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Coronary Imaging Outcomes Informed by Heart Disease-Related Genetic Risk Factors

NEW YORK – Several genetic features associated with coronary artery disease (CAD) in the past may also provide insights into individuals' heart disease-related outcomes after receiving coronary angiography imaging, according to new research by a Massachusetts General Hospital- and Harvard Medical School-led team.

"While genomics has conventionally been perceived as most helpful in primary CAD prevention, recent evidence shows a strong ability to even predict risk of recurrent events after a CAD diagnosis," senior and corresponding author Akl Fahed, an interventional cardiologist and physician-scientist with the Mass General Hospital's Cardiovascular Research Center, and his colleagues wrote in JAMA Network Open on Tuesday.

To look at additional insights that genomic information may provide for individuals who are already receiving CAD-related testing, the researchers performed a retrospective analysis that included 3,518 Mass General Brigham Biobank project participants who received coronary angiography imaging to test for CAD and track arterial blood flow into the heart.

By bringing in exome sequencing data for the participants, the team evaluated potential relationships between monogenic or polygenic germline risk variants and age-related somatic changes encompassed by clonal hematopoiesis of indeterminate potential (CHIP) using angiogram outcomes and other heart-related outcomes.

Within the participant group, the researchers identified 26 individuals with familial hypercholesterolemia (FH), a single-gene condition characterized by higher-than-usual levels of low-density lipoprotein cholesterol, coupled with enhanced risk of developing early-onset CAD. Another 1,191 participants were classified as having increased risk of CAD based on a polygenic risk score (PRS), while 466 individuals appeared to be at increased CAD risk due to CHIP.

"While associations of these genomic drivers with first-incident CAD events are well established in large cohorts, little is known about how genetically driven disease might present on coronary imaging among patients with known or suspected CAD," the authors explained, noting that the new work "underscores the added prognostic value of genomic risk assessments at the time of coronary angiography in forecasting future outcomes."

The investigators' results suggested that the CAD PRS and the single-gene changes in FH were each linked to CAD presentation, CAD severity and disease burden, clinical outcomes, and response to angiography treatment, including angiographic conditions such as revascularization after the procedure, the need for a repeat angiogram, or the appearance of scar tissue around a stent, known as in-stent restenosis.

Higher CAD PRSs coincided with an uptick in a measure of coronary artery lesion known as the Gensini score, along with a rise in risks of revascularization and in-stent stenosis. Similarly, the team found that the presence of a risky germline FH variant corresponded with enhanced risk of revascularization and higher likelihood of a repeat angiogram over an average of 9.2 years of follow-up.

The researchers did not see similar angiographic outcomes in the subset of participants with CHIP, on the other hand. Instead, their results hinted that CHIP carriers may be at increased heart failure and all-cause mortality risk.

"This cohort study observed that monogenic and polygenic risk of CAD were associated with an ACS presentation, with severity and burden of atherosclerotic plague on coronary angiography, and with a future risk of repeat angiography, revascularization, and in-stent restenosis," the authors reported.

Even so, they cautioned that "[a]dditional research is needed to establish generalizability of the findings in diverse ancestries, especially as the CAD PRS notably underperforms in individuals of African ancestry."