Discussion
It has been suggested that COVID-19 is a disorder of the microvasculature. Given that microvascular dysfunction is seen in the subcutaneous and retinal vasculature in COVID-19 patients, several investigators have speculated that the same should also be true for the coronary microvasculature, but direct evidence was missing so far (17-20). Present study supports the validity of this latter hypothesis, since our findings indicate that CFVR, which is a measure of CMD, is lower in COVID-19 patients. Moreover, these findings also indicate a relationship between troponin and the degree of reduction in CFVR, thus providing a possible explanation for the “cryptic” troponin elevations in severe COVID-19 patients.
Several explanations have been offered to explain microvascular dysfunction in Sars-COV-2 infection. Sars-COV-2 gains access to cells by binding to the ACE2 receptor, which is expressed ubiquitously is many tissues (21,22). There is histopathologic evidence to suggest that Sars-COV-2 infects endothelial cells and possibly inducing endothelial dysfunction (23,24). There is also a well-known tendency towards thrombosis in patients with moderate-to-severe COVID-19 infection. Microvascular thrombosis and obstruction reduces recruitable capillaries, which in turn leads to microvascular dysfunction (25-27). Overactivation of inflammatory pathways with accompanying “cytokine storm”, which is somewhat common in patients with severe COVID-19, can exacerbate endothelial dysfunction by either worsening endothelial inflammation or by activating prothrombotic cascades (17,28). Probably not a single pathway is responsible for the development of CMD but rather all pathways are interwoven into each other, all of which ultimately leading to endothelial dysfunction and CMD.
Present observations are in line with the available evidence showing an abnormal capillary density and/or function in COVID-19 patients. Previous studies have suggested that COVID-19 patients have reduced flow reserve in the forearm skin, as well as reduced microcirculatory flow index and perfused vessel density in the sublingual circulation (29-31). Interestingly, in one of these observations Sabioni et al. have observed that peak hyperemic flow was impaired in either moderate or severe COVID-19 patients, but basal flow velocity was only affected in patients with severe COVID-19 (31). These findings were strikingly similar to the present results and suggests that small vessel disease is present in all COVID-19 patients with at least moderate disease (32). Moreover, our findings also demonstrated that CFVR is closely associated with biomarkers of fibrin turnover and inflammation, and thus suggesting that the aforementioned mechanisms could be responsible for CMD in COVID-19 patients. Theoretically, treatments aimed to disrupt the pathways of microvascular dysfunction, such as anticoagulants or anti-inflammatory agents, should improve microvascular dysfunction in those with moderate or severe COVID-19 infection, but this assumption needs further studies.
Troponin elevation is a common observation and a marker of worse prognosis in COVID-19 patients. Myocarditis was initially regarded as the most plausible cause of myocardial injury in the early stages of the pandemic, but histopathologic proof is scarce and is unlikely to explain the majority of cases (33). Other explanations, such as overt myocardial infarction or stress cardiomyopathy are usually self-evident and has other electrocardiographic and imaging findings that are not present in many cases with COVID-19 infection (5,6,34). Although direct evidence was lacking, it has been long speculated that CMD could explain myocardial injury seen in severe COVID-19 patients (15,20). Present findings indicate that the degree of CMD correlates with both troponin and B-type natriuretic peptide concentration, suggesting a relationship between CMD, myocardial injury and an increased left ventricular filling pressure. To note, correlation should not be interpreted as causality and all of these findings might simply represent the severity of the underlying disease rather than a causal association between CMD and myocardial damage. Present findings are nonetheless intriguing and warrants further search for a causal association between CMD and myocardial injury.