Current understanding of the link between COVID-19 and cardiovascular disease
The rapid outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in the pandemic of the ongoing coronavirus disease 2019 (COVID-19). To date, this pandemic has claimed more than five million lives worldwide. Scientists have indicated that the elderly with comorbidities, such as cardiovascular disease (CVD) and/or diabetes are more susceptible to severe COVID-19 infection.
Study: Increased complications of COVID-19 in people with cardiovascular disease: Role of the renin–angiotensin-aldosterone system (RAAS) dysregulation. Image Credit: Irina Shatilova/ Shutterstock
Therefore, understanding the mechanism that links CVD and SARS-CoV-2 susceptibility and knowing why this group is more susceptible to SARS-CoV-2 infection is crucial for protecting them from the disease. A review published in Chemo-Biological Interactions has focused on the prevalence of COVID-19 in CVD patients associated with ACE2 mechanisms.
COVID-19 and cardiovascular disease
SARS-CoV-2 is an RNA virus that belongs to the genus Betacoronavirus of the family Coronaviridae. It primarily infects the lungs, and symptoms range from mild flu-like to severe pneumonia. In the case of acute COVID-19 infection, many complications, such as lymphopenia, disseminated intravascular coagulation (DIC), coagulopathy, myositis, and renal or liver damage, occur.
Previous studies on the clinical manifestation of SARS-CoV in the cardiovascular system showed infiltration of monocytes plasma cells (B cells) and other lymphocytes into blood vessel walls and also fibrinoid necrosis. These events lead to vasculitis in various organs, such as the heart, lungs, liver, kidneys, etc., and the formation of blood clots in small veins. Similarly, earlier studies revealed that patients with underlying CVDs, e.g., pericarditis, cardiac arrhythmias, and acute myocarditis, had suffered severe MERS-CoV infection, compared to the healthy group of individuals.
Previous studies revealed that the cytokine storm is caused due to the increased interleukin (IL)-2, IL-6, IL-7, interferon gamma-induced protein 10 (IP10), granulocyte colony-stimulating factor (GSCF), macrophage inflammatory protein 1 A (MIP1A), and tumor necrosis factor α (TNFα), following SARS-CoV-2 infection. Scientists revealed that the cytokine storm leads to acute increases in the left ventricular (LV) dysfunction in patients with CVD.
The study of a large cohort, which included five thousand SARS-CoV-2 patients, found that patients with pre-existing diseases (e.g., CVDs, cancers, or diabetes) are at the highest risk of increased mortality. Scientists stated that the main mechanism behind the increased susceptibility to COVID-19 infection in patients with CVDs, to be increased expression of angiotensin-converting enzyme-2 (ACE2) receptor in this group of patients, especially in those who were under ACE inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) treatment.
However, another group of researchers strongly negated this theory by stating that patients receiving ACEI/ARB therapy were not susceptible to severe COVID-19 or hospital admission. Therefore, more studies are required to understand better the actual mechanism behind the association between CVDs and severe COVID-19 infection. A recent study revealed that two of the common treatments, i.e., the use of hydroxychloroquine (antimalarial medication) and azithromycin (antibiotics), have serious side effects in people with CVDs.
ACE2 and COVID-19 infected patients with CVDs
ACE2 is a metalloprotease that is richly expressed in endothelial cells, cardiomyocytes, and cardiac fibroblasts. These cells comprise the majority of heart tissue. Elevated ACE2 levels have been found in patients after myocardial infarction (MI). Scientists believe this might be the mechanism that counteracts the activation of the renin-angiotensin-aldosterone system (RAAS). Hence, the ACE2 system acts as a preventive mechanism against MI, hypertension, lung disease, and diabetic complications.
ACE2 is also the main host receptor for SARS-CoV-2 infection. The spike protein of the SARS-CoV-2 binds with the ACE2 receptor of the host and, subsequently, penetrates the host cells. Angiotensin 1-9 and Angiotensin 1-7 have important cardioprotective functions, including reducing blood pressure. Upon SARS-CoV-2 infection, this protective effect is reversed due to the impairment of the conversion of Angiotensin I to Angiotensin 1-9 and Angiotensin II to Angiotensin 1-7.
Previous studies have revealed that coronaviruses affect various endocrine and metabolic pathways through the RAAS system. Animal models showed increased ACE2 expression was effective in improving acute lung injuries and treatment with RAAS inhibitors mitigated lung damage. A recent study reported RAAS inhibitors, which are used to treat hypertension and CVDs, had better outcomes in COVID-19 patients than those under other anti-hypertensive drugs (e.g., calcium channel blockers).
A murine model of SARS-CoV infection revealed that a reduction in the expression of ACE2 led to an increase in angiotensin II levels which increased vascular permeability and respiratory complications. These complications were reversed by the treatment with recombinant ACE2 or an ARB (losartan). Additionally, murine models and analysis of human autopsy samples showed that SARS-CoV infection downregulated ACE2 expression in both myocardial cells and type 2 alveolar epithelial cells. This led to inflammatory responses and respiratory distress in COVID-19 patients.
The authors recommended that future research focus on developing in vitro and in vivo models that are analogous to various cardiovascular complications. This will enable scientists to understand better pathogenic mechanisms associated with increased susceptibility to SARS-CoV-2 infections and complications in CVD patients. More studies are needed to test the hypothesis that one of the plausible reasons for increased complications of SARS-CoV-2 in CVD patients is the excessive accumulation of Angiotensin II.
- Augustine, R. et al. (2021) Increased complications of COVID-19 in people with cardiovascular disease: Role of the renin–angiotensin-aldosterone system (RAAS) dysregulation. Chemo-Biological Interactions. doi: https://doi.org/10.1016/j.cbi.2021.109738
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Dr. Liji Thomas
Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.
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