COVID-19 cardiovascular epidemiology, cellular pathogenesis, clinical manifestations and management

Abstract

Coronavirus Disease 2019 (COVID-19) is a rapidly progressing global pandemic that may present with a variety of cardiac manifestations including, but not limited to, myocardial injury, myocardial infarction, arrhythmias, heart failure, cardiomyopathy, shock, thromboembolism, and cardiac arrest. These cardiovascular effects are worse in patients who have pre-existing cardiac conditions such as coronary artery disease, hypertension, diabetes mellitus, and coagulation abnormalities. Other predisposing risk factors include advanced age, immunocompromised state, and underlying systemic inflammatory conditions. Here we review the cellular pathophysiology, clinical manifestations and treatment modalities of the cardiac manifestations seen in patients with COVID-19.

Keywords: COVID-19; Cardiovascular; Complications, and treatment; Coronavirus disease 2019; Pathophysiology; SARS-CoV-2.

Fig. 1

Flowchart demonstrates the SARS-CoV-2 induced cardiotoxicity. Caption: SARS-CoV-2 binds to the ACE-2 receptor(ACE-2R), leading to downregulation of ACE-2R that leads to pathway shift towards conversion of more angiotensin II that binds to Angiotensin II type 1 receptor (AT1R), Endothelin 1 receptor (ET1) promoting increased reactive oxygen species (ROS) by NADPH oxidase enzyme. NADPH oxidase is also activated by low BH4, High BH2, high iNOS. Increased ROS can cause cell apoptosis causing heart failure worsening, vascular damage, and sinus node dysfunction. Increased ROS can also cause CAMK-II activation causing early depolarization and arrhythmias. Increased ET1 also leads to increased thrombosis by increased endothelial dysfunction by oxidizing low density lipoprotein and PAI-1. Lipopolysaccharide binds to receptor TLR-4 increasing NFKBeta, that can increase IL-6, TNF-alpha, other inflammatory cytokines, and causes diffuse vascular damage and organ dysfunction. Ang 1–7 and Ang 1–9 have a positive role in our body, and can fight against COVID 19 but their levels, and downstream pathways are decreased in COVID-19 patients due to low ACE-2 R levels. eNOS, NPR A/B R, AT 2R, MASR normally counteracts the negative effects of AT1R, ET1 but this balance is disturbed in COVID-19 causing switch of pathway towards AT1R downstream effects. Abbreviations: SARS-CoV-2: Severe Acute Respiratory Syndrome Coronavirus-2; IL-6: Interleukin 6; Ang II: Angiotensin II; ET1: Endothelin 1; Ang1-9: Angiotensin 1–9; Ang 1–7: Angiotensin 1–7; ACE: Angiotensin Converting Enzyme; AT1R: Angiotensin II receptor type 1; AT2R: Angiotensin II receptor type 2; NPR A/B Natriuretic peptide receptor A/B guanylate cyclase; TNFα: Tumor necrosis factor alpha; INOS: Inducible nitric oxide synthase; ENOS: endothelial nitric oxide synthase; TGF-β: Transforming growth factor beta; ROS: Reactive oxygen species; CAMK-II: calmodulin dependent protein kinase II; CAM: Calmodulin; cGMP: Cyclic guanosine monophosphate; ANP/BNP: Atrial/Brain natriuretic peptide; PDE5/PDE5i: Phosphodiesterase 5 enzyme/inhibitor; BH4: Tetrahydrobiopterin; BH2: Dihydrobiopterin; TLR4: transmembrane lipopolysaccharide receptor 4; ICAM: intercellular adhesion molecule; VCAM: vascular cell adhesion molecule; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; PGE2: Prostaglandin E; MASR: Mitochondrial assembly g protein coupled receptor; NEPA: Neprilysin A receptor; NEPB: Neprilysin B receptor; NPR A/B: Neprilysin receptor A/B; HDAC: Histone Deacetylase; GATA: Globin transcription factor; NFAT: Nuclear factor of activated T-cells; PPAR-γ: Peroxisome proliferator-activated receptor gamma; Ca 2+: Calcium ion; Na +: Sodium ion; NCX: Sodium-Calcium exchanger; MEF2: myocyte-enhancer factor-2; STEMI: ST-segment elevation myocardial infarction. Color coding: Green frames resemble the protective and anti-inflammatory mechanisms, which are imbalanced by the pro-inflammatory COVID-19 state depicted in red causing overt inflammation and cell destruction; Brown color depicts the potential therapeutic targets that can help balance this inflammatory state; Yellow color shows all enzymes involved in RAAS or COVID induced cardiovascular cytotoxicity pathway. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)