, he and his colleagues sequenced the exomes of 5,942 people with heart failure from the the Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity (CHARM) and the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) clinical trials. Most of the patients in the CORONA and CHARM trial had heart failure with reduced ejection fraction, though a portion of the CHARM study patients had heart failure with preserved ejection fraction. The studies included 13,156 unrelated controls.

In their analysis of all heart failure subtypes, the TTN gene reached studywide significance, with the strongest association in a dominant protein truncation variant model. Protein truncation variants in TTN are a known cause of cardiomyopathy, particularly dilated cardiomyopathy. Most of the cardiomyopathy-associated variants cluster in the distal exons, and the likelihood that a variant is pathogenic can be captured by the proportion spliced-in (PSI) metric.

More than 55 percent of heart failure patients with TTN-truncating variants with high PSI scores had ischemic heart disease as their primary etiology, suggesting that even though TTN variants are only known to cause nonischemic cardiomyopathies, they are enriched among heart failure patients with ischemic disease, as compared to controls. 

Similarly, the researchers noted that the TET2 gene reached significance in a protein truncation variant model among the subgroup with heart failure with reduced ejection fraction from the CORONA trial.

In a diagnostic analysis of 41 known cardiomyopathy genes, the researchers uncovered 204 diagnostic variants in 201 of 5,916 heart failure patients. A large portion — 61.3 percent — of the diagnostic variants were TTN-truncating variants. Among people with ischemic heart disease, the researchers uncovered diagnostic variants in a number of dilated cardiomyopathy genes like TTN, DSG2, and BAG3.

The researchers additionally validated their findings using data from the UK Biobank cohort.

The results show that cardiomyopathy-related genes may also contribute to more common forms of heart failure. In a related commentary also appearing in JAMA Cardiology, Northwestern University School of Medicine's Elizabeth McNally and Harvard Medical School's Christopher O'Donnell suggested that the combination of a cardiomyopathy risk allele with an ischemic insult "may represent a primary and secondary hit combination, akin to what is observed in cancer genetics."