Long-term Risk of Heart Attack, Stroke and Death Doubles with History of COVID-19 Infection

Podcast Transcript

Announcer:

Welcome to Cleveland Clinic Cardiac Consult, brought to you by the Sydell and Arnold Miller Family Heart, Vascular and Thoracic Institute at Cleveland Clinic.

Stanley Hazen, MD, PhD:

My name is Stanley Hazen. I'm the co-section head of Preventive Cardiology and Cardiac Rehabilitation at the Cleveland Clinic. My interests are in trying to identify novel contributors to cardiovascular disease, in particular beyond the traditional risk factors for a heart attack or stroke. So beyond cholesterol, blood pressure, diabetes, weight, exercise, we know that if you treat all of those things, still the majority of events continue to happen. We know that there are additional pathways and processes that contribute to residual cardiovascular risk. One of the things that we've noticed clinically over the last few years is that there is a surprising increase in the number of heart attacks and strokes that are happening to younger people. Part of this brought us to the interest in trying to study what the impact of COVID is on cardiac health because early on we saw that patients who experienced COVID and were hospitalized for COVID had a higher incidence of thrombotic events in the hospital like heart attack and stroke.

In our study, we looked at the UK Biobank. This is a cohort of subjects in the United Kingdom that were enrolled in 2000 and followed over time. Because they had very good access to whether or not the subjects in the cohort, and this is over a quarter of a million people, had experienced COVID and had a PCR-positive COVID test, we could leverage use of this database to ask questions like, for those individuals amongst the quarter of a million who experienced a positive COVID test, what was their risk for then experiencing, subsequent to COVID, a heart attack, stroke, or death? Now, at the time that we began our studies, it had already been published that in the near term, that is in the one month or up to three month range after experiencing COVID, one saw an increase in the risk of heart attack and stroke.

But long-term risk for cardiovascular events following a COVID infection had not been reported. So using UK Biobank in approximately a quarter of a million subjects, we looked at the dataset and saw that individuals who just had a PCR-positive COVID test, this is before vaccinations were given out, so in the year 2020. And out of a quarter million people enrolled, we had thousands of COVID-positive subjects. And then amongst those, there was at least a two-fold increased risk for heart attack, stroke, or death over the ensuing period of follow-up. So that was up to three years of follow-up now are available. So in the years 2021, 2022 and 2023, we saw a doubling in the risk of heart attack, stroke, and death. Now, the subjects that we're looking at are all 50 and older, and it's a community-based cohort. And we saw that this increase in risk was independent of traditional risk factors.

So whether or not the subjects had high blood pressure or diabetes or high cholesterol really did not impact the risk for heightened cardiovascular event risk. The increased risk was seen predominantly in thrombotic events like heart attack and stroke. Another thing that was quite surprising is that if we looked at the trajectory of the increase in risk, it did not attenuate over time. So what I mean by that is by looking at subjects in the first year after the COVID infection versus the second year or even waiting to look only between year two and year three in that third year, there still was the same increase in risk observed. So something about COVID seems to be rewiring subjects and making them more prone to developing cardiovascular events in the future.

Another thing that we looked at is what is the impact of severity of disease on the risk for a heart attack, stroke, or death following COVID infection? We used severe COVID as defined by being hospitalized for COVID as an indication for the hospitalization. We found that subjects who had severe COVID were at even higher risk, somewhere between four and sevenfold risk. So the severity of the COVID infection seems to result in a long-lasting effect on long-term cardiac risk, incident risk for MI, stroke or death. And the magnitude of that increase in risk following severe COVID infection was comparable in magnitude to a coronary artery disease risk equivalent. What we mean by that is that if for someone who had coronary artery disease or like a heart attack, what their risk for a second heart attack is is the same risk as a subject who had never had documented coronary artery disease or cardiovascular disease, and they experienced severe COVID. What their risk for experiencing an incident cardiovascular event was, is the same as if someone who had no COVID and had one heart attack, what their risk is for the next heart attack.

So these results suggest to us that we need to reappraise the use of incorporating COVID history, especially severe COVID infection, into risk assessment in patients, because we traditionally use a coronary artery disease risk equivalence as a threshold for changing our preventive recommendations to subjects in terms of escalating preventive efforts in subjects who have a CAD risk equivalent. What do I mean by escalating preventive efforts? So we lower our LDL cholesterol goals. We recommend low dose aspirin as long as it's not contraindicated, and just become more globally aggressive with monitoring blood pressure control, diabetes control, and all of the traditional cardiovascular risk factors in patients who have documented coronary artery disease or a coronary artery risk equivalent. So I think one of the interesting findings of these studies and which suggests future research area needs to focus on is whether or not people who experience severe COVID should be managed by their physicians in a more aggressive way for preventive cardiovascular risk reduction into the future.

Another thing that was done in our studies was to try to get a handle on why or how is COVID increasing risk for cardiovascular disease. And to get at that, we looked at the genetics of what genetic susceptibility factors seem to be linked to heightened post-COVID cardiovascular disease risk. We looked at this in a targeted way by looking at known genetic variants that are linked to heightened risk for coronary artery disease or heart attack and stroke or risk for adverse cardiac events. Also we looked at genetic susceptibility factors for susceptibility for infection with COVID. What was surprising is the vast majority of known genetic determinants of heart disease and COVID susceptibility were not responsible for heightening the risk post-COVID for cardiovascular events like heart attack and stroke. The only thing that showed up as a risk was ABO blood type. That's actually a genotype that controls a carbohydrate group on the surface of our red blood cells as well as other cells in our body, and previous studies by some investigators have implicated this locus, this genetic variant as being a contributor to plaque vulnerability or susceptibility to adverse events. It looks like whatever ABO blood type, however it's linked to cardiovascular disease risk, is somehow being impacted by COVID infection and increased post-COVID cardiac risk. I think, if anything, this highlights the need for further research to be done on how is blood type linked to susceptibility for adverse cardiovascular events. I don't think it's anything unique to COVID since this risk has been seen in just blood type in general.

I also wanted to point out which blood type. What we found is that subjects who have O blood type were at a lower risk post-COVID infection than individuals who had a non-O blood type, meaning A, B, or AB. That is 60% of the world's population are non-O and 40% have O blood type. The type that is non-O, so A, B, or AB, are at particularly heightened risk for a clotting event, post severe COVID infection. But even O blood type was at higher risk following severe COVID infection, just not as high as the subjects with A, B, or the AB blood type.

So altogether, what's the take home message from these studies? I think we need to consider COVID infection, particularly severe COVID infection as a risk factor for heart disease. With over a billion people worldwide having experienced a COVID infection to date, I think it's reasonable to expect that cardiac risks worldwide are going to increase since the onset of the COVID pandemic. I think that also it's important to consider that subjects who've had severe COVID should be considered to be at higher risk long-term, particularly middle-aged subjects who've had severe COVID are at higher risk long-term for developing a heart attack, stroke, or dying.

One other question that might come up is I'm often asked, what's the impact of vaccination on this whole process? We know that vaccination for COVID lowers risk for susceptibility to infection with COVID, as well as severe COVID infection and hospitalization from COVID or mortality from COVID. For all of these reasons, we suspect, although we don't have the data to prove, that vaccination should lower the risk for post-COVID cardiovascular disease risk. What is interesting is that early on, some of the safety studies that were done with the first vaccines, which included nearly 50 million subjects, did show that following vaccination within six months, one could see a lower risk for thrombotic events like heart attack, stroke, pulmonary embolism, venous thromboembolism, and lower extremity DVTs. But the mechanism wasn't clear and there's no connection that's been reported for whether or not it's linked to post-COVID or not, but it is at least aligned with the concept that vaccinations should lower risk of post-COVID cardiac events.

We intentionally selected the year 2020 before vaccines were in play because the clinical database allowed us to do those analyses cleanly. Once vaccines became available, and there are so many different kinds of vaccines and scheduling for vaccines and boosters, it became very messy and difficult to do the analyses. Those are ongoing, those kind of future analyses now, but they weren't really available with the current database that we were using. That's why we limited our study to the 250,000 subjects who were enrolled in this study and did or did not have a COVID PCR-positive test in the year 2020.

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