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.