RAS: Renin-Angiotensin System; Trop T: Troponin T; CVDs: Cardiovascular Diseases; ACE2: Angiotensin-Converting Enzyme-2; AT1R: ACE-angiotensin II receptor type 1; MasR: Mitochondrial assembly Receptor; SARS-CoV-2: Severe Acute Respiratory Syndrome Coronavirus-2; TNF: Tumor Necrosis Factor; NADPH: Nicotinamide Adenine Dinucleotide Phosphate; RNA: Ribonucleic Acid; aPTT: activated Partial Thromboplastin Time

As of writing this article, there were 396 million cases of coronavirus in the world and counting; with more than 78 million cases in the United States of America alone having more than 926 thousand deaths. The mode of transmission is mainly through exposure to respiratory droplets carrying infectious viruses. Multiple ways respiratory viruses are transmitted; direct contact with an infectious person, larger or smaller droplets and particles exhaled by corona virus-positive person, and through exposure to those virus-containing droplets which can remain suspended in the air [1]. The disease ranges from asymptomatic infection, mild upper respiratory tract infection to life-threatening pneumonia, acute respiratory distress syndrome requiring hospitalization, mechanic ventilation, and life supporting measures. Heart diseases are the leading cause of death in the United States causing 23.1% of total deaths [2]. There is no denial of underlying cardiovascular diseases has higher mortality among COVID-19 patients [3]. One hundred consecutive patients diagnosed with COVID-19 underwent transthoracic echocardiography in the first 24 hours of hospitalization, 68 patients were found to have abnormal echocardiography [4]. Acute myocardial injury and history of hypertension doubled the odds of in-hospital mortality in patients admitted for COVID-19 after other variables had been controlled [5]. According to the Chinese center for diseases control and prevention the study of 44672 laboratory-confirmed cases, the overall case-fatality rate was 2.3%, however, among pre-existing cardiovascular diseases patients, the case fatality rate was 10.5% [6].

Coronavirus 2019, a Beta-coronavirus genus; enveloped, ssRNA virus with 50 to 200nm diameter. It typically causes respiratory symptoms ranging from fever, dry cough, fatigue, myalgia, and influenza-like symptoms. Nevertheless, it has been recognized to cause a devastating inflammatory response and cytokine inclement ensuing in multi-organ dysfunction [7]. Cardiac involvement has been proven to be one of the serious complications of COVID-19 causing a range of manifestations including but not limited to acute myocardial infarction, right ventricular enlargement, right ventricular heart failure, left ventricular systolic dysfunction, heart failure, arrhythmias, and myocarditis [8]. The challenges faced by Coronavirus disease 2019 on the cardiovascular system are severe enough to mandate further investigation on pathogenic mechanisms. A single-center retrospective study showed a 16% prevalence of myocardial injury in COVID-19 patients; among those, they found significantly higher ICU admission and in hospital mortality after adjusting other variables compared to those without cardiac injury patients [9].

There are inimitable features of the COVID-19 virus that makes it exclusive. It has a bilayer of lipid with an envelope that crafts it exceedingly durable in the environment and simple to deactivate by sterilizers. The unique disarray of spike proteins formulates it amply infective and enriches its affinity to its receptor by several folds. This correspondingly can infect animals mainly cats. There are multiple ways coronavirus affects the heart and circulatory system. It may include direct virulence of coronavirus, ACE2 downregulation causing cardiac tissue damages, immunological reaction causing myocardial injury, hypoxia causing devastating effects on the heart, and pre-existing cardiovascular diseases preceding to higher chances of disease severity.

Direct virulence of SARS-CoV-2 to cardiovascular system

Coronavirus entry depends on binding spike proteins to cellular receptors and S protein priming by host cell proteases. The main receptor for the COVID-19 strain is Angiotensin-converting enzyme-2 (ACE2), which is expressed throughout the body including the respiratory tract, airways, heart, and vasculature [10]. ACE2 receptors are in the oropharynx and upper airway which allows binding of coronavirus to it, likely increasing its efficiency for person-to-person transfer. This means high infectivity even by normal speaking, coughing, or sneezing. A vitro study suggests that SARS-CoV-2 infects cardiomyocytes in ACE2 and cathepsin-dependent manner [11]. In one study, a Viral load of 1000 copies per μg RNA in the myocardium was recorded on 16 out 39 (41.0 %) COVID-19 pharyngeal swab positive patient’s autopsy with increased pro-inflammatory markers on cardiac tissues [12]. Cheng et al. described ACE2 as highly expressed in pericytes of adult human hearts, patients with basic heart failure diseases exhibited increased expression of ACE2 and might have a high possibility of heart attack and progressing to severe condition after infection [13]. Another study suggested SARS-CoV-2 infection facilitates the induction of endotheliitis in several organs as a direct consequence of viral involvement and the host inflammatory response. In addition, induction of apoptosis and pyroptosis might have an important role in endothelial cell injury in COVID-19 patients [14].

In addition, pre-existing heart diseases or damaged cardiomyocytes increase the sensibility to ACE2 receptors. A recent study suggested increased cardiomyocyte-related ACE2 receptor transcription in preexisting cardiovascular disease likewise dilated cardiomyopathy, hypertrophic cardiomyopathy which provide an extensive explanation for increased mortality among pre-existing cardiovascular diseases patients [15]. The initial stress state of cardiac cells could play a role in the determination of infectivity by the coronavirus and contribute to the vulnerability to the infection of patients with cardiomyopathies.

ACE2 is a critical part of the Renin-Angiotensin System (RAS). The RAS first axe ACE-angiotensin II receptor type 1 (AT1R) receptor elevates reactive oxygen species and superoxide levels which impairs endothelial function and microcirculation; and ACE2-Angiotensin (1-7)-MasR axis decreases inflammation and produces vasodilation [16]. Dysfunction of ACE2 due to COVID-19 infection causes elevated activation of AT1R axis leads to increased adhesion, aggregation of platelets, and exposure to the possibility of thromboembolism in multiple organs including the heart. After binding to ACE2, SARS-CoV-2 impairs the intracellular stress granule formation via its accessory protein which allows the virus to replicate intracellularly in the cardiomyocytes. These viral antigens in the cell prime the T lymphocyte causing myocardial inflammation through cell-mediated cytotoxicity. This cytotoxicity is strengthened in the presence of the cytokine storm due to pro-inflammatory cytokines released in the circulation [17]. This explains myocarditis as an adverse outcome. The long-term follow-up suggests increased rates of systolic dysfunction and clinical heart failures due to stress cardiomyopathy and myocarditis [18].

Inflammatory response causing cardiac injury

It has been known that respiratory viruses including influenza can develop in localized production of inflammatory elements escalating chances of cardiac injuries. Candid viral infection of endothelial cells triggering diffuse endothelial injury amalgamated with inclement in an immune storm causing neutrophilic infiltrates and cytokine expression. These inflammatory cells play a major role in causing myocardium injury. An autopsy study of 39 consecutive COVID-19 confirmed cases illustrated the existence of viral genome or viral load does not correlate with the existence of inflammatory cells in the myocardium [12]. Systemic inflammation identified as an overactive immune response involving redundant cytokines in blood has an eminent role in the mortality of COVID-19 patients [19]. Inflammatory cells take a key role in combating infection, but excess pro-inflammatory cells instigate unnecessary injurious effects to the vital organs of the body. The evidence suggests that SARSCoV-2 driven ACE2 down-regulation leads to an array of complex and intertwined molecular interactions via increased activation of ACE2/bradykinin and complement cascades resulting in observed cytokine storm in severe COVID-19 [20]. Moreover, the effect of ACE2 downregulation would impede the cardioprotective effects of angiotensin 1-7 leading to increased TNF-alpha production [21]. TNF-alpha is a common inflammatory cytokine and leads to amplification of inflammatory response causing poor outcomes and facilitating cardiomyocyte damage.

The level of C-reactive protein as inflammatory markers is shown to be in direct correlation with the risk of myocardial infarction due to plaque rupture [22]. Systemic inflammation can also activate the coagulation pathways through several mechanisms; polyphosphates derived from micro-organisms activate platelets, mast cells, and factor XII of coagulation leading to microthrombi and possible Disseminated Intravascular Coagulation development.

Endothelial injury and micro-thrombosis

Increased cytokines due to inflammatory response cause myocardial and endothelium injury. And endothelial injury leads to activation of coagulation cascades and aggregation of platelets leading to thrombus formation. The increased level of catecholamines, as part of systemic inflammation also led to plaque disruption and rupture causing myocardial infarction. The break of atheromatous plaque precedents the exposure of foamy macrophages located under endothelium to the bloodstream. These macrophages prompt the tissue factor escorting to the formation of microthrombi. The other study illustrated coagulation disturbances and found to have elevated Ddimers in COVID-19 patients [23]. Tang et al. described the overall mortality in COVID-19 patients were 11.5%, the non-survivors revealed significantly higher Ddimer (18 out of 21) and fibrin degradation product levels, longer PT and aPTT time compared to survivors on admission(P<0.05); 71.4% of non-survivors and 0.6% survivors met the criteria of disseminated intravascular coagulation during their clinical course [24].

Micro-thrombosis, microangiopathy, large thrombus, and disseminated intravascular coagulation were observed early in the course in severe cases of COVID-19 [25]. SARS-CoV-2 infection interrupts the stimulation of coagulation and secondary hyperfibrinolysis escorting to thromboembolism in respective organs [26]. The other article noted COVID-19 as an endothelial disease stating activated endothelial monolayer leads to expressed leukocyte adhesion molecules. Which produces chemokines and vasoconstrictor due to decreased nitric oxide and thromboxane; pro-coagulant due to tissue factor and thromboxane; pro-oxidant due to NAPDH oxygenase and peroxynitrite [27]. The proposed pathophysiology for myocardial infarction in COVID-19 can include stress and increased sympathetic activity due to viral disease leading to acute coronary syndrome (ACS). In addition, COVID-19 associated cytokine storm, vasoactive molecules leading to endothelial dysfunction, endothelial damage leading to hypercoagulability, and disruption of the fibrous cap; all these factors together destabilize the plaque or de novo formation of plaques leading to plaque rupture and thrombus formation [28].

Hypoxia-induced cardiac Injury

Infection at large intensifies the oxygen demand; furthermore, inflammatory processes and fever lead to high oxygen consumption at the cellular level. To boot, lung infection decreases the lung capacity which leads to decreased oxygen exchange at the alveoli level. These factors impose hypoxemia in the blood. Endothelial impairment in the pulmonary vasculature contributes to the thrombotic process that may augment the risk of acute respiratory distress syndrome (ARDS). Respiratory failure causes a lack of oxygen to the heart which interrupts the demand and supply ratio of oxygen to the heart causing heart failure. These all cause reduce oxygen in the blood leading to ischemic myocardial injury [29]. The initial single-center study indicated that patients with higher SpO2 levels after oxygen supplementation were associated with reduced mortality independently of age and sex showing hazard ratio per 1-Unit SpO2 0.93 (95% CI: 0.91-0.95; P<0.001) [30].

Also, hypoxia/hypoxemia causes activation of procoagulant pathways leading to fibrin deposition, expression of tissue factor, and suppression of fibrinolysis promoting thrombosis in blood [31]. Hypoxia and inflammation are fundamental parts of the advancement of atherosclerosis. Tissue hypoxia seems to be one of the commonest features in the pathophysiology of various cardiovascular diseases including atherosclerosis, vascular remodeling, and heart failure [32].

Pre-existing cardiovascular diseases

Pre-existing CVD was described as a risk factor for COVID-19 induced heart injury. Shi et al. earlier in July 2020 demonstrated a total of 82 patients in the study had a cardiac injury; these patients were older (median 74 years), had hypertension in 49 out of 82 (59.8%). Patients with cardiac injury had higher mortality than those without cardiac injury (42 out of 82 [51.2%] vs 15 out of 334 [4.5%]; P<0.001). On Cox proportional hazard regression analysis model patients with versus without cardiac injury were at higher risk of death; both during the time from symptom onset (Hazard ratio, 4.26 [95% CI: 1.92-9.49]) and admission to endpoint (Hazard ratio, 3.41 [95% CI: 1.62-7.16]) [33]. It can be logically presumed that patients with pre-existing cardiovascular comorbidities including hypertension, coronary artery diseases, and cardiomyopathies are vulnerable to cardiac injury; and the virulence of COVID-19 towards cardiac tissues predisposes them to have a high likelihood of cardiac sequelae during their clinical course or sudden onset leading to worsening in their condition. However, the other meta-analysis study found that pre-existing CVDs and hypertension had no independent role in increasing mortality [34]. They claimed pre-existing CVD was having significantly higher correlation of Invasive mechanical ventilation utilization (r:0.28; OR 1.3, 95 % CI: 1.1-1.6) without having any association with mortality (r: -0.01; OR 0.9; 95% CI: 0.9-1.1) among COVID-19 hospitalized patients [34]. In addition, the Danish cohort of hospital-screened COVID-19 patients determined the predicted risk of death for 75 years old males with no comorbidities were 22.3% (95% CI: 19.4%-25.5%) while the corresponding risk for 75-year-old males with single CVD were 15.5 % (95 % CI: 12.1%- 19.8%) in ischemic heart disease patients; 27.6% (95% CI: 20.5%–36.5%) in heart failure patients; and 23.7% (95% CI: 19.0%–29.3%) in atrial fibrillation patients [35]. A retrospective cohort study based on Veterans Health Administrations data after adjustment of medical comorbidities found patients with a pre-existing diagnosis of heart failure versus non-heart failure patients had higher 30-day mortality (5.4% vs 1.5%), and hospitalization (18.5% vs 8.4%) rates after diagnosis of COVID-19 [36]. A meta-analysis of 10898 patients found CVD patients were eight times more likely to have a fatal outcome (OR 7.87, 95% CI: 2.17-28.57, P<0.05) and three times more likely to be admitted to the ICU (OR 3.33, 95% CI: 1.81-6.11, P<0.001) [37].

The COVID-19 pandemic has impacted the world health system intensely by affecting millions of people. The structure of the virus facilitates binding to the ACE2 receptor, which is expressed throughout the body and has a multiorgan systematic inflammatory reaction. Cardiovascular complications are significantly associated with higher mortality among COVID-19 patients. We recognized several possible mechanisms of cardiovascular-related injuries in COVID-19 patients. These may include but are not limited to direct virulence of SARS-CoV-2, exaggerated inflammatory response, endothelial injuries causing micro thrombosis, hypoxia related direct injuries to the heart, and pre-existing cardiovascular diseases as a major indicator in direct relation to morbidity and mortality. Although, it is not wrongful to say that myocardial injury is heavily linked to mortality among COVID-19 patients even without preexisting cardiac-related conditions. To realistically treat

COVID-19 patients, the provider must be more cautious and aggressive in protecting underlying diseases with symptomatic treatment. Cardiovascular diseases are the leading cause of death worldwide. And together with COVID-19, it has emerged as dreadful overall. It will be crucial to look for long-term cardiovascular sequelae among COVID-19 patients. As an advocator of health care, we need to be more vigilant for upcoming chronic consequences of cardiovascular diseases among these patients.

Authors declare no conflict of interest.

Though this article does not contain any studies with direct involvement of human participants or animals performed by any of the authors, all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Any information used in this study has been collected from previously published articles on PubMed and de-identified thus informed consent or IRB approval was not needed for this study.

Conceptualization: Ghanshyam Patel, Mario Affinati, Jeffrey Smith, Luqman Baloch; Writing - original draft preparation: Ghanshyam Patel, Ammar Aqeel; Writing - review, critical feedback, and editing: Mario Affinati, Jeffrey Smith, Luqman Baloch, Ammar Aqeel.