Review identifies possible mechanisms for elevated troponin, cardiac injury in COVID-19
No mechanism has been definitively proved as the cause for elevated troponin in patients with COVID-19, but researchers suggested that risk factors such as myocarditis, ACE2 downregulation, type 2 MI and cytokine storm may be associated with myocardial injury in those with the disease.
A review published in the Journal of Cardiac Failure assessed the current knowledge base and summarized several likely underlying mechanisms associated with increased cardiac troponin levels in COVID-19.
“At present, none of these mechanisms have been definitely proven to be the main driver of troponin elevation and/or myocardial damage in patients with COVID-19,” Gregorio Tersalvi, MD, of the division of cardiology at Fondazione Cardiocentro Ticino in Lugano, Switzerland, and colleagues wrote. “However, we posit that, although COVID-19 initially presents as a primarily respiratory condition, it quickly involves the cardiovascular system through an imbalance of the renin-angiotensin-aldosterone system mediated by ACE2 depletion. This mechanism may complicate the clinical course mediated through the inflammatory response, endothelial dysfunction and microvascular damage.”
Cardiotropic viruses may cause myocarditis
According to the review, the initial stages of viral myocarditis, an effect of cardiotropic viruses, confer direct virus-mediated lysis of cardiomyocytes, followed by a strong T-cell response. This T-cell response can lead to cardiac injury and further ventricular dysfunction.
“In COVID-19, particular attention has been given to the role of ACE2, the binding receptor for SARS-CoV-2 cellular entry,” the researchers wrote. “ACE2 is highly expressed in pericytes of adult human hearts, which indicates an intrinsic susceptibility of the heart to SARS-CoV-2 infection.”
Angiotensin II/angiotensin-(1-7) imbalance
The SARS-CoV-2 virus uses ACE2 as its entry receptor and, therefore, downregulates ACE2 expression. According to the review, reducing ACE2 expression also reduces the conversion of angiotensin II to angiotensin-(1-7), which combats the vasoconstrictor, proinflammatory, pro-oxidant, proproliferative and profibrotic effects of angiotensin II. This imbalance may represent another potential mechanism of myocardial injury in patients with COVID-19.
“A clinical trial testing recombinant human ACE2 as a treatment for patients with COVID-19 is currently ongoing (NCT04335136),” the researchers wrote. “This drug may play a double role, both by acting as a decoy and competitively decreasing viral cell entry, and by restoring ACE2 activity and its beneficial role.”
Type 2 MI ‘unmasked’ by infection
Previous studies had shown that patients with a history of CAD and/or risk factors for atherosclerotic CVD maybe at increased risk for ACS and other inflammatory diseases, according to the review. This may result from an oxygen supply and demand imbalance in the acute setting in a way that increased cardiac troponin levels may be interpreted as a type 2 MI.
“By definition, a type 2 MI can occur with or without underlying CAD,” the researchers wrote. “However, considering the higher prevalence of elevated troponin in patients with COVID-19 with previous CVD, it is possible that the type 2 MI when underlying stable coronary disease is unmasked by the acute infection.”
Cytokine storm
Angiotensin-(1-7) opposes the probiotic effects of angiotensin II, including cytokine production, according to the review. Cytokine synthesis has been associated with HF (Stanciu AE. Adv Clin Chem. 2019;doi:10.1016/bs.acc.2019.07.002) due to its effects on inflammatory modulation, myocyte stress or stretch, myocyte injury and apoptosis, fibroblast activation and extracellular matrix remodeling. Therefore, a reduction in ACE2 expression may expand the cytokine storm, prompting an increased T-cell response.
“Systemic inflammatory response with cytokine storm is a plausible cause of myocardial injury in the late phases of disease, usually associated with acute respiratory distress syndrome, multiorgan failure and mortality,” the researchers wrote. “Overall, high cytokine levels may represent the key player of myocardial injury in COVID-19, being related to direct myocardial injury, endothelial dysfunction, destabilization of coronary plaque and microthrombogenesis.” – by Scott Buzby
Disclosures: The authors report no relevant financial disclosures.
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