Patients who were hospitalized for severe COVID-19 in 2020 face an increased risk of major cardiac events that is as high as the risk conferred by having a medical history of heart disease, according to new USC research. The findings, based on data from more than 10,000 COVID-19 cases, could help shape clinical guidelines on preventing heart problems in people who had a severe case of the virus.

“The question now is: Could this finding, along with subsequent studies, change international guidelines for preventive cardiac care, even in the absence of known heart disease?” said Hooman Allayee, PhD, a professor of population and public health sciences and biochemistry and molecular medicine at the Keck School of Medicine of USC and a senior author of the study.

Early in the pandemic, it became clear that COVID-19 infection was linked to increased risk of blood clots and other cardiovascular problems, both during and after the acute phase of infection. But a lack of clear research showing how long that risk lasts, and what factors influence it, means there are not yet official clinical guidelines with respect to cardiovascular disease prevention strategies for individuals who developed COVID-19.

The new research, funded in part by the National Institutes of Health and published in Arteriosclerosis, Thrombosis and Vascular Biology, a journal of the American Heart Association, is beginning to fill that gap. Using data from the U.K. Biobank, a large biorepository that tracks the health of United Kingdom residents over time, a research team from the Keck School of Medicine, UCLA and Cleveland Clinic studied the link between COVID-19 infection and major cardiac events, including heart attacks and strokes, over a period of nearly three years, one of the longest time frames studied so far.

They found that COVID-19 hospitalization was a “CAD risk equivalent,” or a coronary artery disease risk equivalent, a term for a condition that increases risk for future strokes, heart attacks and other problems at least as much as having a prior history of cardiovascular disease. In this case, the risk from COVID-19 hospitalization was even slightly higher.

That increased risk was not the same for all patients in the study. A further genetic analysis revealed that people with A, B and AB blood types and a history of severe COVID-19 infection faced an even greater risk of future heart problems than people with an O blood type who had severe COVID-19 in the past. This suggests that a person’s genetic makeup could also determine whether they have a cardiovascular event in the future after developing severe COVID-19.

The researchers hope the findings can help inform clinical practice guidelines—set by the American Heart Association as well as other national and international regulatory bodies —aimed at preventing heart problems. Already, patients with certain CAD-equivalent risk factors, including a diagnosis of diabetes, are routinely given statins and other preventive therapies to reduce the chance of a heart attack or stroke, even without having a history of cardiovascular disease.

“We’re the first ones to really approach this link from a clinical guidelines standpoint with the CAD equivalence analysis, which can help demonstrate to physicians the potential benefits of taking preventive action,” said James Hilser, MPH, a doctoral candidate in biochemistry and molecular medicine at the Keck School of Medicine and the study’s first author.

COVID-19 and heart problems

The researchers used U.K. Biobank data from 10,005 people who had COVID-19 and 217,730 people who did not get infected between February 1, 2020 and December 31, 2020. To simplify the analysis, they only looked at people who were unvaccinated. The researchers then looked for links between severity of COVID-19 infection and major cardiac events over approximately three years.

All patients who had COVID-19 faced a higher risk for major adverse cardiac events (such as a heart attack, stroke or mortality by any cause) over the study period, which was 1,003 days. Patients hospitalized for COVID-19—with no history of heart disease—had the same or slightly higher risk of a major cardiac event than people with heart disease that did not get COVID-19.

The study also revealed one of the first known “gene-pathogen interactions” for cardiac events—where a person’s genetic code interacts with an environmental exposure (in this case, the COVID-19 virus) to increase their risk for heart problems. People with non-O blood types (A, B or AB) faced a higher risk of adverse cardiac events after getting COVID-19 than people with the O blood type.

The researchers ran several additional genetic analyses to explore that disparity, including whether it could be explained by other genetic factors that increase the risk of getting severe COVID-19 or the risk of developing heart disease.

“We’re trying to rule out other alternative explanations, but it looks like there’s really something biological going on with these specific blood groups,” Allayee said.

Preventing heart attacks and strokes

Knowing that a history of severe COVID-19 is a CAD risk equivalent could change how medical providers approach prevention in certain patients, the researchers said. For example, physicians may consider giving medications, such as aspirin, statins or ACE inhibitors prophylactically to reduce the risk of cardiac events in patients who developed severe COVID-19. Indeed, a preliminary sub-analysis in the study showed that severe COVID-19 patients already taking aspirin for other reasons were less likely to have a heart attack or stroke.

“This study underscores that we should consider history of prior COVID-19 infection when formulating cardiovascular disease preventive plans and goals,” said co-senior author Stanley Hazen, MD, PhD, a physician-scientist and director of the Center for Cardiovascular Diagnostics and Prevention at Cleveland Clinic.

Going forward, the researchers say more direct studies of the link are needed, such as randomized clinical trials to test whether these preventive drugs can directly decrease the risk of cardiac events in people who had severe COVID-19. They also plan to study other genetic factors that might influence the association and to conduct mechanistic studies to better understand what is occurring in the arteries to increase a person’s risk of heart attack and stroke.

About this research

In addition to Allayee, Hilser and Hazen, the study’s other authors are Neal J. Spencer, Kimia Afshari, Frank D. Gilliland, Howard Hu and Jaana A. Hartiala from the Keck School of Medicine of USC, University of Southern California; Arjun Deb and Aldons J. Lusis from the David Geffen School of Medicine, University of California, Los Angeles; and W. H. Wilson Tang from Cleveland Clinic, Cleveland, Ohio.

This work was supported by the National Institutes of Health [R01HL148110, R01HL168493, U54HL170326, P30ES007048, R01DK132735, P01HL147823 and R01HL147883].