Review European Journal of Preventive Cardiology Cardiovascular disease and COVID-19: 2020, Vol. 27(10) 1017–1025 ! The European Society of les liaisons dangereuses Cardiology 2020 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/2047487320924501 Andrea Barison1,2, Alberto Aimo2,3, Vincenzo Castiglione2,3, Downloaded from https://academic.oup.com/eurjpc/article/27/10/1017/5925346 by UAB-05 Communications Lib user on 31 January 2022 journals.sagepub.com/home/cpr Chiara Arzilli3, Josep Lupon4,5, Pau Codina4,5, Evelyn Santiago-Vacas , Germán Cediel4,5, Michele Emdin1,2 4,5 and Antoni Bayes-Genis4,5 Abstract Patients with cardiovascular risk factors or established cardiovascular disease have an increased risk of developing coro- navirus disease 19 and have a worse outcome when infected, but translating this notion into effective action is challenging. At present it is unclear whether cardiovascular therapies may reduce the likelihood of infection, or improve the survival of infected patients. Given the crucial importance of this issue for clinical cardiologists and all specialists dealing with coro- navirus disease 19, we tried to recapitulate the current evidence and provide some practical recommendations. Keywords Coronavirus, cardiovascular, comorbidities, risk factors, COVID-19, SARS-CoV-2 Received 13 April 2020; accepted 15 April 2020 As of 12 April 2020, over 1.7 million cases of infection severe disease, the cytokine storm, high catecholamine by the novel coronavirus severe acute respiratory syn- levels and profound hypoxia may contribute to cardi- drome coronavirus 2 (SARS-CoV-2) and almost omyocyte damage and acutely reduce cardiac function 109,000 deaths have been reported, and coronavirus (myocardial stunning).5 These mechanisms may disease 19 (COVID-19) is the leading cause of daily explain HF decompensation or the occurrence of deaths in the United States, before heart disease and cardiogenic shock, which can require extracorporeal cancer.1,2 Although the clinical picture of COVID-19 is membrane oxygenation.3 Atrial fibrillation or other usually dominated by respiratory symptoms, these tachyarrhythmias triggered by systemic inflammation patients may also develop cardiovascular disorders, are other possible precipitants of HF decompensation.5 which may even become the ultimate cause of death. Furthermore, a generalised activation of coagulation The following cardiovascular complications have been mechanisms may elicit acute venous thrombo- reported: myocarditis, acute coronary syndrome embolism,6 or lead to disseminated intravascular coag- (ACS), decompensated heart failure (HF), pulmonary ulation (DIC),7,8 which is often fatal. embolism (PE), cardiogenic shock and infection of a heart transplant recipient.3 COVID-19-related myocar- 1 ditis may be caused by coronavirus-induced cardio- Cardiology Division, Fondazione Toscana Gabriele Monasterio, Italy 2 Insitute of Life Sciences, Scuola Superiore Sant’Anna, Italy myocyte damage or an excessive immune response to 3 University Hospital of Pisa, Italy cardiomyocyte infection; it is characterised by chest 4 Heart Institute, Hospital Universitari Germans Trias i Pujol, Spain pain, prominent electrocardiographic changes, such as 5 CIBERCV, Instituto de Salud Carlos III, Spain diffuse ST-segment elevation, and troponin elevation, Corresponding author: which may be accompanied by fever and respiratory Andrea Barison, Fondazione Toscana Gabriele Monasterio, Via Moruzzi, symptoms or be isolated manifestations.3–5 This condi- 1 – 56124 Pisa, Italy. tion must be differentiated from ACSs. In patients with Email: barison@ftgm.it 1018 European Journal of Preventive Cardiology 27(10) A high proportion of patients with COVID-19 have moderate clinical presentation.16 Analogously, a met- cardiovascular risk factors or an established cardiovas- analysis on 1527 COVID-19 patients reported higher cular disease, which are even more prevalent than respi- incidences of cardiovascular disease (three-fold), hyper- ratory disorders,9,10 and are associated with a reduced tension (two-fold) and diabetes (two-fold) among those survival.10 At present, it is unclear whether cardiovas- who required intensive care unit (ICU) admission com- cular therapies may reduce the likelihood of infection, pared to non-ICU counterparts.17 or improve the outcome of infected patients. Given the In fact, various reports have demonstrated that car- Downloaded from https://academic.oup.com/eurjpc/article/27/10/1017/5925346 by UAB-05 Communications Lib user on 31 January 2022 uttermost importance of this issue for clinical cardiol- diovascular disorders, hypertension and diabetes are ogists and all specialists dealing with COVID-19, we among the most relevant negative prognostic factors tried to recapitulate the current evidence and provide for COVID-19, together with advanced age, male some practical recommendations. gender, chronic respiratory diseases and cancer.18–20 Indeed, in a series of 44,672 confirmed COVID-19 cases from Wuhan, China, the overall case fatality Prevalence and prognostic impact of rate was 2.3%, but it was significantly higher in cardiovascular disease in COVID-19 patients with an underlying cardiovascular disease The presence of underlying cardiovascular disease and/ (10.5%), hypertension (6.0%) and diabetes (7.3%); or risk factors was common in patients with severe notably, patients with cardiovascular diseases were acute respiratory syndrome (SARS) and Middle East only 4.2% of total cases, yet constituted 22.7% of all respiratory syndrome (MERS). In SARS, cardiovascu- fatal cases.21 More recently, data from European cases lar disease or diabetes mellitus were reported in about have become available. In Italy, the first western coun- 8% and 11% of cases, respectively,11 and the presence try to be struck by COVID-19, the fatality rate was of either of the two was associated with a 12-fold particularly high (13% as of April 9).22 The fatality higher risk of mortality.12 In MERS, about 30% of rate rises steeply with age and is higher in men (67% of cases). Overall, 96.7% of deceased patients had at patients presented with a cardiovascular disease, and least one comorbidity: 14.4% had one, 20.5% had two the prevalence of cardiovascular comorbidities was and 61.9% had three or more comorbidities; hyperten- even higher (50% had hypertension, 50% diabetes mel- sion was present in 70%, diabetes in 32%, ischaemic litus and 16% obesity).13 Similarly, several small cross- heart disease in 28%, atrial fibrillation in 23%, chronic sectional studies from China have supported the notion renal failure in 23%, chronic lung disease in 18%, HF that patients with underlying cardiovascular disease in 16% and stroke in 11% of patients. and/or cardiovascular risk factors are at higher risk As highlighted previously, SARS-CoV-2 infection of developing COVID-19, especially its most severe can cause a cardiac injury of variable degree in a sub- manifestations. However, an accurate estimation of stantial proportion of patients, and the presence of the prevalence and prognostic impact of cardiovascular underlying cardiovascular comorbidities can contribute disease and risk factors is limited by the lack of stand- to the occurrence of this complication. In a study on ardisation in COVID-19 testing and data collection 113 COVID-19 deceased patients, common complica- between different countries as well as the inhomoge- tions included acute cardiac injury (77%), HF (49%), neous definitions of cardiovascular disease and the ret- acute kidney injury (25%) and hypoxic encephalopathy rospective enrolment with different inclusion criteria in (20%); patients with cardiovascular comorbidity were the epidemiological studies published so far. In a recent more likely to develop cardiac complications.23 Guo meta-analysis on 10 cross-sectional studies inclusive of et al.24 investigated the association between cardiovas- 3403 hospitalised COVID-19 patients from China, the cular disease/risk factors and myocardial injury with pooled prevalence of cardiovascular disease, smoking fatal outcomes in 187 hospitalised patients with history, hypertension and diabetes was 12.11%, 7.63%, COVID-19 (43 died; 144 discharged). In that study, 16.37% and 7.87%, respectively.14 Similarly, a system- 35% had an underlying cardiovascular comorbidity atic review on 3470 COVID-19 patients from 72 studies (hypertension, coronary heart disease, or cardiomyop- (including case reports, case series, case–control and athy), and 28% showed evidence of acute myocardial cross-sectional studies) from different countries injury (defined as troponin T (TnT) >99th percentile (mostly China) reported a pooled prevalence of cardio- upper limit). Patients with high TnT levels were older, vascular disease, hypertension and diabetes of 8.3%, more likely to be men and had more comorbidities 13.3%, and 7.3%, respectively.15 A recent study on including hypertension, coronary heart disease, cardio- 476 COVID-19 patients from three Chinese hospitals myopathy and chronic kidney disease. Patients with a underscored that the incidence of cardiovascular high TnT level showed a higher incidence of complica- comorbidities was higher in those with either severe tions such as acute respiratory distress syndrome or critical manifestations compared to those with a (ARDS), malignant arrhythmias, acute renal injury Barison et al. 1019 and acute coagulopathy. The mortality during hospi- 19 patients.25 For this reason, the European Society of talisation was 7.62% (eight of 105) for patients without Cardiology (ESC), Heart Failure Society of America, underlying cardiovascular disease and normal TnT American College of Cardiology and American Heart levels, 13.33% for those with underlying cardiovascular Association have recommended to continue RAAS disease and normal TnT, 37.50% for those without antagonists for those patients who are currently pre- underlying cardiovascular disease but elevated TnT scribed such agents for indications for which these and 69.44% for those with underlying cardiovascular agents are known to be beneficial, such as HF, hyperten- Downloaded from https://academic.oup.com/eurjpc/article/27/10/1017/5925346 by UAB-05 Communications Lib user on 31 January 2022 disease and elevated TnT.24 sion, or ischaemic heart disease. In the event that patients with cardiovascular disease are diagnosed with COVID- Cardiovascular drugs and risk of infection 19, individualised treatment decisions should be made according to each patient’s haemodynamic status and It has been hypothesised that patients with cardiovascu- clinical presentation.35,36 lar risk factors or cardiovascular disease are dispropor- Other commonly prescribed drugs are statins, which tionately affected by COVID-19 because widely used medications such as angiotensin-converting enzyme are believed to have anti-inflammatory properties. In inhibitors (ACEis) or angiotensin receptor blockers some observational studies on patients with influenza (ARBs) increase the susceptibility to infection by virus or bacterial pneumonia, statin therapy was asso- SARS-CoV-2 and viral replication. This point has been ciated with a reduction in various cardiovascular out- discussed extensively in a dedicated review.25 Briefly, comes and even mortality.37–42 Randomised controlled angiotensin-converting enzyme 2 (ACE2) is a key trials (RCTs) investigating the effects of the oral counter-regulatory enzyme that degrades angiotensin II administration of statins in patients with ventilator to angiotensin 1–7 thereby attenuating its effects on vaso- associated pneumonia have provided mixed results,43,44 constriction, sodium retention and fibrosis.25 SARS- but there are currently no other large-scale observa- CoV-2 appears not only to gain initial entry through tional or randomised studies about the effects of statins ACE2 but also subsequently to down-regulate ACE2 on coronavirus infection. On the other hand, caution expression such that the enzyme is unable to exert pro- should be given to the potential interaction of statins tective effects in organs. Down-regulation of ACE2 activ- and some antiviral agents such as ritonavir and cobici- ity in the lungs facilitates the initial neutrophil infiltration stat, which could increase the risk of statin-related in response to bacterial endotoxin and may result in adverse effects such as myopathy and liver injury. unopposed angiotensin II accumulation and local The human dipeptidyl peptidase 4 (DPP-4) acts as a renin–angiotensin–aldosterone system (RAAS) activa- functional receptor for the spike protein of the MERS tion.25–28 In a small study, patients with COVID-19 coronavirus,45 and a dysregulated immune response appeared to have elevated levels of plasma angiotensin mediated by DPP-4 seems to play a role in infection II, which were in turn correlated with total viral load and development.46 Based on these premises, the intriguing the degree of lung injury.27 Dysregulated ACE2 may the- hypothesis that DPP-4 inhibitors might reduce the risk oretically also attenuate cardiac protection in the setting of infection or modulate the immune response in of myocardial involvement and abnormal pulmonary patients with COVID-19 has been formulated.47 haemodynamics in COVID-19.29,30 ACEis and ARBs Colchicine is a widely available, safe anti- are known to induce ACE2 expression: on the one inflammatory drug representing the mainstay of thera- hand they would promote SARS-CoV-2 infection, on py for pericarditis and a possible option for myocardial the other hand they would activate the ACE2/angioten- infarction. Colchicine shows pleiotropic immunomod- sin 1–7/Mas receptor axis, which exerts beneficial antihy- ulatory activities including the non-selective inhibition pertrophic, antifibrotic, antioxidant and vasodilating effects in different tissues.25 Previous studies, performed of NLRP3 inflammasome, which is a major pathophys- before the SARS-CoV-2 pandemic outbreak, demon- iological component in the development of ARDS. strated that ACEis and ARBs have significant immuno- Based on this evidence, it has been proposed that col- modulatory effects and protect against acute lung injury chicine may improve the clinical course and prevent by blocking the classic ACE pathway.31–33 Currently it is complications in patients with COVID-19.48 still uncertain if effects on ACE2 expression are uniform across different drug classes acting on the RAAS (for Cardiovascular disease and COVID-19 example, ACEis or ARBs), and even in response to dif- ferent drugs from the same class.25,34 Moreover, there are Several mechanisms may account for the greater pro- currently no experimental or clinical data demonstrating pensity of patients with cardiovascular disease or car- beneficial or adverse outcomes with the background use diovascular risk factors to COVID-19, and the worse of ACEis, ARBs or other RAAS antagonists in COVID- outcome of this condition (Figure 1): 1020 European Journal of Preventive Cardiology 27(10) Risk of symptomatic infection Older age CV risk factors CV disease Downloaded from https://academic.oup.com/eurjpc/article/27/10/1017/5925346 by UAB-05 Communications Lib user on 31 January 2022 Systemic inflammation Hypoxia, haemodynamic changes ACS/worsening HF/ COVID-19 cardiogenic shock Myocarditis Procoagulant status Pulmonary embolism Figure 1. Interplay between cardiovascular (CV) disease or risk factors and coronavirus disease 19 (COVID-19). Arrows indicate association or cause–effect relationship. ACS: acute coronary syndrome; HF: heart failure. • These patients are usually older and have a greater and platelet activation; it may increase further the burden of comorbidities, including chronic obstruc- risk of ACS. tive pulmonary disease.49 Smoking is another major • An impaired blood pressure regulation may occur risk factor for both cardiovascular and pulmonary in critically ill patients, manifesting with either pro- diseases, including COVID-19. found hypotension53 or hypertension;19 whether this • Cardiovascular risk factors are associated with is a reaction to the illness or is due to the potential systemic inflammatory activation,50 which combines derangements in ACE2 expression is still unknown. with the virus-induced immune response and increases the global inflammatory burden. Can we reduce the risk of infection and • The cardiovascular effects of the viral infection are potentially more dangerous in patients with under- mortality in patients with cardiovascular lying cardiovascular disease, in which SARS-CoV-2 disease? cytotoxic damage superimposes on an already Aggressive compliance with basic hygiene skills, social impaired myocardial or vascular function. distancing, widespread use of personal protective • Increased heart rate, hypoxia and hypotension may equipment such as gloves and face masks are key to precipitate an ischaemia–supply imbalance in preventing COVID-19 and should be strongly imple- patients with coronary atherosclerosis, but also mented, particularly in patients with cardiovascular potentially in those with cardiac hypertrophy and disease and in people who care for them. In selected microvascular dysfunction. cases, such as HF outpatients, self-isolation should be • Systemic inflammation (often leading to a cytokine recommended. Moreover, healthy lifestyle habits, storm) and adrenergic activation can trigger pre- healthy diet and a regular self-monitoring (blood pres- existent plaque disruption, resulting in an ACS sure, heart rate, weight) should be encouraged in all event.51 patients with cardiovascular disease; periodical phone • A procoagulant state in COVID-19 has been calls or email contacts with their general practitioner consistently reported,5,52 including endothelial, might be helpful to check adherence to medical therapy smooth muscle cell and macrophage activation, and to detect early signs of cardiac or non-cardiac dis- tissue factor expression in atheromatous plaque eases. The ESC has also released specific Barison et al. 1021 recommendations on how to provide cardiac rehabili- As of 12 April there are 458 clinical trials on tation activities despite limitations imposed by the pan- COVID-19.58 Pharmacological research is mainly demic.54 On the other hand, patients should be focused on antiviral and anti-inflammatory drugs, but instructed to contact the emergency services in case of there are some trials focusing on cardiovascular drugs. new symptoms, in order not to delay life-saving thera- Several potential therapeutic targets against SARS- pies for fear of SARS-CoV-2 infection. CoV-2 infection involve the ACE2 axis.59 Systemic In case of COVID-19 infection, patients with cardio- delivery of recombinant ACE2 (NCT04287686 and Downloaded from https://academic.oup.com/eurjpc/article/27/10/1017/5925346 by UAB-05 Communications Lib user on 31 January 2022 vascular disease are at increased risk of complications NCT04335136) is expected to sequester viral SARS- and death, particularly those with increased troponin CoV-2 particles in the circulation preventing their levels:24 myocardial biomarkers should be evaluated in interaction and subsequent internalisation through patients with COVID-19 for risk stratification and pos- endogenous ACE2 receptors, acting as a bait to neu- sible early and more aggressive intervention, particu- tralise the Spike protein. Moreover, recombinant larly in patients with underlying cardiovascular disease; ACE2 protein may be beneficial in restoring the biomarkers may also reduce the need for cardiac imag- ACE2/angiotensin 1–7/Mas receptor axis to relieve ing, which requires strict isolation and increases the lung injuries and to prevent angiotensin II-induced risk to the medical staff. Sometimes the differential hypertension, myocardial hypertrophy, injury and diagnosis between COVID-19 and more common car- fibrosis. diac diseases, such as ACS, PE and HF decompensa- As outlined previously, ACEis and ARBs may tion, is not straightforward, and patient management influence mortality and morbidity in patients with should target all possible concomitant diseases.3 COVID-19: some observational studies are undergoing Because of the risks incurred by transporting infected to investigate how epidemiological and outcome patients and subjecting them to percutaneous interven- measures in COVID-19 patients are related to concom- tion, some centres are reconsidering thrombolytic ther- itant ACEi or ARB therapy (NCT04318301, apy for ACS,55 although this may not be the case in NCT04318418). An open label, phase 1 clinical trial areas where regional ST-segment elevation myocardial aims to evaluate the safety of losartan 50 mg in respi- infarction (STEMI) networks are smoothly set up. ratory failure due to COVID-19 (NCT04335123). Besides supportive care, several anti-inflammatory Paired double-blinded, phase 2 trials of losartan as a and antiviral drugs are being used to treat treatment for COVID-19 are being conducted among COVID-19,56 and special care should be taken to patients who have not previously received treatment avoid potentially dangerous cardiovascular side effects, with ACEis or ARBs and are either hospitalised particularly in patients with underlying cardiovascular (NCT04312009) or not hospitalised (NCT04311177). disease. First, many antiviral, anti-inflammatory and As stated above, colchicine immunomodulatory cardiovascular drugs (such as anticoagulants, antipla- properties may prove effective in patients with telets, anti-arrhythmics and statins) are inhibitors of COVID-19; this hypothesis is currently being tested the P-glycoprotein transporter and/or the cytochrome by four RCTs (COLCORONA, NCT04322682; P450: their co-administration may significantly increase GRECCO-19, NCT04326790; COLCOVID, NCT043 drug concentrations and cause potentially serious 28480; NCT04322565). adverse effects (bleeding, arrhythmias). Second, the SARS-CoV-2 infection increases the risk of DIC and use of corticosteroids, convalescent plasma or intrave- venous thromboembolism, and anticoagulant therapy nous immunoglobulin in COVID-19 patients may (mainly low molecular weight heparin) lowers 28-day precipitate HF decompensations because of the haemo- mortality in selected patients, such as those with a dynamic effects of sodium/water retention. Third, sepsis-induced coagulopathy score of 4 or greater many antiviral, antibiotics and anti-inflammatory (40.0% vs. 64.2%, P ¼ 0.029) or D-dimer more than agents may induce conduction abnormalities and QTc six-fold of the upper limit of normal (32.8% vs. prolongation, necessitating careful electrocardiograph- 52.4%, P ¼ 0.017).60 Similar results were found in ic monitoring, particularly in patients affected by another study, in which heparin improved 28-day mor- structural heart disease or treated with anti- tality in COVID-19 patients with D-dimer greater than arrhythmic drugs: this is the case with chloroquine, 3.0 lg/mL (32.8% in heparin-treated patients vs. 52.4% hydroxychloroquine and azithromycin. Table 1 sum- in controls, P ¼ 0.017).61 Given the high incidence of marises pharmacological interactions between the acute cardiac injury in COVID-19 patients and the main cardiovascular drugs and those currently used impossibility to perform routine cardiological tests (often empirically) to treat COVID-19, and provides for a definite aetiological diagnosis, another trial some indications about the use of cardiovascular (NCT04333407) will randomly allocate patients to a drugs in this setting.57 cardioprotective medical therapy (aspirin 75 mg, 1022 European Journal of Preventive Cardiology 27(10) Table 1. Cardiovascular drugs and coronavirus disease 19 (COVID-19): drug interactions and recommendations for use. Downloaded from https://academic.oup.com/eurjpc/article/27/10/1017/5925346 by UAB-05 Communications Lib user on 31 January 2022 Drug interaction data are modified from Liverpool Drug Interaction Group.57 ACEi: angiotensin-converting-enzyme inhibitor; ARB: angiotensin receptor blocker; ARNI: angiotensin receptor neprilysin inhibitor; ATV: atazanavir; CCB: calcium channel blocker; CLQ: cloroquine; FAVI: favipiravir; HCLQ: hydroxychloroquine; IFN-b: interferon beta; LPV/r: lopinavir/ritonavir; MRA: mineralocorticoid receptor antagonist; NOAC: non-vitamin K oral anticoagulant; RBV: ribavirin; RDV: remdesivir; SGLT2i: sodium-glucose co-trans- porter-2 inhibitor; TCZ: tocilizumab. Barison et al. 1023 clopidogrel 75, rivaroxaban 2.5 mg, atorvastatin 40 mg 6. Danzi GB, Loffi M, Galeazzi G, et al. Acute pulmonary and omeprazole 20 mg) or control. embolism and COVID-19 pneumonia: a random associ- ation? Eur Heart J, Epub ahead of print 30 March 2020. DOI: 10.1093/eurheartj/ehaa254. 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