Clinical Review & Education JAMA Cardiology | Review Potential Effects of Coronaviruses on the Cardiovascular System A Review Mohammad Madjid, MD, MS; Payam Safavi-Naeini, MD; Scott D. Solomon, MD; Orly Vardeny, PharmD Viewpoint page 743 and IMPORTANCE Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes Editorial page 751 coronavirus disease 2019 (COVID-19) has reached a pandemic level. Coronaviruses are known Related articles pages 811, 819, to affect the cardiovascular system. We review the basics of coronaviruses, with a focus on and 802 COVID-19, along with their effects on the cardiovascular system. CME Quiz at OBSERVATIONS Coronavirus disease 2019 can cause a viral pneumonia with additional jamacmelookup.com and CME extrapulmonary manifestations and complications. A large proportion of patients have Questions page 852 underlying cardiovascular disease and/or cardiac risk factors. Factors associated with mortality include male sex, advanced age, and presence of comorbidities including Author Affiliations: McGovern hypertension, diabetes mellitus, cardiovascular diseases, and cerebrovascular diseases. Acute Medical School, Department of cardiac injury determined by elevated high-sensitivity troponin levels is commonly observed Medicine, University of Texas Health in severe cases and is strongly associated with mortality. Acute respiratory distress syndrome Science Center at Houston, Houston is also strongly associated with mortality. (Madjid); Texas Heart Institute, Houston (Safavi-Naeini); Brigham and CONCLUSIONS AND RELEVANCE Coronavirus disease 2019 is associated with a high Women’s Hospital, Harvard Medical School, Boston, Massachusetts inflammatory burden that can induce vascular inflammation, myocarditis, and cardiac (Solomon); University of Minnesota, arrhythmias. Extensive efforts are underway to find specific vaccines and antivirals against Minneapolis (Vardeny). SARS-CoV-2. Meanwhile, cardiovascular risk factors and conditions should be judiciously Corresponding Author: Mohammad controlled per evidence-based guidelines. Madjid, MD, MS, McGovern Medical School, Department of Medicine, University of Texas Health Science JAMA Cardiol. 2020;5(7):831-840. doi:10.1001/jamacardio.2020.1286 Center at Houston, 6431 Fannin, MSB Published online March 27, 2020. 1.246, Houston, TX 77030 (mmadjid @gmail.com). oronaviruses (CoVs) are single-stranded positive-sense RNA viruses, with the capacity for rapid mutation and Coronaviruses in Humans recombination. Coronaviruses are known to cause respi- C 1 ratory or intestinal infections in humans and animals. Acute Coronaviruses are named for crownlike spikes on their surface respiratory infections, including influenza, respiratory syncytial and belong to the Coronavirinae subfamily, which are further clas- virus, and bacterial pneumonias, are well-recognized triggers for sified into 4 groups: the α, β, γ, and δ CoVs by phylogenetic clus- cardiovascular diseases (CVD),2,3 and the underlying CVD is usu- tering, of which α and β are known to cause infection in humans.7 ally associated with comorbidities, which may increase the inci- Coronaviruses contain 4 major structural proteins: the spike (S) dence and severity of infectious diseases.4 The emergence of protein (which mediates attachment to the host receptor and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) subsequent fusion of the virus and cell membrane), the nucleo- virus, which causes coronavirus disease 2019 (COVID-19), has capsid (N) protein, the membrane (M) protein, and the envelope rapidly grown into a pandemic, and a large proportion of affected (E) protein.8 patients have been reported to have underlying CVD.5,6 In this The first human CoV (HCoV) was identified in the mid-1960s in report, we briefly review the basics of coronaviruses and their human embryonic tracheal organ cultures, and until 2003, only 2 potential effects on the cardiovascular system. Our knowledge of HCoV species, HCoV-229E and HCoV-OC43, were recognized. Cur- COVID-19 is still evolving rapidly, and this review discusses previ- rently, 7 different CoV strains are known to infect humans, includ- ous learnings from outbreaks of SARS and Middle East respiratory ing HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1, which syndrome (MERS), as well as seasonal influenza, to obtain further generally cause self-resolving infection. There are also severe acute insight into effects of coronaviruses on the cardiovascular system. respiratory syndrome coronavirus (SARS-CoV), Middle East Respi- Understanding the effects of COVID-19 on the cardiovascular sys- ratory Syndrome coronavirus (MERS-CoV), and newly identified tem is essential for providing comprehensive medical care for SARS-CoV-2, which can cause lethal respiratory infections in cardiac patients. humans.9,10 jamacardiology.com (Reprinted) JAMA Cardiology July 2020 Volume 5, Number 7 831 © 2020 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Clinical Review & Education Review Potential Effects of Coronaviruses on the Cardiovascular System Table 1. Coronaviruses Known to Cause Severe Viral Pneumonia Abbreviations: CVD, cardiovascular % Incubation disease; MERS CoV, Middle East Coronavirus Receptor period, d R0 Prevalence of underlying CVD Average case fatality rate respiratory syndrome coronavirus; SARS CoV ACE2 2-11 3 10 10 R0, the basic reproduction number; SARS CoV, severe acute respiratory MERS CoV DPP4 2-13 2 to 5 30 30 syndrome coronavirus; SARS-CoV-2, SARS-CoV-2 ACE2 2-14 2 to 3 4.2 Overall and up to 40 in 0.7 to 8 (Varies per location severe acute respiratory syndrome hospitalized patients and time) coronavirus 2. In 2003, a total of 8096 people in 29 countries were reported Endemic Coronaviruses illwithSARSand774ofthemdied(around10%).IntheUnitedStates, there were 8 laboratory-confirmed and an additional 19 probable Four HCoV types, including HCoV-229E (α-CoV), HCoV-NL63 (α- SARS cases, with no causal fatalities. The global SARS outbreak cost CoV), HCoV-OC43 (β-CoV), and HCoV-HKU1 (β-CoV) are endemic the world around $40 billion over a period of 6 months.23,24 Cur- in humans and usually cause mild, self-limiting respiratory infec- rently,there is no vaccine or specific antiviral effective against SARS- tions, which account for 15% to 30% of common colds.11 Infection CoV.Therefore, treatment of SARS entailed supportive care and use with these HCoVs typically cause mild upper respiratory infections of broad-spectrum antimicrobial coverage to treat secondary bac- in young adults but may lead to hospitalization in elderly patients terial infection. Advanced age (especially older than 60 years), un- with underlying cardiac and lung disease.12 Typically, coronavi- derlyingcomorbidities(suchasdiabetes,cardiovasculardisease,can- rusesaccountforasmallpercentageofpatientshospitalizedforacute cer, and chronic obstructive pulmonary disease), and high-lactate respiratory illness.13 dehydrogenase (LDH) at presentation were independent predic- tive factors of mortality in SARS-CoV infection.25 Of note, during the SARS outbreak, there was not a significant increase in morbidity or 14 Severe Acute Respiratory Syndrome Coronavirus mortality in infants and children. The SARS-CoV outbreak began in the Guangdong Province in south- Cardiovascular Complications of SARS ern China in November 2002, and was most likely linked to a zoo- The SARS-CoV also may have also resulted in cardiovascular com- notic event in the wild-animal markets in China. Soon after the isola- plications, although most of the data have been anecdotal in the ab- tion of SARS-CoV, SARS-CoV–like viruses were found in Himalayan sence of systematic studies. Acute coronary syndrome and myo- palm civets and raccoon dogs, with 99.8% nucleotide homology to cardial infarction were noted to occur after SARS.26,27 In a limited human SARS-CoV.14 study of 75 patients hospitalized with SARS, acute myocardial in- The SARS-CoV belongs to the β-CoVs group and binds to the zinc farction (AMI) was the cause of death in 2 of 5 fatal cases.26 Find- peptidase angiotensin-converting enzyme 2 (ACE2), a surface mol- ings from this limited study have not been confirmed in other re- ecule that is localized on the endothelial cells of arteries and veins, ports. A small prospective study among 46 patients with established arterial smooth muscle, respiratory tract epithelium, epithelia of the clinical diagnosis of SARS and without preexisting cardiac disease small intestine, respiratory tract epithelium, and immune cells, to collected information at the acute stage of infection (baseline) and enter the host cell.15-17 Suppression of ACE2 expression during SARS- 30 days later and showed no significant change in systolic function.28 CoV infection has been proposed to play a role in the pathologic However, transient diastolic function was detected during SARS in- changes in the lung and contribute to the severe pneumonia and fection which was resolved on follow up.28 acute lung failure observed with this virus.18 In another study of 121 patients (mean [SD] age of 37.5 [13.2] Further studies of wild animals proved robust evidence that years; 36% men) with a diagnosis of SARS, in whom 12 patients had SARS-CoV might have originated in bats, when a SARS-like CoV was underlying cardiovascular disease, tachycardia was the most com- identified in Chinese horseshoe bats with a sequence similarity of mon finding (72%), and other complications were hypotension 87% to 92% with human SARS-CoV,and