COVID-19 and CVD ‘inextricably linked’
The medical community during the past year has learned, among other things, that SARS-CoV-2 has numerous short-term and long-term consequences on the CV system.
The CV consequences of SARS-CoV-2 include myocarditis, thrombosis — leading to venous thromboembolism, stroke and other conditions — and HF. Moreover, individuals with existing CV conditions and risk factors are more likely to have severe consequences from COVID-19 than those who do not, and CV effects from the disease can linger after apparent recovery, even in patients who were not severely symptomatic.
“It’s fair to say that cardiovascular disease and COVID-19 are inextricably linked,” Clyde W. Yancy, MD, MSc, vice dean of diversity and inclusion, Magerstadt Professor of Medicine, professor of medical social sciences and chief of the division of cardiology at Northwestern University Feinberg School of Medicine and associate director of Bluhm Cardiovascular Institute at Northwestern Memorial Hospital, told Cardiology Today.
Knowledge about COVID-19 and the heart continues to accumulate as the pandemic lingers. There is much that has not yet been learned, including the extent to which CV risks are present after recovery from COVID-19, the optimal treatment strategies during and after illness, and why certain cohorts appear to be more susceptible to severe CV consequences than others.
“In the post-acute phase, there are individuals with persistent symptoms of chest pain and shortness of breath, and we are trying to better understand the causes of these symptoms,” Anuradha Lala-Trindade, MD, assistant professor of medicine (cardiology) and of population health science and policy at Mount Sinai, said in an interview. “We recognize there are individuals with long-term sequelae but have much to learn, pointing to the importance of following such patients longitudinally. In some sense, similar to how we followed patients after the World Trade Center calamity, we know patients were exposed to an unknown, but with time we realized there were long-term effects, and we are still learning about those many years down the line. For patients who have recovered from COVID-19, understanding the underpinnings of residual CV effects serves as an area that is ripe for research, and we need to keep pushing.”
The SARS-CoV-2 virus infects individuals by using ACE2 as a receptor, which is abundantly expressed in the CV system; thus, it can proceed to affect the CV system in numerous ways.
“The observed pathology is consistent with an inflammation of the connecting tissues within the heart and the perivascular apparatus, but not the myocytes per se. Nevertheless, it is fairly evident, based on magnetic resonance interpretations, that markers usually trending with inflammation of the heart are positive, and evidence of fibrosis via gadolinium-delayed hyperenhancement is similarly present,” Yancy said. “These findings are worrisome for myocardial involvement and even more so for longer-term cardiac consequences including heart failure.”
Tracy Y. Wang, MD, MHS, MSc, professor of medicine in the department of cardiology, member in the Duke Clinical Research Institute and director of health services and outcomes research at Duke University School of Medicine, told Cardiology Today there are three main explanations for how the virus causes CV consequences.
“The first is that it’s a physiologic stressor, like any sort of stress we put on the body. It could predispose the heart to damage if the stress outweighs the possibility to bear with the stress. It causes a situation like type 2 MI, a demand-related infarct.
“The second mechanism is that the virus that causes COVID-19 predisposes the heart to inflammation and to thrombosis. It is probably mediated more through inflammatory markers and thrombosis.
“The third mechanism is direct viral injury, ie, viral myocarditis. This is the least proven, although we know the myocardium has receptors for the virus itself, and there have been autopsy studies that have shown coronavirus in myocardium,” Wang said.
The CV consequences of COVID-19 can develop soon after infection and can extend to numerous areas, including myocarditis; thrombosis that can manifest itself as CAD, pulmonary embolism or stroke; arrhythmia disorders such as atrial fibrillation; and ventricular dysfunction that can lead to HF.
“There is an early infection phase, where there’s a viral infection inoculation that may lead from an asymptomatic to a symptomatic stage,” Manesh Patel, MD, professor of medicine, the Richard Sean Stack, MD, Distinguished Professor, chief of the division of cardiology and of the division of clinical pharmacology, core faculty in innovation and entrepreneurship and member in the Duke Clinical Research Institute at Duke University School of Medicine, told Cardiology Today. “During this phase, there is often an increase in inflammation in the body and maybe some risk for thrombosis. The cardiovascular consequences of that are mostly due to hypoxia, but then potentially panvasculitis, which is leading to thrombosis and vascular inflammation. So, people have been described to have pulmonary embolism, myocardial dysfunction and venous thromboembolism. Then, if they are in the hospital and they go into the inflammatory response phase, they can actually get cardiac failure.”
Research has clearly established that patients with preexisting CV conditions are more likely to have serious adverse effects, including those on the heart, from COVID-19.
“We must recognize the work attributable to overcoming a severe pneumonia and multi-system organ failure,” Yancy said. “Particularly in the patient with preexisting cardiovascular disease, eg, heart failure, hypertension or coronary disease, there can be clinical consequences typified by elevation of myocardial injury markers.”
The initial sense of the CV consequences of COVID-19 came from case series and small observational studies, but now data from large registries are enhancing clinicians’ understanding.
Initial data from the American Heart Association COVID-19 CVD registry covering 14,889 patients from April to September 2020 (Graphic on page 11) revealed that CV death, stroke, MI, HF or shock occurred in 8.8% of patients hospitalized for COVID-19, MI in 3%, stroke in 1.3%, new-onset HF in 1.8%, cardiogenic or mixed shock in 1.7%, myocarditis in 0.3%, new-onset AF in 7.9% and VTE in 3.6%. The in-hospital mortality rate was 16.7%, and 10% of deaths were from cardiac causes. These rates were all lower than those reported in initial data from regions hit hard early in the pandemic such as New York City and Wuhan, China.
“Most patients who get COVID-19 will experience mild illness. However, we know that a small but significant proportion of individuals will experience severe disease that requires hospitalization,” Fatima Rodriguez, MD, MPH, assistant professor of cardiovascular medicine at Stanford University School of Medicine, who presented some of the data from the AHA COVID-19 CVD registry at the AHA Scientific Sessions, told Cardiology Today.
Data from a private health care database created by Cerner Corp. and Amazon Web Services also presented at AHA were similar. In that cohort of 19,584 patients, followed through July 1, in-hospital mortality occurred in 20.7%, mechanical ventilation was required in 32.6%, MI occurred in 5%, PE occurred in 2% and stroke occurred in 1.5%, and the mortality rates in patients with mechanical ventilation, MI, PE or stroke were high.
Disparities in COVID-19
The CV complications of COVID-19 have varied by race, and COVID-19 has disproportionately affected people from traditionally underrepresented backgrounds and people with lower socioeconomic status.
“We have observed higher event rates among Black patients who contract COVID-19,” Lala-Trindade said. “Disentangling the cause for these observations is challenging. Is it lack of access to care? Increased exposure? Or is it due to a higher prevalence of comorbid conditions? A complex combination? We certainly need to better understand related factors and devote efforts to mitigate risk.”
The observations were borne out in the AHA COVID-19 CVD registry data, which showed that Black and Hispanic individuals were overrepresented compared with local census data; Black patients had higher rates of diabetes, obesity and hypertension compared with other patients; and Black patients were more likely than others to require mechanical ventilation and renal replacement therapy.
Of note, in both the AHA and private insurance registries, race was not associated with mortality or major adverse CV events after adjustment for CV risk factors. However, in the AHA registry, Asian/Pacific Islander patients had higher risk for COVID-19 disease severity compared with white patients, and in the private insurance registry, Hispanic ethnicity was protective against mortality.
In a study of patients from a Louisiana health care system hospitalized for COVID-19 from March 1 to April 11, 2020, published in The New England Journal of Medicine, Black patients had higher rates of COVID-19 hospitalization and mortality compared with the health system’s overall population, but race was not independently associated with mortality.
“Historically disadvantaged communities — Hispanic/Latinx, Black and Native American communities — are disproportionately affected by COVID-19 and have a greater burden of underlying cardiac comorbidities such as hypertension, diabetes and obesity that can result in higher rates of CV complications,” Rodriguez told Cardiology Today. “Because of factors like structural racism and decreased access to preventive care, we hypothesize that these communities will also experience a greater burden of chronic CV complications following COVID-19 infection.”
There are also sex disparities in the impact of COVID-19, Cardiology Today Chief Medical Editor Carl J. Pepine, MD, MACC, said.
“Men clearly continue to fare poorly compared with women among those with COVID-19,” Pepine, emeritus professor of medicine at the University of Florida, Gainesville, said. “An improved understanding of the mechanism(s) underling this disparity would contribute to improve outcomes for all people who are disadvantaged.”
Although uncertainty remains in many areas relating to COVID-19 and CVD, some answers have emerged about medications. Early in the pandemic, there was skepticism about whether renin-angiotensin-aldosterone system inhibitors elevated risk for severe COVID-19 because, like the SARS-CoV-2 virus, they bind to the ACE2 receptor. Observational studies did not show this, and the early studies have now been confirmed by two randomized controlled trials, BRACE CORONA and REPLACE COVID, of patients with COVID-19 taking renin-angiotensin-aldosterone system inhibitors. Both BRACE CORONA and REPLACE COVID reported no differences in outcomes between patients with COVID-19 who discontinued their medication and those who did not.
“We have now fairly well shown that at least ACE inhibitors or [angiotensin receptor blockers] in patients at risk for COVID-19 have not led to worse clinical outcomes and, in fact, may, in some levels at least, ensure their cardiovascular systems are protected if they were on those medications beforehand,” Patel said.
More answers have been provided about hydroxychloroquine, which was used as a treatment for COVID-19 early in the pandemic but raised concerns about risk for sudden cardiac death, as it prolongs the QT interval. Randomized trials have shown hydroxychloroquine is not effective as a treatment or prophylactic for COVID-19.
Existing CV medications may come into play as part of the COVID-19 treatment regimen, Patel said.
“Aspirin, antiplatelet drugs or antithrombotic drugs are used in patients with COVID-19 sometimes because they are having vasculitis or thrombosis,” he said.
Yancy noted randomized trials have shown full-dose unfractionated heparin reduces morbidity from COVID-19 in patients not requiring ICU care or organ support.
However, there are some promising early data. A single-center study of patients with diabetes and COVID-19 found those who took statins were less likely to die during COVID-19 hospitalizations than those who did not, and a small first-in-human study found icosapent ethyl (Vascepa, Amarin) reduced levels of inflammatory biomarkers and improved symptoms in patients with COVID-19.
In January, the Montreal Heart Institute announced the top-line results of the COLCORONA trial, in which colchicine, an anti-inflammatory drug that has shown CV benefits, improved outcomes in certain patients with COVID-19 compared with placebo. A preprint of the abstract that had yet to be peer-reviewed as of the time of publication was posted online at medrxiv.org.
A question that remains is whether patients with COVID-19 should receive anticoagulation after hospital discharge. Wang said several ongoing trials aim to provide answers.
One, ACTIV-4, on which Wang is an investigator, is “testing the strategy of whether or not empiric anticoagulation in the next 30 days helps prevent some of the cardiovascular complications that could happen after a patient with COVID-19 goes home,” Wang said. “This is someone who doesn’t really have a strong indication for anticoagulating, meaning they didn’t have a clot during their hospitalization, but [there is concern] because we know COVID-19 in and of itself predisposes to thrombosis.”
One of the most important questions that remains to be answered is whether CV problems persist after recovery from COVID-19, in whom and to what extent.
In one study published in JAMA Cardiology in July, researchers found 78% of patients recently recovered from COVID-19 had cardiac abnormalities on biomarker testing and cardiac MRI, and 60% had myocardial inflammation.
“As a consequence of inflammatory processes at play, we are seeing pericarditis and fibrosis by MRI in select cases,” Lala-Trindade said. “We are seeing residual complaints of shortness of breath after the acute phase, wherein it is challenging to decipher between cardiac and pulmonary limitations.”
Rodriguez said some COVID-19 survivors report a “post-COVID-19 long-hauler syndrome,” which is associated with postural tachycardia and shortness of breath with minimal activity.
“We have also seen long-lasting effects on the myocardium, including signs of inflammation and in some rare cases cardiomyopathy,” Rodriguez said.
Lala-Trindade noted that only recently have many patients who had COVID-19 during the first wave of the pandemic seen their cardiologist for follow-up.
Fatigue, lung damage, myocarditis and cardiac dysfunction are all conditions associated with “long-hauler syndrome,” and ongoing vigilance is important for those and other reasons, Patel said.
The pandemic could have indirect consequences on CV health due to people avoiding doctors’ offices and hospitals for fear of getting infected there, Rodriguez told Cardiology Today.
“The unintended consequences of delayed cardiovascular care will present a growing clinical and public health challenge,” she said.
Illustrating those challenges, two studies published in the Journal of American College of Cardiology showed the prevalence of cardiac diagnostic procedures fell up to 64% globally during the first wave of the pandemic, and deaths caused by ischemic heart disease increased by 11% during March and April 2020 compared with the same period in 2019.
Implications for future health
Although much has been learned about the CV effects of COVID-19, there is much more work to be done, even as the population starts to get vaccinated.
Numerous research efforts are underway, including the ACTIV trials studying anticoagulation in various COVID-19- afflicted populations, studies of anti-SARS-CoV-2 monoclonal antibodies and convalescent plasma as treatments, and studies of the CV and other effects on athletes from COVID-19.
“The opportunity to potentially test different interventional therapeutics is going to be critical, especially in people who have evidence of myocardial damage,” Patel said.
In some cases, hospitalization for COVID-19 has revealed underlying but previously undiagnosed conditions, Wang said.
“A lot of the patients who get really sick with COVID-19 may have had cardiovascular issues that needed to have been addressed, so it might be unmasking a lot of AF or hypertension or heart failure that preceded the infection but was undiagnosed,” she said.
This underscores that “COVID-19 is a wake-up call for us on so many different fronts,” she said.
“We already knew that we were far from ideal in doing cardiovascular prevention, but COVID-19 has really brought that to the forefront,” Wang said. “If there was a silver lining to the pandemic, it’s bringing patients to the opportunity for medical care and saying, we ... could, if we actively manage it, help long-term cardiovascular health.”
Yancy said the intersection of COVID- 19 and CVD “has been disruptive, painful, but also informative. We should not believe that COVID-19 is a once-in-a-generation crisis. Another crisis will come along. Failure to address our social ills, our uncontrolled CV risk factors, a full exploration of the science predisposing to COVID-19 and exhaustion of all therapeutic strategies including successful vaccine implementation will haunt us when we face our next crisis. The new normal we all seek requires that we think, educate, advocate, research and treat differently than ever before.”
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- For more information:
- Anuradha Lala-Trindade, MD, can be reached at firstname.lastname@example.org; Twitter: @dranulala.
- Manesh Patel, MD, can be reached at email@example.com; Twitter: @manesh_patelmd.
- Carl J. Pepine, MD, MACC, can be reached at firstname.lastname@example.org.
- Fatima Rodriguez, MD, MPH, can be reached at email@example.com; Twitter: @farodriguezmd.
- Tracy Y. Wang, MD, MHS, MSc, can be reached at firstname.lastname@example.org; Twitter: @tywangmd.
- Clyde W. Yancy, MD, MSc, can be reached at email@example.com; Twitter: @nmhheartdoc.