key: cord-0719349-17hyh3n5
authors: Tomasoni, Daniela; Italia, Leonardo; Adamo, Marianna; Inciardi, Riccardo M.; Lombardi, Carlo M.; Solomon, Scott D.; Metra, Marco
title: COVID 19 and heart failure: from infection to inflammation and angiotensin II stimulation. Searching for evidence from a new disease
date: 2020-05-15
journal: Eur J Heart Fail
DOI: 10.1002/ejhf.1871
sha: a619cd12f236c3d43060f4ad56bc99d83efd4105
doc_id: 719349
cord_uid: 17hyh3n5

Patients with cardiovascular disease and, namely, heart failure are more susceptible to coronavirus disease 2019 (COVID‐19) and have a more severe clinical course once infected. Heart failure and myocardial damage, shown by increased troponin plasma levels, occur in at least 10% of patients hospitalized for COVID‐19 with higher percentages, 25%–35% or more, when patients critically ill or with concomitant cardiac disease are considered. Myocardial injury may be elicited by multiple mechanisms, including those occurring with all severe infections, such as fever, tachycardia, adrenergic stimulation, as well as those caused by the exaggerated inflammatory response, endotheliitis and, in some cases, myocarditis that have been shown in patients with COVID‐19. A key role may be that of the renin–angiotensin‐aldosterone system. Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infects human cells binding to angiotensin‐converting‐enzyme 2 (ACE2), an enzyme responsible of the cleavage of angiotensin II into angiotensin 1–7, which has vasodilating and anti‐inflammatory effects. Virus‐mediated downregulation of ACE2 may increase angiotensin II stimulation and contribute to the deleterious hyper‐inflammatory reaction of COVID‐19. On the other hand, ACE2 may be upregulated in patients with cardiac disease and treated with ACE inhibitors or angiotensin receptor blockers. ACE2 upregulation may increase the susceptibility to COVID‐19 but may be also protective versus angiotensin II mediated vasoconstriction and inflammatory activation. Recent data show the lack of untoward effects of ACE inhibitors or angiotensin receptor blockers for COVID‐19 infection and severity. Prospective trials are needed to ascertain whether these drugs may have protective effects. This article is protected by copyright. All rights reserved.

In late December 2019, an outbreak of viral pneumonia was reported in Wuhan, Hubei, China and rapidly affected several countries becoming a pandemic disorder. The pathogen is a novel enveloped positive RNA strand betacoronavirus, provisionally named 2019 novel coronavirus (2019-nCoV) and subsequently officially named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 1 Although has been initially associated with respiratory symptoms, it has become rapidly clear that it may affect multiple organs including the heart. [4] [5] [6] [7] [8] This is shown by the high prevalence of comorbidities involving the cardiovascular system as well as by their dramatic impact on patients' outcomes in COVID-19. [9] [10] [11] [12] [13] [14] [15] [16] More recent studies have shown the prominent role of heart failure (HF) both as a risk factor of a more severe clinical course and of increased mortality and as a possible consequence of COVID-19 related myocardial damage. 5, 17, 18 The aim of this review is to describe the role of cardiac injury and HF in COVID-19, its pathogenetic mechanisms and potential implications for treatment, including the use of drugs affecting the renin-angiotensin-aldosterone system (RAAS): ACE inhibitors (ACEi) and angiotensin type 1 (AT1) receptor blockers (ARBs).

The clinical presentation of COVID-19 is extremely variable. It may be asymptomatic or cause mild symptoms such as fever, dry cough and fatigue. Other patients develop severe pneumonia, which can eventually cause acute respiratory distress syndrome (ARDS) and death. First reports already This article is protected by copyright. All rights reserved.

showed a high prevalence of comorbidities and their association with severity of COVID-19 and increased mortality. 10, 12, [14] [15] [16] [19] [20] [21] [22] [23] The role of cardiovascular disease seemed more important, among different comorbidities. In a report of 72 314 cases from the Chinese Center for Disease Control and Prevention the overall case-fatality rate of COVID-19 was 2.3% (1023 deaths among 44 672 confirmed cases), but it rose up to 10.5% for those with pre-existing cardiovascular disease, 7.3% for diabetes, 6.3% for chronic respiratory disease and 6.0% for hypertension. 24 No more than a generic definition of cardiovascular comorbidities was, however, used in most of these reports and the contribution of each condition, including HF, was unsettled . 10, 13, 19, 21 Current data are summarized in Table 1 .

As in the case of many other acute conditions, myocardial injury during COVID-19 may be asymptomatic and can be detected only by laboratory markers. Observational studies of hospitalized patients with COVID-19 have detected myocardial injury through troponin levels and defined it as their increase above the 99th percentile upper reference limit. Cardiac troponin levels were increased in 8-12% of unselected COVID-19 cases 12, 21, 22, [25] [26] [27] and their percentage rose up to 23-33% in critically ill patients with a further rise when those with concomitant cardiac disease are considered ( Table 2) . 12, 18, 20, 21 Most studies and one meta-analysis showed their independent prognostic role for in-hospital mortality. 18, 25, 26, 28 Few studies evaluated also N-terminal pro-brain natriuretic peptide (NT-proBNP) plasma levels and found them higher in the patients with myocardial injury, although not independently related with outcomes ( Table 2) . [25] [26] [27] In other cases, cardiac involvment may be clinically evident. In addition to chest pain, suggestive of myocardial ischaemia or myocarditis, and palpitations, patients may present with acute HF. After ARDS and sepsis, HF was the most frequent cause of death, in a series of 113 patients who died with COVID-19. 29 Similar, in the series by Zhou et al., HF was the fourth most frequent complication of COVID-19, after sepsis, ARDS and respiratory failure, and developed in 23% of the patients, 52% in non-survivors versus 12% of the survivos. 21 Severe acute HF or end-stage HF has been described as the main clinical manifestation of COVID-19 in other smaller series of patients or case reports. [30] [31] [32] [33] Cardiac complications, including hypotension, HF and cardiomegaly, were already described in SARS-CoV infections. 34 Rabbits models of dilated cardiomyopathy were also described after coronavirus infection. They presented increased heart weight, biventricular dilatation, myocyte hypertrophy, myocardial fibrosis and myocarditis with histopathological signs of interstitial and replacement fibrosis. 35 In COVID-19, HF or worsening of cardiac dysfunction may develop as a consequence of myocardial damage or as acute myocarditis. This last diagnosis is, however controversial and often difficult.

So far, few cases of COVID-19 related acute myocarditis are described in literature. [31] [32] [33] [36] [37] [38] Althought rare, their presentations might be severe with hypotension and low cardiac output requiring inotropic therapy. Cardiac magnetic resonance may show diffuse ventricular wall thickening and oedema. However, endomyocardial biopsy may show different degrees of myocardial inflammation and limited or absent myocardial necrosis. 31, 32, [36] [37] [38] Among two patients who underwent endomyocardial biopsy, criteria for acute myocarditis were met in only one case. 37 In the other case, SARS-CoV-2 was shown although within macrophages, but not in cardiomyocytes, and biopsy showed only low-grade interstitial myocardial inflammation and aspecific changes of cardiac myocytes with myofibrillar lysis and lipid droplets. 32 These data show that the virus can reside within the heart but do not prove that it has a direct pathogenetic role. 6, 39 Thus, although a few cases of direct virus related myocarditis may exist, other mechamisms are responsible of myocardial injury in most of the patients, rather than viral infection alone. 5, 6, [39] [40] [41] As for SARS-CoV, a viraemic response may occur with SARS-CoV-2 shedding and migration from lungs to other organs, possible via the vascular route. This is also consistent with the large expression of ACE2, the tissue receptor of SARS-CoV-2 (see below), in the vascular system 42 as well as with the finding of acute endotheliitis in patients with COVID-19. 41, 43, 44 This article is protected by copyright. All rights reserved.

COVID-19 may cause myocardial damage through different mechanisms, all independent from direct effects of viral infection. These are summarized in Figure 1 and Table 3 . First, there are aspecific mechanisms shared by COVID-19 with other severe infections ( Table 3) . [45] [46] [47] [48] [49] [50] has general deleterious effects such as those caused by fever, sympathetic activation and tachycardia with increased myocardial oxygen consumption and energy expenditure. 47 Prolonged bed rest, another general consequence of severe infection, predisposes to thromboembolic events, a major complication of COVID-19. 51 Hypoxemia, another hallmark of COVID-19, is associated with enhanced oxidative stress with reactive oxygen species (ROS) production, intracellular acidosis, mithocondrial damage and cell death. 12, 28, 47, 52 A second series of mechanisms are those related with the peculiar abnormal inflammatory response that COVID-19 may elicit. Approximately 7-10 days after from COVID-19 onset, a hyperinflammatory response with massive cytokine release (cytokine storm) may occur. Such a response is likely the main cause of COVID-19 pneumonia and ARDS and may be the cause of acute HF as well as other complications such as thromboembolic events, renal failure, shock and multiorgan failure. 21, 22, 25, 26, 53 The increased mortality of COVID-19 patients with HF might also be explained by this mechanism as inflammatory activation and oxidative stress are present in these patients and may predispose them to a more sever clinical course once infected. 54 Accepted Article hysthological findings showed lymphocytic endotheliitis with apoptotic bodies and viral inclusion structures in multiple organs including lungs, heart, kidneys, gut. 38, 43 Marked inflammation with endotheliitis can also lead to disseminated intravascular coagulation with small or large vessels thrombosis and infarction. 57 Consistent with this inflammatory hypothesis of COVID-19, a persistent increase in inflammatory markers, such as c-reactive protein, d-dimer, ferritin, interleukin-6, is associated with major complications and increased mortality. 21, 22, 25 A positive correlation was also noted between the increase in inflammatory markers and myocardial damage consistent with the role of hyperinflammation as a cause of cardiac dysfunction. 25, 26 Lastly, antinflammatory therapies are currently studied for COVID-19. 41, 56, 58 However, also drugs active on endothelial function, such as statins and ACEi or ARBs may be beneficial. 43 The role of ACE 2 SARS-CoV attaches human cells after binding with its spikes to the angiotensin converting enzyme 2 (ACE2), a peptide highly expressed on the surface of lung alveolar epithelial cells, arterial and venous endothelial cells, arterial smooth muscle cells and enterocytes of the small intestine. 4, [59] [60] [61] [62] The spike glycoprotein S on the virion surface is cleaved into S1 and S2, forming a receptor domain capable of binding to ACE2 in the S1 subunit. 59 SARS-CoV has a prominent cardiotropism.

Autopsy reports of patients died for SARS showed viral RNA in the cardiac muscle in 35% of cases. The presence of SARS-CoV in the heart was associated with marked reduction in ACE2 protein expression. 63 The binding domains of SARS-CoV and SARS-CoV-2 are almost identical. However, the SARS-CoV-2 binding site is more compact and stable with enhanced affinity for ACE2 and has a furin cleavage site that can further increase its ability to infect cells. 7, 64 Once binding is complete, the virus attaches ACE2 throughout membrane fusion and invagination, causing a downregulation in ACE2 activity (Figure 2) . 59 The dowregulation of ACE2 may be the result of ADAM-17/TACE activation by SARS spike protein, which is known to cleave and release ACE2, and/or to the endocytosis of the ligand/receptor complex and subsequent intracellular degradation. 65, 66 ACE2 is an enzyme involved in the RAAS pathway. It has a catalytic domain 42% identical to ACE. 67 Despite this similarity, ACE2 cannot convert angiotensin I into angiotensin II and its catalytic efficiency is much higher towards angiotensin II. ACE2 cleaves angiotensin II, converting it into the heptapeptide angiotensin 1-7, which binds to Mas receptors that, opposite to angiotensin type 1 receptors, have vasodilatory, anti-fibrotic and anti-hypertrophic effects. 68 Of note angiotensin 1-7 can be also syntetized by alternative pathways. ACE2 also has a weaker affinity for angiotensin I and can convert it into the nonapeptide angiotensin 1-9, limiting angiotensin II synthesis by ACE, and with vasodilatatory effects through angiotensin type 2 (AT2) receptor stimulation (Figure 2) .

Thus, ACE2 can counteract the untoward effects of angiotensin II with vasodilatatory, antinflammatory, antioxidant and antifibrotic effects. [68] [69] [70] In experimental models, ACE2 knockout mice were more likely to develop left ventricular systolic dysfunction and HFrEF. 63 Overexpression of the ACE2 gene resulted in a more favorable post-myocardial infarction remodelling and recovery. 71 ACE2 may have arole also for HF with preserved ejection fraction. ACE2 gene overexpression improved left ventricular diastolic function in experimental models through a reduction in reactive oxidative stress, fibrosis, myocardial hypertrophy. 72, 73 Interestingly, ACE2 has also immunomodulatory properties both direct, through its interaction with macropahges, and indirect reducing angiotensin II which favors inflammation. 7, 74 

In the heart, ACE2 is localized on the surface of coronary endothelial cells, cardiomyocytes and cardiac fibroblasts. ACE2 may have opposite effects in COVID-19. First, it is upregulated in patients with cardiovascular disease, diabetes, and/or treated with ACEi or ARB. [75] [76] [77] [78] [79] [80] This has been shown in experimental models, 75, 77 tissue samples from the myocardium of patients with end-stage HF, 76, 79 and using assays of ACE2 plasma levels. 78, 80 A first study where circulating levels of This article is protected by copyright. All rights reserved. Accepted Article ACE2 were measured in a large population of 1485 European men and 537 women with HF and results were validated in another, independent cohort, has been recently published. 80 Plasma levels of ACE2 were increased in patients with HF and, interestingly, their strongest predictor was male sex in both cohorts, consistently with the increased prevalence and severity of COVID-19 in males. 9, 19, 24, 80 ACE2 upregulation may thus increase the susceptibility to COVID-19 and favour a more severe clinical course of the illness through a larger viral burden into the cells. According to this hypothesis, which, however, has never been proven, concerns regarding the administration of ACEi/ARBs, as a cause of ACE2 upregulation, were expressed. [81] [82] [83] [84] Second, ACE2 is down-regulated by SARS-CoV-2 infection and this may potentiate angiotensin II release and favour AT1 receptor stimulation, because of loss of its counter-regulatory effects.

Thus, ACE2 may have a protective role and heightened angiotensin II activity secondary to its downregulation may be a major mechanism leading to cardiac and/or lung injury, ARDS and other COVID-19 complications. 83, 85, 86 According to this second hypothesis, ARBs may have protective effects with respect of the COVID-19 related organ damage.

Based on what stated above, treatment with ACEi/ARBs may either be considered as harmful, as it may increase susceptibility to COVID-19, or protective, as it may counteract increased angiotensin II AT1 receptors stimulation favoured by the loss of the counter-regulatory effects of the downregulated ACE2. Mechanisms associated with potentially favourable or untoward effects of ACEi/ARBs in COVID-19 patients are reported in Figure 3 .

Data from observational studies regarding plasma ACE2 levels and ACEi/ARB treatment in patients with COVID-19 suggest at least a neutral role of ACEi/ARB treatment. In two large cohorts of patients with HF (index cohort, 2 022 patients, validation cohort, 1698 patients), circulating ACE2 levels were increased in the patients with HF but the use of ACEi or ARBs had no This article is protected by copyright. All rights reserved.

Accepted Article relation with them in the index cohort and was associated with lower ACE2 levels in the validation cohort, suggesting a protective effect of these drugs. 80 Other studies regard the relation between ACEi/ARB treatment and the severity of COVID-19.

In a retrospective, single-center case series including 362 patients with hypertension hospitalized with COVID-19, no difference in infection severity and mortality was found between patients who were receiving ACEi/ARBs and the others. 87 A larger series of 1128 hypertensive patients with COVID-19 from a retrospective, multi-center study from nine hospitals in Hubei, China, showed a lower mortality in the patients receiving ACEi/ARBs versus the others (3.7% vs. 9.8%; P = 0.01).

This difference remained significant after adjustment for risk factors and baseline variables at multivariable analysis and propensity analysis (adjusted hazard ratio, 0.42; 95% confidence interval, 0.19-0.92; P =0.03, for ACEi/ARBs versus non ACEi/ARB). 88 Similar results came from non-Chinese series. A population-based case-control study from the Lombardy region of Italy compared 6272 hypertensive patients with COVID-19 with 30,759 control subjects. Use of ACEi/ARBs was more frequent among patients with COVID-19 than among controls because of their higher prevalence of cardiovascular disease. However, it was not an independent predictor of COVID-19 or its severity. 89 The analysis of a large registry including 8910 patients by Mehra et al. showed no increase in in-hospital deaths in the patients on ACEi or ARBs with actually a reduced risk in those on ACEi. 17 Similar data were found in smaller series. 18 Ongoing trial testing ACEi and ARBs use/discontinuing in COVID-19 are reported in Table 4 .

A few conclusions can be drawn at this stage. First, we have shown the high prevalence of cardiac injury following COVID-19 and this may be diagnosed only through biomarkers measurements.

This may become indicated in all patients hospitalized for COVID-19 as independent prognostic markers. The clinical implications of the detection of myocardial injury remain, however, uncertain. This article is protected by copyright. All rights reserved.

No specific treatment is available. Agents with favourable effects on endothelial function may be tested in clinical trials.

A second aspect regards the role of ACEi/ARB treatment. No data have shown an increased susceptibility or COVID-19 severity in the patients receiving these agents. These agents must be therefore continued also during COVID-19 pandemic. In addition, as they may have a protective role for angiotensin II mediated organ damage during COVID-19, they should also be tested in clinical trials to improve the still dramatic patients' clinical course.

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