COVID-19 and the cardiovascular system
SARS-CoV-2 reaches the heart and blood vessels through ACE2, the receptor it uses to enter cells. It harms them both by infecting their cells and through the inflammation that infection of other organs sets off, and the conditions that follow range from myocarditis and changes in blood pressure to clots, infarction, arrhythmia and heart failure. Preexisting heart disease seems to make COVID-19 more severe, which raised the question whether certain cardiovascular medicines alter the risk of infection or of severe disease. Several drugs tried against COVID-19 have been linked to cardiac risks of their own.
How firm the evidence was in mid-2021
In mid-2021 new scientific information on COVID-19 and the cardiovascular system was accumulating weekly. By then, about a year and a half after SARS-CoV-2 and COVID-19 were identified, much had been learned about SARS-CoV-2 infection patterns and the comorbidities of COVID-19. Some of the information then current was conjecture, drawn from studies of the first SARS coronavirus or of patients without COVID-19. Some rested on only a few small studies and needed stronger support. Longitudinal studies were still needed to determine the long-term effects of SARS-CoV-2 and COVID-19 on human health.
How the virus harms the heart and vessels
SARS-CoV-2 infects cells through an interaction between its spike (S) protein and angiotensin-converting enzyme 2 (ACE2) on the host cell. Within the cardiovascular system, ACE2 is reportedly found on heart muscle cells, on the endothelial cells that line blood vessels and regulate clotting and blood pressure, on the pericytes that surround and aid them, and on the arterial smooth muscle cells that control vessel diameter and so blood pressure and flow. SARS-CoV-2 infection of these cells hinders their health-promoting work.
Cardiovascular health is also threatened when SARS-CoV-2 invades organs outside the heart and triggers immune responses. Local white blood cells activate, recruit other white blood cells and produce pro-inflammatory chemicals, which increases inflammation. One source of these chemicals may be direct infection of macrophages, a type of white blood cell that expresses ACE2. As the immune system battles the virus, the affected organ may temporarily malfunction, and these malfunctions and the pro-inflammatory chemicals released into the blood may harm the blood vessels and the heart. Viral infection of other organs may also affect the cardiovascular system in other ways.
The conditions that follow
The cardiovascular conditions these direct and indirect effects induce include myocarditis, blood pressure irregularities, thrombus formation, hypoxia, arteriosclerotic heart disease (ASHD), myocardial infarction, arrhythmia and heart failure. If left unchecked or if severe enough, they could be fatal. Some of the mechanisms behind them were confirmed and others only plausible. The other conditions the infection initiates, if prolonged and severe enough, cause arrhythmia and heart failure.
Myocarditis, inflamed heart tissue, compromises the contractility of the heart muscle. To keep delivering blood and oxygen to the body, the heart compensates by at least two methods: thickening its muscle layer (hypertrophy) or raising its rate (tachycardia). Either could progressively worsen the heart's already precarious condition.
Some patients with COVID-19 present with hypertension, and the causal link may be ACE2, which besides being the binding target of the S protein is part of the renin–angiotensin system. That pathway controls the contraction and relaxation of smooth muscle cells and so influences blood pressure. Contraction narrows the vessels (vasoconstriction) and raises pressure, and relaxation widens them (vasodilation) and lowers it. Angiotensin II brings about the contraction and angiotensin (1-7) the relaxation. In the pathway, renin, produced by the kidneys, converts angiotensinogen, produced by the liver, into angiotensin I. ACE1 converts this relatively inactive molecule into angiotensin II, a highly active vasoconstrictor, and ACE2 converts angiotensin II into angiotensin (1-7), a vasodilator. ACE2 levels likely decline in infected cells, so angiotensin (1-7) would decrease and angiotensin II would likely increase, tipping the balance toward vasoconstriction and raised pressure. This explanation, although plausible, needs strengthening with further research. Another explanation for hypertension lies in direct infection of endothelial cells and perhaps pericytes, both of which affect vessel diameter. A deficit of vasodilation or a prevalence of vasoconstriction likely causes hypertension. Some patients instead develop low blood pressure (hypotension), which is a symptom of acute respiratory distress syndrome and so is likely the result of infection of lung cells.
Thrombi, abnormal blood clots in arteries or veins, are found in some patients with COVID-19. They are induced by injured endothelial cells or by pro-inflammatory chemicals. Endothelial cells may be damaged by direct infection, and damaged cells activate platelets and make them sticky, so that they adhere to the vessel wall and to each other. Clotting factors in the blood set off a chain reaction that turns fibrinogen into fibrin, whose threads attach to the platelet mass to form the clot. Where the endothelium is undamaged, a clot may still form, since pro-inflammatory chemicals may activate platelets and clotting factors. A clot in an artery jeopardises the delivery of oxygen and nutrients downstream, and one in a vein may cause swelling upstream. Pieces may also break off the clot, travel through the bloodstream and lodge in another vessel, and these travelling clots, emboli, endanger other organs. An embolus carried from a large systemic artery into a narrower artery within an organ may get stuck and deprive the tissue downstream of oxygen.
Emboli in veins pose a significant risk to the lungs, since they could pass through the right heart chambers, lodge in the lungs' narrow arterial branches and impede blood flow to the pulmonary capillaries. To force blood past a pulmonary embolism, the right ventricle hypertrophies in an attempt to strengthen its pumping power, which is at best a temporary fix. If the embolism persists, pressure rises in the right side of the heart and in the veins, and this raised pressure induces edema, most prominent in the lower limbs because of gravity. Edema also occurs in the lungs, where the fluid impedes the diffusion of oxygen from the alveoli into the pulmonary capillaries and reduces alveolar ventilation as fluid-filled sacs fail to stay open. Diminished blood flow to the alveoli on account of pulmonary emboli may also keep the blood from picking up enough oxygen. Together these emboli-initiated events cause hypoxia.
Thrombi may form in the coronary arteries of some patients with COVID-19, a condition known as ASHD. The coronary arteries carry oxygen-rich blood to the heart tissue, and their partial or complete blockage is life-threatening. Whether through blocked delivery or through hypoxia, insufficient oxygen causes heart muscle cells to malfunction and die, and the likelihood of myocardial infarction increases. Infarction had been reported in a small number of patients with COVID-19. Arrhythmias had also been reported in some patients. In the general population arrhythmias are caused by ASHD, infarction, myocarditis and heart hypertrophy, so those conditions were the suspected causes in COVID-19.
Persistence of these cardiovascular problems gradually weakens the heart, compromises its pumping, and can lead to heart failure, in which the heart becomes progressively less able to deliver oxygen- and nutrient-rich blood to the body. Preexisting heart failure appears to increase the likelihood of death in patients with COVID-19.
Why preexisting heart disease matters
COVID-19 affects the cardiovascular system, and the inverse may also be true. The proportion of patients with COVID-19 who have cardiovascular conditions is not higher than the prevalence of those conditions in the general population, so the conditions do not appear to increase the risk of developing COVID-19. Preexisting hypertension, ASHD, arrhythmia, myocardial infarction and heart failure do seem to increase the severity of COVID-19 symptoms. This observation led scientists to examine whether certain cardiovascular medicines alter the risk of infection or of severe disease. Classifications of severity vary among studies, distinguishing normal from high troponin concentrations in the blood, nonsevere from severe disease, nonhospitalised from hospitalised patients, non-ICU from ICU patients, and survivors from nonsurvivors.
What was known about blood-pressure medicines
Research on cardiovascular medicines and COVID-19 focused on some antihypertensive medicines. To lower high blood pressure, physicians may prescribe ACE inhibitors, angiotensin receptor blockers or both. These respectively minimise the production of angiotensin II and block its interaction with its receptors, so preventing the vasoconstriction that raises pressure. Certain of these drugs likely increase the levels and activity of ACE2 throughout the body. Because ACE2 is the receptor SARS-CoV-2 binds, it is important to ascertain whether they alter the risk of infection or of developing COVID-19.
Studies of the question, sampled from a regularly updated compilation of newly published research, varied widely in design. They differed in comparison groups, ethnic groups, statistical analyses, sample sizes, dates before or after widespread testing, time on the drugs, attention paid to confounding health issues, and definitions of severe COVID-19. Some were retrospective observational studies, which are subject to selection bias. For example, a cohort of hypertensive patients tested for COVID-19 leaves out those never tested because they were asymptomatic. Identifying patients prescribed the drugs also assumes they take them as prescribed, which may not be the case.
Most studies published by mid-2021 nevertheless concluded that ACE inhibitors and angiotensin receptor blockers do not increase the risk of SARS-CoV-2 infection or severe COVID-19. In mid-2021 the CDC and other cardiovascular health organisations advised patients to continue these prescriptions unless a physician advised otherwise. Clinical trials concerning the drugs and COVID-19 were then ongoing. The rise in ACE2 the drugs induce may be advantageous, by counteracting the virally induced fall in ACE2 and so preserving the production of angiotensin (1-7). Angiotensin (1-7) lowers raised blood pressure, promotes the structural health of blood vessels and endothelial cells, protects against cardiac hypertrophy and may enhance blood cell production.
What was known about COVID-19 treatments with cardiac risks
Lopinavir/ritonavir, hydroxychloroquine, favipiravir, remdesivir and tocilizumab, drugs tried in treating patients with COVID-19, have been linked to cardiovascular side effects. Lopinavir/ritonavir, hydroxychloroquine, favipiravir and remdesivir may cause arrhythmias. Lopinavir/ritonavir may trigger myocardial infarction. Lopinavir/ritonavir and tocilizumab may compromise the effectiveness of cardiovascular medicines. In mid-2021 these risks were inferred primarily from a small number of studies with few subjects, none of whom had COVID-19. A more robust examination in patients with COVID-19 had begun in several clinical trials funded by the NIH. Awareness of drug side effects likely reduces health complications.