key: cord-0978953-pksf1voe
authors: Mai, Francesca; Del Pinto, Rita; Ferri, Claudio
title: COVID-19 and Cardiovascular Diseases
date: 2020-07-22
journal: J Cardiol
DOI: 10.1016/j.jjcc.2020.07.013
sha: 049e19a2794c9da8147f972fc7120be81917b653
doc_id: 978953
cord_uid: pksf1voe

Infection by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is responsible for the second pandemic of the XXI century after influenza A in 2009. As of mid-June 2020, more than 440000 fatal cases of SARS-CoV-2-related disease (COVID-19) have occurred worldwide. Besides its prominent expression at the level of the respiratory apparatus, COVID-19 is also characterized by a substantial degree of cardiovascular involvement, both in terms of deterioration of pre-existing conditions, and as the effect of inflammation-facilitated acute events. They include ischemic/inflammatory heart disease, ventricular arrhythmias, conduction disturbances, thrombotic events at the level of the lungs, and systemic activation of the coagulation cascade, configuring the scenario of disseminated intravascular coagulation. Herein, we summarize the main COVID-19 features of relevance for the clinicians in the cardiovascular field. The rationale, concerns, and possible side effects of specific therapeutic measures, including anticoagulants, renin-angiotensin-aldosterone system inhibitors, and anti-inflammatory/antiviral medications applied to the treatment of COVID-19 are also discussed.

Hospital, V.le San Salvatore -Delta 6 Building, Coppito 67100 AQ</sa:organization><sa:country>Italy</sa:country></sa:affiliation></ce:correspondence><ce:footnote id=fn1><ce:label>1</ce:label><ce:note-para id=npar0005>Francesca Mai and Rita Del Pinto contributed equally to this work.</ce:note-para></ce:footnote></ce:author-group><ce:date-received day=30month=4ÿear=2020/><ce:date-revised day=17month=6ÿear=2020/><ce:date-accepted day=11month=7ÿear=2020/><ce:abstract id=äbs0005class=äuthor-highlights><ce:section-title id=sect0005>Highlights</ce:section-title><ce:abstract-sec id=äbst0005><ce:simple-para id=spar0005><ce:list id=lis0005><ce:list-item id=lsti0005><ce:label>bull;</ce:label><ce:para id=par0005>COVID-19 poses an additional burden on pre-existing cardiovascular diseases</ce:para></ce:list-item><ce:list-item id=lsti0010><ce:label>bull;</ce:label><ce:para id=par0010>Inflammation-related hypercoagulability can be dramatic</ce:para></ce:list-item><ce:list-item id=lsti0015><ce:label>bull;</ce:label><ce:para id=par0015>Monitor electrocardiograms, electrolytes, coagulation, and congestion in severe COVID-19</ce:para></ce:list-item><ce:list-item id=lsti0020><ce:label>bull;</ce:label><ce:para id=par0020>Discontinuing renin-angiotensin-aldosterone system inhibitors is not supported by evidence and could be detrimental</ce:para></ce:list-item></ce:list></ce:simple-para></ce:abstract-sec></ce:abstract><ce:abstract id=äbs0010><ce:section-title id=sect0010>Abstract</ce:section-title><ce:abstract-sec id=äbst0010><ce:simple-para id=spar0010>Infection by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is responsible for the second pandemic of the XXI century after influenza A in 2009. As of mid-June 2020, more than 440000 fatal cases of SARS-CoV-2-related disease (COVID-19) have occurred worldwide. Besides its prominent expression at the level of the respiratory apparatus, COVID-19 is also characterized by a substantial degree of cardiovascular involvement, both in terms of deterioration of pre-existing conditions, and as the effect of inflammation-facilitated acute events. They include ischemic/inflammatory heart disease, ventricular arrhythmias, conduction disturbances, thrombotic events at the level of the lungs, and systemic activation of the coagulation cascade, configuring the scenario of disseminated intravascular coagulation. Herein, we summarize the main COVID-19 features of relevance for the clinicians in the cardiovascular field. The rationale, concerns, and possible side effects of specific therapeutic measures, including anticoagulants, renin-angiotensin-aldosterone system inhibitors, and anti-inflammatory/antiviral medications applied to the treatment of COVID-19 are also discussed.</ce:simple-para></ce:abstract-sec></ce:abstract><ce:keywords id=kwd0005class=keyword><ce:section-title id=sect0015>Keywords</ce:section-title><ce:keyword id=kw0005><ce:text>Severe acute respiratory syndrome coronavirus 2</ce:text></ce:keyword><ce:keyword id=kw0010><ce:text>COVID-19</ce:text></ce:keyword><ce:keyword id=kw0015><ce:text>Cardiovascular diseases</ce:text></ce:keyword><ce:keyword id=kw0020><ce:text>Renin-angiotensin-aldosterone system inhibitors</ce:text></ce:keyword><ce:keyword id=kw0025><ce:text>Coagulation</ce:text></ce:keyword><ce:keyword id=kw0030><ce:text>Electrocardiography</ce:text></ce:keyword></ce:keywords></head><body><ce:sections><ce:s id=sec0005role=background><ce:section-title id=sect0020>Background</ce:section-title><ce:para id=par0025><!-<ForCovergt;Mai F, Del Pinto R, Ferri C, COVID-19 and Cardiovascular Diseases, Journal of Cardiology (2020), doi: https://doi.org/10.1016/j.jjcc.2020.07.013

3

Rhinolophus hipposideros (commonly known as "horseshoe bats") are habitual hosts of coronaviruses. The Rhinolophus affinis, in particular, is very common in the wide Chinese province of Yunnan [1] , and it is believed to represent the natural reservoir host for the progenitor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [2] that is responsible for the second pandemic of the XXI century after that of influenza A (H1N1) in 2009 [3] . Anthropization of wild territories, as well as low food safety standards, are the most likely conditions that allowed the spillover of the wild virus to humans in Wuhan, the capital city of the Hubei province [4] . In fact, the large wholesale market of the city is considered the plausible scenario for animal-to-human transmission of the virus [5] . Whatever the exact contingency of human infection, the outbreak of SARS-CoV-2-related disease (defined as COVID-19) has quickly reached the proportion of a pandemic, an effect facilitated by viral contagiousness, late information sharing, inadequate preparedness for a new disease, and jeopardized readiness to face the health emergency worldwide [6] . More than 8000000 cases, including over 430000 deaths, have occurred as of mid-June 2020 worldwide [7] . Patients with COVID-19 and either cardiovascular risk factors or established cardiovascular disease represent a particularly vulnerable population [8] .

For the purpose of this narrative mini-review, a comprehensive search of major electronic databases (PubMed, EMBASE) was conducted for articles in the English language published in medical journals from inception through June 2020. The search used the terms "COVID-19"

"SARS-CoV-2", "cardiovascular disease(s)", "hypertension", "ECG", "arrhythmia", "QT interval", "embolism", "thrombosis", "coagulation", and "renin-angiotensin-aldosterone system inhibitors" in several combinations. The search results were accessed, and relevant references were made for the purpose of this review.

J o u r n a l P r e -p r o o f

Fatal COVID-19 cases are significantly more common among elderly individuals and in the presence of comorbidities [9] . Of 3335 Italian patients dying in-hospital as of June 4th and for whom it was possible to analyze clinic charts, only 136 deceased patients (4.1%) had no preexisting pathologies, while 493 (14.8%), 716 (21.5%), and 1990 (59.7%) reported having one, two, or at least three chronic diseases, respectively, with hypertension being the most frequently reported comorbidity, followed by diabetes, and ischemic heart disease (Fig. 1, A and B ) [9, 10] .

Although mortality was much higher in men, the mean number of pre-existing diseases was similar between genders (median±standard deviation 3±1.9) [10] . In keeping with these data, an analysis of 44,672 confirmed COVID-19 cases from Wuhan, China indicated increased case-fatality rates in the presence of cardiovascular diseases (10.5%) and hypertension (6.0%) (overall case-fatality rate: 2.3%) [11] . In a retrospective case series from Italy, hypertension was the most common comorbidity among COVID-19 patients referred to the Intensive Care Unit (ICU) irrespective of age, with a global prevalence of 49%, followed by cardiovascular diseases (21%) and

hypercholesterolemia (18%) [12] . Also, the prevalence of hypertension was higher among critically ill patients who died in the ICU compared with individuals discharged from the ICU (+23%, p<0.001) [12] .

As the most commonly pre-existing conditions, cardiovascular diseases might have potentially exacerbated the severity of COVID-19. COVID-19, in fact, is mostly a lung disease, where initial local damage can be followed by an intense and relatively late cytokine storm originating from imbalance of T cell activation with dysregulated release of interleukin (IL)-6, IL-17, and other cytokines (Fig. 2 ) [13] . In parallel, COVID-19 can also begin with signs of a severe coronary artery disease or myocarditis in the absence of a history of cardiovascular diseases, or in the presence of isolated cardiovascular risk factors [14, 15] . Myocardial damage can be caused by direct myocardial injury related to upregulation of angiotensin-converting enzyme 2 (ACE2) in the heart and coronary vessels, but it can be also secondary to molecular mimicry following the activation of adaptive auto-immune type mechanisms, or be exacerbated by hypoxia in the context of respiratory failure [8] . Severe respiratory distress can be the expression of both pulmonary and cardiogenic edema, independent of pre-existing cardiovascular disease, a possibility that J o u r n a l P r e -p r o o f conditionates the choice of specific supportive therapies and the clinical outcome [16] . In patients with established cardiovascular diseases, COVID-19 contributes to precipitate hardly balanced conditions, as well as those previously well controlled by therapy [15] . A possible explanation is the immune dysregulation occurring in the course of the viral infection, similarly to what was previously described for other pathogens [17] , but the role of pre-existing age-related immunologic dysfunction should not be discarded [18] . The destabilizing effect of pulmonary hypertension on chronic heart failure, as well as the impact of COVID-19 emergency on the clinical course, including the fast triage, of patients with pre-existing cardiovascular conditions have been also pointed out [16] . Therefore, a reciprocal influence is evident between COVID-19 and cardiovascular diseases, with pre-existing pathologies exacerbating the infectious disease, and SARS-CoV-2 favoring or inducing acute cardiovascular events. The possible interference of antiviral drugs with statins, the risk of cardiotoxicity induced by anti-inflammatory agents such as hydroxychloroquine and chloroquine, and the effects of corticosteroids, such as methylprednisolone, on water retention and ionic imbalance deserve appropriate consideration [16] . The long-term effects of COVID-19-related inflammatory burst on cardiovascular health are unknown, but appropriate monitoring has been suggested [8] .

Consistent data from case series indicate that massive, inappropriate activation of the coagulation cascade can occur in COVID-19 patients. For instance, among 94 patients with documented viral infection, circulating antithrombin III was significantly reduced, while D-dimer and fibrinogen were elevated, compared with 40 healthy volunteers [19] . Further, the first-month mortality rate was including their anti-inflammatory effect, represent an additional rationale for their use in severe COVID-19 [23] . Low molecular weight heparin or fondaparinux prescription has been recommended in hospitalized COVID-19 patients [24] . A similar recommendation was made by the World Health Organization to prevent incident thrombophlebitis in these patients [25] . However, it must be noted that the site of thrombosis during COVID-19 is atypical, as it occurs rather in the lungs than in lower limbs, even in the absence of specific risk factors and/or history of thromboembolism [26] . Therefore, given the elevated risk of localized thrombotic events and/or DIC, coagulation parameters should be carefully monitored in COVID-19 patients, particularly in J o u r n a l P r e -p r o o f those with severe disease. The impact of antiviral drugs on the metabolism of anticoagulants and antiplatelets agents is another issue deserving appropriate consideration [16] .

Finally, two additional aspects in the relationship of COVID-19 with cardiovascular diseases deserve to be briefly explored.

First, there has been concern regarding the potential favoring role of ACE inhibitors and angiotensin-receptor blockers (ARBs) in terms of viral infection. In fact, ACE inhibitors and sartans promote the expression of ACE2, i.e. the enzyme that converts the vasoconstrictor angiotensin II (Ang II) into the vasodilator, anti-inflammatory Ang-(1-7) and that works as the functional receptor for the entry of SARS-CoV2 into the cell, with a facilitating effect mediated by the type II transmembrane serine protease TMPRSS2 (Fig. 3 ) [27] [28] [29] [30] . However, experimental data do not fully support this hypothesis [31, 32] . Indeed, ACE2 appears to play a protective role against pulmonary inflammation [33, 34] . In accordance with this, for COVID-19 as for SARS [35] , AT1 receptor blockade and the subsequent increase in ACE2 activity/availability might be protective against the pulmonary involvement related to the infection [36, 37] . Therefore, the concern on the use of renin-angiotensin-aldosterone system (RAAS) inhibitors during the coronavirus outbreak is currently not supported by causal evidence. According to this, first reports from China do not indicate a harmful effect of ACE inhibitors or sartans in COVID-19 patients [38] . Meta-analytic data indicate that ACE inhibitor/ARB exposure was not associated with a higher risk of SARS-CoV-2 infection, nor with increased risk of severe COVID-19 [39] [40] [41] . Indeed, treatment with RAAS inhibitors was associated with reduced risk of mortality compared to non-treatment among over 19000 COVID-19 cases (OR 0.48, 95 % CI, 0.29-0.81; p=0.006) [39] . Similar findings were described for patients with hypertension and COVID-19 infection (OR 0.57, 95 % CI 0.38-0.84, p=0.004) [40] . A meta-analysis of 16 studies that involved 24676 COVID-19 patients indicated that the combined risk of death and/or critical disease was reduced by about 23% among RAAS users, with ACE inhibitors, but not ARBs alone, explaining the observed protective effect [41] . In addition, findings from an Italian cohort of 133 consecutive SARS-CoV-2 positive hypertensive subjects J o u r n a l P r e -p r o o f presenting with acute respiratory symptoms and/or fever, who were grouped according to prior antihypertensive therapy (ACE inhibitor, N=40; ARBs, N=42; not on RAAS inhibitors, N=51), indicate no difference between ACE inhibitors and ARBs groups in terms of hospital admission rate, oxygen therapy, and need for non-invasive ventilation [42] .

In analogy with adults, there is no evidence at present that children with hypertension, cardiovascular diseases, or chronic kidney disease, whether or not on RAAS inhibitors, are at increased risk for SARS-CoV-2 infection or severe COVID-19 [43] . Indeed, the benign clinical course of COVID-19 in children compared with adults triggered the question as to whether any differences in the Ang-(1-7) pathway, also impacting on the effects of RAAS inhibitors, might depend on age [43] .

On the other hand, whether infection by coronaviruses might affect ACE2 function adversely, thus potentially contributing to the disease burden, is a possibility that deserves careful consideration. In fact, a consistent activation of the RAAS, possible expression of the decreased degradation of Ang II to Ang-(1-7) after virus binding to ACE2, has been described, with possible pro-inflammatory effects and prognostically negative consequences [44] . Elevated Ang II in COVID-19 patients has been linked to vascular hyperpermeability and severe acute lung injury [44, 45] , as well as to hypokalemia [46] as a possible sign of hyperaldosteronism [47] . Previous evidence supported a detrimental role of elevated Ang II in association with decreased Ang-(1-7) in left ventricular remodeling in response to myocardial infarction [48] . A postulated possibility for increased cardiovascular risk in the context of COVID-19 is also the reduced cardioprotection due to Ang-(1-7) depletion and the lack of its anti-inflammatory, antioxidant, and vasodilating properties. Before the results of specifically designed studies become available (more than 20 trials on this topic are currently registered in ClinicalTrials.gov), a report on the association between in-hospital use of ACE inhibitors/ARBs and all-cause mortality in 1128 COVID-19 patients with hypertension indicated that such risk was 37% to 30% lower among ACE inhibitors/ARBs users than in nonusers after controlling for potential confounders [49] . Since ACE inhibitors prevent the formation of Ang II and, therefore, that of Ang-(1-7), while ARBs determine an accumulation of Ang II that J o u r n a l P r e -p r o o f serves as substrate to ACE2 for conversion into Ang-(1-7) [27] , it is possible that different molecular events occur with the use of one or the other drug class in the course of COVID-19.

Thus, any discontinuation of drugs with proven cardiovascular benefit, such as ACE inhibitors and ARBs, should be discouraged until otherwise proven, due to the foreseeable risk of adverse cardiovascular outcomes if this treatment is negated to patients with appropriate indication [50] .

Specific studies are awaited to clarify this issue.

Last, but not least, the effect on the QT interval of drugs used for COVID-19 deserve mention as one of the possible cardiovascular implications of the viral infection, especially in patients who have a baseline abnormality [51] . In particular, hydroxychloroquine, azithromycin, lopinavir, and ritonavir can all interfere with the IKr (rapid delayed rectifier current) and prolong the QT interval.

Hypokalemia secondary to diarrhea could represent another potential mechanism favoring QT prolongation [15] . Lopinavir and ritonavir may result also in PR interval prolongation. The role of hypoxia and neurohormonal imbalance related to lung infection and systemic inflammation must be also considered as a cause of arrhythmias during COVID-19. These mechanisms contribute to explain the particularly high incidence of arrhythmias among infected patients treated in intensive care units [52] . Some anti-inflammatory agents, such as hydroxychloroquine or chloroquine, can increase the risk of torsade des pointes in patients with electrolyte abnormalities or with concomitant use of QT prolonging agents, or decrease the metabolism of beta-blockers, with impact on heat rate [16] . In summary, besides the large number of patients with COVID-19 and pre-existing atrial fibrillation (Fig. 1A) , the therapy used to treat the viral infection, as well as some clinical manifestations of the disease, can trigger the development of ventricular tachyarrhythmias or conduction disturbances. Therefore, monitoring ECG parameters becomes of particular relevance in the context of the SARS-CoV-2 pandemic [51] .

Conclusions COVID-19 is mainly a lung disease. However, a hyperergic immune reaction, or "cytokine storm", with a dramatic systemic impact can be also observed in a later stage of the disease (Fig. 2) . In addition, COVID-19 prognosis can be deteriorated by pre-existing cardiovascular diseases, or acute cardiovascular events can be induced by COVID-19 even in the absence of a related history. 

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