key: cord-0764430-406dfdih
authors: Srivastava, Kamna
title: Association between COVID-19 and cardiovascular disease
date: 2020-07-14
journal: Int J Cardiol Heart Vasc
DOI: 10.1016/j.ijcha.2020.100583
sha: 91dc3a9dde3336d4e3f03898f405a953c8fee05c
doc_id: 764430
cord_uid: 406dfdih

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19) has reached a pandemic level. SARS-CoV-2 infects host cells through ACE2 receptors, leading to COVID-19-related pneumonia. The rapid increase in confirmed cases makes the prevention and control of COVID-19 extremely serious. Real-time reverse transcription-PCR (RT-PCR) assays remain the molecular test of choice for the etiologic diagnosis of SARS-CoV-2 infection while radiographic findings (chest computed tomography [CT]) and antibody-based techniques are being introduced as supplemental tools. Novel virus also cause chronic damage to the cardiovascular system, and attention should be given to cardiovascular protection during treatment for COVID-19. Acute cardiac injury determined by elevated high-sensitivity troponin levels is commonly observed in severe cases and is strongly associated with mortality. This review suggests that cardiovascular comorbidities are common in patients with COVID-19 and such patients are at higher risk of morbidity and mortality. The continuation of clinically indicated ACE inhibitor and ARB medications is recommended in COVID-19. We review the basics of coronaviruses, novel molecular targets for the coronaviruses with a focus on COVID-19, along with their effects on the cardiovascular system.

.This invasion process requires S protein priming which is facilitated by the host cell produced serine protease TMPRSS2 [8] . The interaction between viral Spike protein and ACE2 on the host cell surface is of significant interest since it initiates the infection process. It is reported that binding affinity of SARS-CoV-2 S protein to ACE2 is about 10−20 times higher than that of SARS-CoV S protein [4, 7] . Hence, it is speculated that this may contribute to the reported higher transmissibility and contagiousness of SARS-CoV-2 as compared to SARS-CoV [10] . The rapid increase in confirmed cases makes the prevention and control of COVID-19 extremely serious [2, 3].

The SARS-Cov2 virus achieves cell entry through an S (spike) high-affinity protein binding to the catalytic domain of the ACE2 receptor; pneumocytes are particularly vulnerable [4] . Both SARS-CoV and influenza preferentially infect type II cells compared to type I cells [11] [12] [13] . Moreover, it is known that not all pneumocytes are equally threatened by SARS-CoV-2 infection, but Type II pneumocytes are in greater danger, that really matters for short and long term prognosis in terms of acute lung injury and pulmonary fibrosis. There are a number of promising treatments and vaccines under investigation, but none with proven clinical efficacy at this time.

The investigator reviewed and summarized the rapidly evolving data regarding evidence linking COVID-19 with increased morbidity and mortality from cardiovascular disease. Search methods and strategies for identification of studies Literature search was performed in WHO reports, PubMed, Scopus, Science Direct and also in American Heart Association journals, Nature, JAMA, BMJ and THE LANCET journals using following terms:ACE2, coronavirus, COVID-19 and 2019-nCoV, COVID-19 and CVD, Cardiovascular Risk and Diseases to find articles published from January 05 to May 20, 2020. Old data that had inappropriate topics and were not pertinent to the focused purpose of the study were excluded from the studies. Some of the information pertaining to India is taken from the Ministry of Health, Government of India as the data on infection, mortality and survival from COVID-19 are rapidly changing.

SARS-CoV-2 is spread predominantly via respiratory droplets. Transmission may occur from both symptomatic and asymptomatic patients, with secondary infection rates ranging 0.5-5% [13, 14] .

SARS-CoV-2 has been demonstrated to remain stable [15] and the median incubation time is 4-5 days and 97.5% will experience symptoms within 11.5 days of exposure [16, 17] . The most common symptoms are fever and dry cough, which are shared with many other viral syndromes.

Conspicuously, rhinorrhea and diarrhea were also reported with COVID-19 in some cases 14 Reports from China [18] demonstrate that a significant majority of patients (81%) had mild symptoms (no pneumonia or mild pneumonia) from COVID-19. Among those with more significant symptoms, people experienced severe symptoms (dyspnea, respiratory rate ≥30/min, blood oxygen saturation ≤93%, partial pressure of arterial oxygen to fraction of inspired oxygen ratio <300, and/or lung infiltrates >50% within 24 to 48 hours) and 5% were critical (respiratory failure, septic shock, and/or multiple organ dysfunction or failure. 

Pathogen of COVID-19 has been detected in upper and lower respiratory tracts in initial assessments. It is also detected in fecal and blood samples. 

With the exposure of ACE2 as a target for SARS-CoV-2 invasion, blocking the combination of virus and ACE2 has become one of the therapeutic directions. No approved drug regimen has been reported to treat infected cases so far. However, recently another proposed treatment Chloroquine, an old drug for treatment of malaria, has been suggested with apparent effectiveness and acceptable safety against COVID-19 associated pneumonia [20, 21] . While several drug trials are ongoing, there is currently no proof that hydroxychloroquine or any other drug can cure or prevent COVID- 19 . The misuse of hydroxychloroquine can cause serious side effects and illness and even lead to death. WHO is coordinating efforts to develop and evaluate medicines to treat COVID-19. Using monoclonal antibodies has not been proven in viral respiratory diseases and influenza, as yet [22] . Table-1 .

The RAAS is well characterized in hypertension, heart failure, and beyond. ACE2 is involved in heart function and the development of hypertension and diabetes mellitus. ACE converts angiotensin I (Ang I) to Ang II, predominantly in the lungs. The effects of Ang II are dependent on receptor binding: AT1 receptor binding stimulates the classical effects of Ang II, ranging from increased oxidative stress, through to vasoconstriction. ACE2 is an enzyme attached to cell membranes in the lungs, endothelium, and heart, as well as the kidneys. Its main pharmacological effect is to lower blood pressure by catalysing the cleavage of Ang I to Ang 1-9 and of Ang II to Ang 1-7 (vasodilatory, anti-inflammatory activity). ACE2 has additional affinity for other vasoactive substrates, including apelin-13 and bradykinin. ACE2 has a strong affinity for type 1 and type 2 receptors of Ang II and regulates blood pressure, humoral balance, inflammation, cell proliferation, hypertrophy, and fibrosis. Moreover, the tissue specific expression of ACE2 suggests There are reports that sex difference exists, with men having higher ACE2 levels. Higher circulating levels were reported in heart failure, atrial fibrillation, and renal disease [38] . SARS-CoV-2 shares both high sequence similarity and the use of the same cell entry receptor, angiotensin-converting enzyme 2 (ACE2), with severe acute respiratory syndrome coronavirus (SARS-CoV).

COVID-19 patients with pre-existing heart disease may suffer a heart attack or develop congestive heart failure. This due to a combination of the severe viral illness and its increased demands on the heart, increased heart rate compounded by low oxygen levels due to respiratory symptoms, myocarditis and increased propensity for blood clot formation. In addition to the increase in these heart problems, a more unusual condition called myocarditis has also been observed in COVID- understanding the underlying mechanisms is of the greatest importance, so that treatment of these patients can be timely and effective and mortality reduced.

There has been a clinical controversy whether the use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) might be detrimental or beneficial in COVID- 19 . These two classes of drugs are widely prescribed in patients with hypertension and cardiovascular disorders. We have reported [42] our work on ACE gene expression in patients with essential hypertension and normal healthy population. In another study [43] , we have reported the role of Angiotensin type I receptor in patients with essential hypertension and normal healthy controls as pathological and physiological differential expression at mRNA and protein levels.

Individuals have proposed stopping such drugs due to concern over up-regulation of the ACE2 receptor acting as the SARS-CoV-2 entry point; others paradoxically suggest prescribing this class of drugs to counteract a dysregulated angiotensin-aldosterone system. Symptoms are more severe in patients with CVD, which might be associated with increased levels of ACE2 in these patients compared with healthy individuals. There is a links between the renin-angiotensin-aldosterone system (RAAS) and the ACE2 receptor specifically; expanding on the observation that hypertension is prevalent among those diagnosed with COVID-19 [44] [45] [46] . Whether patients with COVID-19 and hypertension who are taking an ACE inhibitor or angiotensin-receptor blocker should switch to alternative antihypertensive therapy remains controversial, and further investigation is required.

Antiviral treatments are used to alleviate the disease symptoms. Studies on Remedesevir, as an antiviral agent, revealed its in vitro activity against the COVID-19 virus and its safety was proven Umifenovir and Oseltamivir against COVID-19 virus is interesting but lacks any biological plausibility. Many antiviral drugs can cause cardiac insufficiency, arrhythmia or other cardiovascular disorders. Antiviral drug induced heart damage during COVID-19 treatment is a major concern and the monitoring of the risk of cardiac toxicity with the use of antiviral drugs is important. In a study of 138 patients with COVID-19, 89.9% were given antiviral drug [1, 47] .

In a report by Huang et al [3] myocardial injury associated with the SARS-CoV-2 was found in 5 of the first 41 patients diagnosed with COVID-19 in Wuhan. These patients had elevated cardiac troponin I (hs-cTnI) levels (>28 pg/ml) levels. In this report, four of five patients with myocardial injury were admitted to the intensive-care unit (ICU) and the systolic blood pressure levels were chest tightness rather than with respiratory symptoms and fever were later diagnosed with COVID-19. Therefore, in patients with COVID-19, the incidence of cardiovascular symptoms is high, owing to the systemic inflammatory response and immune system disorders during disease progression. The exact mechanism of cardiac involvement in COVID-19 remains unclear. One potential mechanism is direct myocardial involvement mediated via ACE2. ACE2 is widely expressed not only in the lungs but also in the cardiovascular system and, therefore, ACE2-related signalling pathways might have a role in heart injury. Other proposed mechanisms of myocardial injury include a cytokine involvement [3-6], and respiratory dysfunction caused by COVID-19, is detrimental to myocardial cells. Some COVID-19 patients who appear to be having a heart attack are instead suffering from marked inflammation of the heart muscle, called myocarditis. It is not clear whether myocarditis is due to a direct effect of the virus on the heart muscle, or whether it is due to an overactive immune response to the virus, so doctors do not yet know how best to treat these patients. Coronavirus disease 2019 is associated with a high inflammatory burden that can induce vascular inflammation, myocarditis, and cardiac arrhythmias.

Wu et al [49] reported in a 12-year follow-up survey of 25 patients who recovered from SARS-CoV infection that 68% had hyperlipidaemia, 44% had cardiovascular system abnormalities and 60% had glucose metabolism disorders. In these patients, the serum concentrations of free fatty acids, lysophosphatidylcholine, lysophosphatidylethanolamine and phosphatidylglycerol were significantly increased as compared to individuals without a history of SARS-CoV infection 49 Here, we cannot ignore the role of ethnicity as there could also be some peculiar genetic characteristics of the population that may have an impact on the susceptibility to viral infection, the disease severity. 

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