Penn Team Finds Genetic Variant Largely Found in Patients of African Descent that Increases Heart Failure Risk

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African American man having pains holding his chest.

A genetic variant found in about 3% of people of African ancestry is a more significant cause of heart failure than previously believed, according to a multi-institution study led by researchers at Penn Medicine. The researchers also found that this type of heart failure is underdiagnosed. According to their study, 44% of TTR V122I variant carriers older than age 50 had heart failure, but only 11% of these individuals had been diagnosed with hATTR-CM. The average time to diagnosis was three years, indicating both high rates of underdiagnoses and prolonged time to appropriate diagnosis

“This study suggests that workup for amyloid cardiomyopathy and genetic testing of TTR should be considered, when appropriate, to identify patients at risk for the disease and intervene before they develop more severe symptoms or heart failure,” said the study’s lead author Scott Damrauer, M.D., an assistant professor of Surgery at Penn Medicine and a vascular surgeon at the Corporal Michael J. Crescenz VA Medical Center. (Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania and the University of Pennsylvania Health System.)

In this study, researchers from Penn Medicine and the Icahn School of Medicine at Mount Sinai used a ‘genome-first’ approach, performing DNA sequencing of 9,694 individuals of African and Latino ancestry enrolled in either the Penn Medicine BioBank (PMBB) or the Icahn School of Medicine at Mount Sinai BioMe biobank (BioMe). Researchers identified TTR V122I carriers and then examined longitudinal electronic health record-linked genetic data to determine which of the carriers had evidence of heart failure.

The findings, which were published today in JAMA, are particularly important given the US Food and Drug Administration’s (FDA) approval of the first therapy (tafamidis) for ATTR-CM in May 2019. Prior to tafamidis’s approval, treatment was largely limited to supportive care for heart failure symptoms and, in rare cases, heart transplant.

“Our findings suggest that hATTR-CM is a more common cause of heart failure than it’s perceived to be, and that physicians are not sufficiently considering the diagnosis in certain patients who present with heart failure,” said the study’s corresponding author Daniel J. Rader, M.D., chair of the Department of Genetics at Penn Medicine. “With the recent advances in treatment, it’s critical to identify patients at risk for the disease and, when appropriate, perform the necessary testing to produce an earlier diagnosis and make the effective therapy available.”

hATTR-CM, also known as “cardiac amyloidosis,” typically manifests in older patients and is caused by the buildup of abnormal deposits of a specific transthyretin protein known as amyloid in the walls of the heart. The heart walls become stiff, resulting in the inability of the left ventricle to properly relax and adequately pump blood out of the heart. However, this type of heart failure—which presents similar to hypertensive heart disease— is common, and the diagnosis of hATTR-CM is often not considered.

Tafamidis meglumine is a non-NSAID benzoxazole derivative that binds to TTR with high affinity and selectivity. TTR acts by transporting the retinol-binding protein-vitamin A complex. It is also a minor transporter of thyroxine in blood. Its tetrameric structure can become amyloidogenic by undergoing rate-limiting dissociation and monomer misfolding.

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