The coronavirus disease 2019 (COVID-19) pandemic led to well over 200 million infections, with a fatal outcome in over 4.5 million cases. In the survivors, most recovered completely but some showed long-haul symptoms – now often called Long COVID.
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One important potentially long-term clinical consequence of COVID-19 seems to be heart damage. This has been recognized as far back as the Wuhan, China, outbreak. Several patients hospitalized with the disease at that time had high levels of cardiac troponin, which is a molecular biomarker of myocardial injury.
Echocardiographic evaluation of these patients showed the presence of functional deficits in the heart. The obvious conclusion was that COVID-19 severity was correlated with the presence of myocardial injury.
It was quite clear that people that came into the hospital sick that had heart injury were the ones that were at greatest risk of requiring mechanical ventilation and, ultimately, at the greatest risk of dying.”
Aaron Baggish, of Massachusetts General Hospital
However, the large number of asymptomatic cases coupled with a lack of focused research means that the question of how common this complication is, remains unanswered. It is also not clear whether the damage to the heart muscle is due to the systemic inflammatory reaction in COVID-19 or because of myocarditis.
Most importantly, the chances of long-term injury are also unclear at this point, though it is a very significant one, considering the huge number of infections that have occurred so far.
Heart inflammation appears to be prominent in COVID-19, in some patients at least. This could involve both the myocardium and the pericarditis, causing severe fatigue without other obvious symptoms.
Myocarditis in COVID-19 is often fulminant, and mostly self-resolving, though occasionally it results in arrhythmias, heart failure, cardiac arrest, and sudden death. Cardiogenic shock is the cause of death in this case.
The diagnosis of myocarditis is relatively inaccurate because both tests and diagnostic protocols are lacking. The course of the illness is therefore unknown at present, but some early reports have shown that symptoms lingered for a median of 47 days before diagnosis was accomplished by cardiac magnetic resonance (CMR) imaging.
More than half the patients in one study had edema, indicating active inflammation, and many had scarring and impaired right ventricular function.
However, up to 60% of patients in another study from Germany, which included only patients who had cleared the virus as confirmed by a negative nasal swab, still had signs of myocardial inflammation after 2-3 months. Still more had high troponin levels. Heart enlargement and inefficient pumping were detected in this study, compared to controls.
Active inflammation was confirmed on heart muscle biopsy in a few patients who had severe changes on CMR. This study included a majority of non-hospitalized patients, including several who were asymptomatic, with a mean age of <50 years. The severity of COVID-19, underlying medical conditions, and the time since onset were not related to the risk of heart inflammation.
Recovered athletes in one study showed the same signs of myocarditis, current or recovering, after mild or asymptomatic COVID-19. In this study, 12/26 competitive athletes showed these features at up to 53 days from quarantine.
The results suggested that scores of otherwise healthy people who recovered from COVID-19—even those who didn’t get very sick—could have potentially harmful inflammation smoldering in their hearts months later.”
Notably, many of the patients in the German study had symptoms potentially related to myocarditis, which may have led to a bias in the study. Many of the patients with abnormal imaging findings had borderline positive results compared to controls matched for the same risk factors.
Since other viral respiratory illnesses are not monitored using CMR or troponin, the data is insufficient to allow a valid comparison between COVID-19 and this data or to conclusively say that the abnormalities are a specific sequel of COVID-19.
Myocarditis in viral infection is usually the result of direct heart muscle infection, but in COVID-19, it could also be the result of the cytokines circulating as part of the systemic inflammation. The latter could explain the arrhythmias and even the cardiac ischemic events that occur, due to plaque rupture and blockage of the heart vessels by plaque fragments.
Monkey models support this mechanism, showing scarring of the heart in infected recovered monkeys but not in controls.
ACE2 downregulation and myocardial edema
Conversely, the angiotensin-converting enzyme 2 (ACE2), which acts as the viral receptor, is widespread in its distribution and has significant cardiovascular functionalities such as normal vascular permeability. The reduced ACE2 expression that occurs with COVID-19, therefore, enhances the influx of fluid into the heart muscle, causing mild edema.
This could be aggravated by systemic inflammation, also a feature of COVID-19. This cardiac edema can cause severe persistent tiredness and may be a major contributor to COVID-19-related cardiac injury. Since glucocorticoids rapidly control such inflammatory swelling, this could be one mechanism by which these drugs reduce mortality among patients with severe COVID-19 who are on respiratory support.
COVID-19 can also cause an imbalance between oxygen supply and demand, blood clots, sepsis, cardiomyopathy due to stress, and multisystem inflammatory syndrome. Already present cardiovascular disease may be accelerated by severe COVID-19, as represented by the troponin levels.
Cardiac damage and long COVID
Signs and symptoms of possible heart damage after COVID-19 may include severe fatigue, palpitations, chest pain, shortness of breath, postural orthostatic tachycardia syndrome (POTS) due to neurologic disturbances, post-exertional fatigue, and higher troponin levels with an abnormal electrocardiograph, which may indicate a heart attack.
Some cardiologists attribute these symptoms to cardiac damage. Hospitalized COVID-19 patients who had high troponin levels continued to show myocardial scarring in the absence of edema, indicating that the damage caused by the virus is permanent and predisposing them to a higher risk of heart failure.
The right side of the heart is strained by the need to pump blood through inflamed lungs, often complicated by clot formation within the blood vessels of the heart and lungs which act, together with the inflammation, to reduce the level of oxygenation in these vital organs. This may be exacerbated by the use of higher positive end-expiratory pressure during mechanical ventilation which causes the right ventricle to be stressed.
COVID-19 in pre-existing heart failure
In patients who already have heart failure, the outlook is poor, as the co-occurrence of COVID-19 can trigger myocardial injury, causing the patient’s heart to fail all at once. Heart failure is probably due to the cytokine storm that is associated with severe COVID-19, including elevated levels of interleukins (IL) such as IL3, IL6, IL7, and other inflammatory mediators.
This may cause stress cardiomyopathy and lead to myocardial dysfunction as a result of high cytokine levels. This leads to acute decompensation of the pre-existing heart failure even in patients who were previously stable.
ACE inhibitors are associated with beneficial effects during COVD-19, but with lung involvement, such as pneumonia and acute respiratory distress syndrome (ARDS), their role should be evaluated to prevent unwanted effects. Similarly, drugs that may induce arrhythmias in the presence of electrolyte imbalance and other risk factors, including hydroxychloroquine and azithromycin, should be closely monitored, especially if the patient has structural heart disease and/or coronary artery disease.
More research will be needed to correlate the imaging findings with clinically important events, however. The implications must be worked out, because myocarditis puts a strain on the heart, causing over a tenth of sudden cardiac deaths in young adults, and being recognized as potentially fatal in competitive athletes.
With asymptomatic or mild COVID-19, athletes could return to high-level training too soon, risking death due to myocarditis. The American College of Cardiology (ACC) advises cardiac imaging and other tests for athletes with moderate-to-severe infections before beginning to train again, a measure which has turned up some unsuspected cases.
Overall, however, the clinical implications may not be non-concerning. Some of the heart scarring seen in earlier studies could have been the result of intensive athletic training rather than the viral infection, some scientists say.
Myocarditis could cause myocardial cell death with scarring, heart attacks, and endothelial damage. If irreversible fibrosis sets in, patients could be presenting with heart failure and arrhythmias from five to 20 years later.