Hypercoagulability or coronary artery disease? Polygenic risk score unveils the mystery

Abstract

Background/Synopsis

CB is a 58 year old nonsmoker without significant cardiovascular risk factors presented with a myocardial infarction with unclear etiology.

Objective/Purpose

To review a clinical scenario involving use of polygenic risk score (PRS) to clarify the etiology of cardiovascular event and further risk stratify to guide lipid management.

Methods

CB was seen in the office at Lipid Clinic at Penn for further evaluation.

Results

CB is a 58 year old nonsmoker male without family history of premature coronary artery disease (CAD) or any major cardiovascular risk factors, found to have extensive CAD when he presented with a STEMI s/p DES to RCA and PCI to PLA and PDA, along with non-critical lesions (30-40% stenosis) in LAD and Lcx. The STEMI occurred in the setting of COVID-19 infection, raising the question about true etiology.

Using conventional risk calculators, his 10-year ASCVD risk is estimated at about 6% (“borderline risk”), therefore underestimating his risk and extensive CAD. Some clinicians evaluating the patient focused towards hypercoagulability and thrombosis in the setting of his COVID infection, however that would not sufficiently explain his atherosclerotic disease.

Keeping in mind that the patient has two children and five siblings, it was important to assess his genetic risk despite lack of family history of CAD. His polygenic risk score for CAD riskshowed the 97th percentile risk, clarifying his cardiovascular risk factor and also prompting for more aggressive preventive treatment and cascade screening for family.

Conclusions

Cardiovascular disease is the leading cause of death in the United States and globally. While the Framingham Risk Score and the Pooled Cohort Equations (PCE) provide a useful construct to guide the use of medications for cardiovascular prevention, they miss certain opportunities at early intervention, especially for patients with significant genetic risk. Hence, incorporation of genetics into risk prediction frameworks offer a wide range of opportunity for early detection toward earlier and targeted risk reduction strategies.

Polygenic risk score (PRS) is a novel tool in precision medicine to quantify inherited risk for a given disease based on the cumulative impact of many common sites of DNA variation. Although we do not anticipate PRS to replace traditional guideline based approach, it may indeed be helpful - and akin to other CAD risk-enhancing factors - when there is clinical uncertainty. As seen in our case, using a PRS for CAD can help explain the etiology of CAD, modify treatment goals, and more effectively screen relatives for otherwise unrecognized cardiovascular risk.