Clinical review of COVID-19 and CVD: What the cardiovascular practitioner needs to know
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The novel coronavirus disease, or COVID-19, is now a global pandemic. Clinicians, scientists and public health officials around the world are racing to define the molecular pathway and clinical presentation of the virus, identify risk factors for infection and poor clinical outcomes, and develop effective treatments and preventive interventions.
Although the data on each of these ventures continue to develop on a daily basis across the globe, several trends have emerged showing that CV comorbidities are common in patients with COVID-19 and are independently associated with a greater risk for morbidity and mortality.
This summary reviews the evolving molecular and clinical data on COVID-19, with a focus on the intersection of this virus with CVD and its potential impact on patients with CVD.
The molecular pathway
COVID-19 is caused by the pathogen SARS-CoV-2, a novel enveloped RNA betacoronavirus that is thought to originate in bats (Zhou P, et al. Nature. 2020;doi:10.1038/s41586-020-2012-7). Infection with SARS-CoV-2 is caused by binding of a spike protein on the viral surface to the ACE2 receptor. The virus is then internalized and propagated with viral replication (Walls AC, et al. Cell. 2020;doi:10.1016/j.cell.2020.02.058). This ACE2 receptor is found on type 2 pneumocytes in the lungs, the primary route of infection, but it is also found in high levels in the heart, arteries, kidneys and intestines (Hamming TW, et al. J Pathol. 2014;doi:10.1002/path.1570). ACE2, when activated, converts angiotensin 2 to angiotensin 1-7, leading ultimately to vasodilation, diuresis and reduced oxidative stress. When SARS-CoV-2 binds to ACE2, it leads to ACE2 downregulation, increased angiotensin II, and increased pulmonary vascular permeability as well as the clinical state of acute respiratory distress syndrome (ARDS) seen in so many severely ill patients with COVID-19 (Zhang H, et al. Intensive Care Med. 2020;doi:10.1007/s00134-020-05985-9).
The potential impact of ACE inhibitors and angiotensin receptor blockers, ubiquitously used in patients with CVD, on this pathway has so far been studied primarily in rodent models. These models have shown that ACE inhibitors lead to an increase in ACE2 (Ferrario CM, et al. Circulation. 2005;doi:10.1161/CIRCULATIONAHA.104.510461). This raises that concern that these medications could, by increasing the viral target, increase a patient’s susceptibility to the virus.
However, ACE2 has a protective effect on the lung as well, as mice treated with ACE inhibitors and recombinant ACE2 were less likely to develop severe disease and ARDS (Imai Y, et al. Nature. 2005;doi:10.1038/nature03712). Similar studies have shown protective effects of recombinant ACE2 on the kidneys and a possible role for the interplay of intrarenal ACE and ACE2 in the development of hypertension (Wang G, et al. Kidney Blood Press Res. 2011;doi:10.1159/000324521).
Ongoing trials in humans with COVID-19 will better elucidate this pathway and impact of ACE inhibitors and angiotensin receptor blockers. With the pandemic potentially persisting for months, the implications of these trials on patients who rely on these medications are quite large. Currently, the American College of Cardiology and American Heart Association have recommended against preemptively stopping or starting an ACE inhibitor or angiotensin receptor blocker in the setting of COVID-19.
Another interesting feature of ACE2 is that its gene is located on the X chromosome. This has led to the suggestion that females have higher levels of ACE2 and are relatively protected against severe disease when compared with males, and serves as a possible explanation for why the death rate in males has been higher than that in females.
Prevalence of CVD in patients with COVID-19
The data evolving from across the globe have revealed CVD, and hypertension in particular, as the most common comorbidity in patients with COVID-19. This could simply be a result of both COVID-19 and CVD being more common in older patients. Additionally, CVD could disrupt this ACE-ACE2-Angiotensin 2 axis, leaving these patients more vulnerable to infection or disease progression, although epidemiological data and mechanistic research in the coming months will further our understanding of these associations.
A recent meta-analysis of 30 studies including 53,000 patients with COVID-19, almost entirely from East Asian countries, found the most common comorbidities were hypertension (19%), diabetes (8.2%) and CVD (2.7%; Zhao X, et al. MedRxIV. 2020;doi:10.1101/2020.03.17.20037572). Furthermore, each of these conditions were significantly more common in severe cases as compared with nonsevere cases. Moreover, CVD, hypertension and diabetes were found to be independent prognostic factors for COVID-19-related death.
These trends further stress the need to intensify the prevention of infection, particularly among patients with established CVD. Moreover, special attention should be paid to heart transplant patients, given their attenuated immune response. Health professionals should be provided optimal protection equipment so that they can effectively protect both themselves as well as their often highly vulnerable patients. Social distancing efforts in the general population are also crucial to minimize the odds of persons with preexisting conditions becoming exposed to the virus.
Acute cardiac complications
There is a growing number of cases of acute cardiac complications — myocardial injury or infarction, arrhythmias, myocarditis, acute-onset HF, cardiogenic shock and cardiac arrest — secondary to COVID-19. In a recent case report of 138 hospitalized patients with COVID-19, 16.7% developed arrhythmias, 7.2% developed myocardial injury (elevated troponin I, new ECG changes or echocardiographic abnormalities) and 8.7% developed shock requiring vasopressors (Wang D, et al. JAMA. 2020;doi:10.1001/jama.2020.1585).
Another study of 400 patients hospitalized with COVID-19 in Wuhan, China, found that 20% of patients had cardiac injury (elevated cardiac biomarkers; Shi S, et al. JAMA Cardiol. 2020;doi:10.1001/jamacardio.2020.0950). Patients with cardiac injury were more likely than those without cardiac injury to require noninvasive ventilation (46% vs. 4%), more likely to require invasive ventilation (22% vs. 4%) and had a higher mortality rate (51% vs. 5%). Furthermore, patients with cardiac injury were more likely to experience ARDS (59% vs. 15%), electrolyte disorders (16% vs. 5%) and coagulopathy (7.3% vs. 1.8%). Case reports of fulminant myocarditis and stress cardiomyopathy secondary to COVID-19 have also been published in recent weeks (Driggin E, et al. J Am Coll Cardiol. 2020;doi:10.1016/j.jacc.2020.03.031).
In summary, these data reveal that COVID-19 is not only more common but also more severe in patients with CVD. COVID-19 infection causes myriad cardiac complications, with myocardial injury a key prognostic factor and significantly associated with mortality in patients with COVID-19.
CV care in a context of limited resources
The high rates of preexisting cardiac comorbidities and of complications among patients with COVD-19 have drawn cardiologists directly into the care of these patients, many of whom are severely ill. This pandemic is already stressing — if not overwhelming — areas of the health care system in certain U.S. states as well as entire countries, and some patients with COVID-19, CVD and complications will be managed under extraordinary circumstances.
Patients with, for example, acute myocarditis, prior heart transplant or acute decompensated HF usually benefit from being few in number at any given time, which means many resources are usually available for their management. If, however, those critical care resources — ICU beds, ventilators, EMCO teams, cardiac anesthesia — are not as readily available as a consequence of a large number of severe cases being treated simultaneously, cardiologists will be forced to make fast decisions in the context of limited resources. This raises the need for clear clinical protocols that can be easily followed under such circumstances.
There are also collateral effects of the COVID-19 pandemic on our non-COVID-19 CVD patients. Cardiology departments across the country are transitioning from in-person to telemedicine visits, removing the crucial physical exam from the visit. Conversely, a positive consequence of this phenomenon may be the acceleration of the adoption of telemedicine, broadening the reach and increasing the efficiency of cardiology care, as well as expanding reimbursement (Hollander JE, et al. N Engl J Med. 2020;doi:10.1056/nejmp2003539). However, clinicians will need to maximize their ability to detect and inquiry about signs that they were used to identify during in-person visits, particularly through the physical exam.
Additionally, the reallocation of hospital resources has led to a necessary delay of some ambulatory procedures — such as cardiac catheterization, cardiac imaging, stress testing — in many centers, and thus delays in the normal progression of care. This will require closer monitoring of patients and further optimization of medical therapy until procedures can be completed.
The CV professional and COVID-19
This COVID-19 pandemic is creating the perfect storm in many centers: a high volume of acute, complex, severe patients often in need for intensive care, with overlapping pulmonary and cardiac disease. It will in many ways stress and strain the field of cardiology, as it will all of health care. Cardiologists all over the world are adapting to temporary roles as internists, intensivists and emergency room physicians.
We cannot stress enough the importance of providing these professionals with appropriate personal protective equipment. Also, mental well-being has never been more important, and the profession must unify in our fight against this virus, with our professional societies leading the way.
With this stress and strain, the field will grow and evolve into one that can meet the challenge of a pandemic that is, in many lessons learned during this first modern coronavirus pandemic will be crucial to optimize our response to potential future upcoming outbreaks.
Editor’s note: Developments in the COVID-19 pandemic are quickly evolving. Information in this article was up to date at the time of publication. To access the latest updates for practicing clinicians, visit Healio’s COVID-19 Resource Center at www.healio.com/coronavirus .
References:
American College of Cardiology. HFSA/ACC/AHA Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19. March 17, 2020. www.acc.org/latest-in-cardiology/articles/2020/03/17/08/59/hfsa-acc-aha-statement-addresses-concerns-re-using-raas-antagonists-in-covid-19.
BMJ Global Health. Sex, Gender and COVID-19: Disaggregated Data and Health Disparities. March 24, 2020. http://blogs.bmj.com/bmjgh/2020/03/24/sex-gender-and-covid-19-disaggregated-data-and-health-disparities/.
European Society of Cardiology. Position Statement of the ESC Council on Hypertension on ACE-Inhibitors and Angiotensin Receptor Blockers. March 13, 2020. https://www.escardio.org/Councils/Council-on-Hypertension-(CHT)/News/position-statement-of-the-esc-council-on-hypertension-on-ace-inhibitors-and-ang.
For more information:
Eamon Duffy, MD, MBA, is a resident at Johns Hopkins Hospital. Andrew Ayers is an undergraduate at Brown University studying public health and biology. Miguel Caínzos-Achirica, MD, MPH, PhD, is a cardiologist and cardiovascular epidemiologist at Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease. Roger S. Blumenthal, MD, is director of the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease and professor of medicine at Johns Hopkins University School of Medicine. He is also the editor of the Prevention section of the Cardiology Today Editorial Board.
Disclosures: The authors report no relevant financial disclosures.
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American College of Cardiology. HFSA/ACC/AHA Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19. March 17, 2020.www.acc.org/latest-in-cardiology/articles/2020/03/17/08/59/hfsa-acc-aha-statement-addresses-concerns-re-using-raas-antagonists-in-covid-19.
BMJ Global Health. Sex, Gender and COVID-19: Disaggregated Data and Health Disparities. March 24, 2020.http://blogs.bmj.com/bmjgh/2020/03/24/sex-gender-and-covid-19-disaggregated-data-and-health-disparities/.
European Society of Cardiology. Position Statement of the ESC Council on Hypertension on ACE-Inhibitors and Angiotensin Receptor Blockers. March 13, 2020.https://www.escardio.org/Councils/Council-on-Hypertension-(CHT)/News/position-statement-of-the-esc-council-on-hypertension-on-ace-inhibitors-and-ang.Read more about
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