As researchers continue to pursue the genetic drivers behind heritable cardiac conditions, new research has revealed genetic variants that cause cardiomyopathy also increase the risk for atrial fibrillation, even in people who do not have heart failure or obvious ventricular disease.

“We found that ventricular cardiomyopathy genes were associated with an increased risk of atrial fibrillation after adjusting for diagnoses of ventricular cardiomyopathy and clinical heart failure — supporting the notion that these genes may be causing atrial fibrillation through a direct impact on the atria,” senior study author Jason Roberts, MD, MAS, told Medscape Medical News.

The study, published in the Journal of the American College of Cardiology, included 655,796 people from two large prospective cohort studies: the UK Biobank and the US-based All of Us. The researchers evaluated associations within genes for three cardiomyopathies — dilated, hypertrophic, and arrhythmogenic right ventricular — and atrial fibrillation.

Study participants who had one of the culprit variants had a 73% increased risk for atrial fibrillation (P < .001). The risk remained high after adjustment for incident ventricular cardiomyopathy or clinical heart failure, with a hazard ratio of 1.55 (95% CI, 1.46-1.64; P < .001).

Impact of Genetic Variants

A putative disease-causing variant combined with a polygenic risk score in the highest quintile for atrial fibrillation was also associated with incident disease.

Specifically, participants who had both the disease-causing variant and an atrial fibrillation polygenic risk score in the top quintile had a 32.5% cumulative risk for atrial fibrillation in the UK group and 32.4% in the US group. In contrast, those without the putative disease-causing variant and a polygenic risk score in the lowest-risk quintile had cumulative risks of 9.8% and 11%, respectively, for atrial fibrillation.

“In this context, although ventricular cardiomyopathy may be more clinically severe, we found that the impact of these genes on the risk of developing atrial fibrillation may be greater than the risk of developing ventricular cardiomyopathy,” said Roberts, an associate professor at McMaster University in Hamilton, Ontario, Canada.

These genes may predispose people to atrial fibrillation or ventricular cardiomyopathy. “Integrating polygenic risk scores into the genetic evaluation of carriers provides insight into being able to predict whether an atrial or ventricular phenotype will develop,” Roberts said.

Traditional science held that heart failure was the reason people with ventricular cardiomyopathy developed atrial fibrillation because the compromised ventricles are causing high filling pressures in the atria, he said.

“However, it’s also very important in these genetic patients, and a lot of patients that develop heart failure, that they probably have some kind of underlying vulnerability in the atria,” he said. “It’s believed the atrial tissue is not completely functional.”

The same genetic variants might have a more prominent impact on the atria, according to Roberts. “That being said, if someone has a ventricular cardiomyopathy at a young age, it can be clinically much more impactful than developing atrial fibrillation later on in life,” he said.

The findings suggest patients with a genetic variant associated with ventricular cardiomyopathy should be counseled not only on the risk for ventricular cardiomyopathy but also on the risk for atrial fibrillation, Roberts added.

“It may encourage the use of polygenic risk scores in patients who possess these variants,” he said, acknowledging that polygenic risk scores are not often used in cardiology clinics. “We feel this represents a powerful use case.”

Role of Polygenic Risk Score

The study’s large sample size provided appropriate statistical power to evaluate the genetic variants in cardiomyopathy. However, the use of the large cohort studies limit the scope of patient details, Roberts said.

The study sheds new light on potential genetic markers of atrial fibrillation, said M. Benjamin Shoemaker, MD, MSCI, an associate professor of cardiovascular medicine at Vanderbilt University Medical Center in Nashville, Tennessee. Shoemaker was not involved in the study.

“Up to now, rare pathogenic variants in only a handful of genes had been shown to be statistically associated with atrial fibrillation,” he said. “Among those were TTN, LMNA, PKP2, and MYBPC3, but many of us in the field believed the other major cardiomyopathy genes were also associated with early-onset atrial fibrillation. The results of this analysis support that idea.”

The findings also support increasing the number of cardiomyopathy genes for which patients with early-onset atrial fibrillation are tested, he said. “This can be readily implemented given the availability of comprehensive cardiomyopathy panels available through a multitude of commercial genetic testing providers,” Shoemaker said.

“A strength of this study is that it asks one of the most important clinical questions that comes up after a patient with early-onset atrial fibrillation is found to carry a pathogenic cardiomyopathy variant in clinic, that is, will the patient progress to also develop ventricular cardiomyopathy or heart failure?” he added. “This study shows we may be able to estimate the risk of that using polygenic risk scores, which are beginning to become available for use in the clinic.”

Future studies should focus on clinical cohorts that have had prospective genetic evaluation that defines both rare variants and polygenic risk, Shoemaker said. “This will enable us to learn how to personalize the care of patients with genetic subtypes of atrial fibrillation to improve their long-term outcomes.”

Roberts and Shoemaker reported having no relevant financial relationships.

Richard Mark Kirkner is a medical journalist based in Philadelphia.