key: cord-0683939-ym8ue50x
authors: Cappuccio, Francesco P.; Siani, Alfonso
title: Covid-19 and cardiovascular risk: susceptibility to infection to SARS-CoV-2, severity and prognosis of Covid-19 and blockade of the renin-angiotensin-aldosterone system. An evidence-based viewpoint
date: 2020-05-29
journal: Nutr Metab Cardiovasc Dis
DOI: 10.1016/j.numecd.2020.05.013
sha: 41228f702cf8500f478052700c94fc9784ed1181
doc_id: 683939
cord_uid: ym8ue50x

Abstract The presence of cardiovascular co-morbidities and the known effects of coronaviruses on the cardiovascular system have called attention to the potential implications for patients with cardiovascular risk factors. This evidence-based viewpoint will address two questions: (a) are individuals with underlying cardiovascular risk factors (e.g. high blood pressure or diabetes) or overt disease (e.g. coronary heart disease, heart failure, kidney disease) more likely to develop severe Covid-19 and to die than those without underlying conditions? (b) does the regular use of angiotensin-converting enzyme inhibitors (ACE-i) or angiotensin-receptor blockers (ARB) make patients more likely to get infected and to die of Covid-19? With a necessary cautionary note that the evidence around the links between Covid-19 and cardiovascular disease is accruing at a fast pace, to date we can conclude that: (a) the greater susceptibility of individuals with underlying cardiovascular conditions to develop more severe Covid-19 with higher mortality rate is likely to be confounded, in part, by age and the type of co-morbidities. Patients with heart failure or chronic kidney disease might show an excess risk; (b) neither ACE-i nor ARB are associated with greater risk of SARS-Cov2 infection, or severity or risk of death in patients with Covid-19. Patients on these drugs should not stop them, unless under strict medical supervision and with the addition of a suitable replacement medicine.

This evidence-based viewpoint will attempt to answer two questions: (a) are individuals with underlying cardiovascular risk factors (e.g. high blood pressure or diabetes) or overt disease (e.g. coronary heart disease, heart failure, kidney disease) more likely to develop severe Covid-19 and to die than those without underlying conditions? (b) does the regular use of angiotensin-converting enzyme inhibitors (ACE-i) or angiotensin-receptor blockers (ARB) make patients more likely to get infected and to die of Covid-19?

The most common comorbidities among patients admitted to hospitals worldwide have been hypertension and diabetes, followed by cardiovascular and respiratory diseases [2] [3] [4] [5] . Table 1 summarises the prevalence of hypertension and diabetes recorded in 18 reports (10 from China 2, 6-9, 14, 16-21 , 3 from USA 5, 13, 15 , 2 from Italy 10-11 and 1 from a multicentre study from 3 continents 12 ) and, where available, the severity and mortality in hospitalised patients with confirmed Covid-19 by underlying risk factors. The reported prevalence of pre-existing hypertension varied from 12.2% 14 to 78.6% 13 , and the prevalence of pre-existing diabetes varied from 7.4% 2 to 38.2% 13 . Furthermore, some studies reported an increased severity of symptoms in hospitalised patients with confirmed Covid-19 and underlying hypertension or diabetes, with a 2.7 and 3.8 folds higher severity 17 The groups with more comorbidities and worse outcomes were, as one would expect in an unselected population, older that the groups with fewer comorbidities and better outcome.

The majority of the case series reported unadjusted results for either age or presence of comorbidities ( Table 1) . Covid-19 case fatality rates and CV risk both increase with age and with the presence of concomitant comorbidities, so that the association between Covid-19 and CV risk factors might reflect the confounding effect of these variables. More recently, a large study of 8,910 hospitalised patients with Covid-19 from 169 hospitals in North America, Europe and Asia confirmed in a multivariate analysis that significant 'independent' predictors of in-hospital death, in addition to age >65 years, are presence of coronary heart disease, heart failure, cardiac arrhythmias, COPD, current smoking, but not hypertension or diabetes 13 . Similarly, a smaller study from Italy confirmed age, heart failure and chronic kidney disease (but not hypertension and diabetes) as independent predictors of death in hospitalised Covid-19 patients 11 . Finally, a meta-regression analysis of the association between diabetes and severity and outcome of Covid-19 indicated that the association was explained primarily by age and concomitant presence of hypertension 23 . Further analyses of incoming data will undoubtedly refine our understanding of the interplay between underlying cardiovascular risk and Covid-19.

Is there any plausible explanation for the potential increased susceptibility to SARS-CoV-2 infection and the excess risk of death from Covid-19 of patients with underlying CV disease?

Severe infections are recognised triggers for CV disease expression 24 , increasing the incidence, severity and mortality from infectious diseases 25 . Numerous mechanisms have been suggested that would explain an increased risk of CV disease 4, 26 . They include vascular endothelial cell dysfunction, myocardial depression, stress cardiomyopathy, myocarditis and arrhythmias, coagulopathies and thrombosis. Early predictive markers of severity and worse prognosis in Covid-19 patients have been detected in raised levels of high-sensitivity cardiac troponin I (hs-TnI) levels 18 and high D-dimer levels on admission 20 .

the renin-angiotensin-aldosterone system (RAAS), via the angiotensin-converting enzyme 2 (ACE2), have been postulated to modulate the infectivity of these viruses and to influence the prognosis of the ensuing respiratory diseases [27] [28] Unlike ACE, ACE2 does not convert Ang I to Ang II, nor do ACE inhibitors (ACE-i) block its activity 29 . The primary substrate of ACE2 is Angiotensin II (Ang II) that is converted to Ang (1-7), thereby attenuating its effects on vasoconstriction, sodium retention and fibrosis ( Figure 1 ). ACE2 also converts Angiotensin I to Ang (1-9). ACE2 is primarily a membranebound enzyme, and its soluble circulating levels in the blood are very low. Membrane-bound ACE2 has been identified as a functional receptor for coronaviruses [29] [30] . The spike protein of the virus binds to the membrane ACE2, highly expressed in lungs and heart, acting as a carrier for the entry (endocytosis) of the virus into the cell and its replication [27] [28] . Ang II activation of AT 1 receptors (type 1) increases soluble ACE2 levels by cleaving the anchoring of ACE2 to the cell membrane (shedding). SARS-CoV-2 bound to soluble ACE2 is, then, kept in solution and prevented from entering the cells [29] [30] . Theoretically, ACE-i, might reduce the shedding of membrane ACE2, increasing the chance of SARS-CoV-2 binding and endocytosis. Conversely, ARB would increase shedding of ACE2, increasing the amount of soluble ACE2 to which SARS-CoV-2 would bind and kept soluble (not entering the cell) [29] [30] .

Is there evidence that the use of ACE-i and ARB increase susceptibility to infection by SARS-CoV-2 and worsen the prognosis of patients with Covid-19? Patients with hypertension and diabetes have been seen to experience a high case-fatality rate. This observation has led to concerns about the safety and the potential effects of therapies that block the RAAS 31 , commonly used in patients with hypertension, diabetes, heart failure and other CV conditions in which they are indicated. This theory, without direct evidence in support, has led to dangerous calls by some to advise patients to stop ACE-i and ARB therapies 32 . Table 2 summarises the studies to date that have addressed these questions with different study designs and in different case-series. All, but one 10 , are retrospective caseseries or observational studies of hospitalised patients with confirmed Covid-19 or positivity to SARS-CoV-2 infection. Two of them were in hypertensive patients only 14, 34 . In all of them the results indicate, with different degree of confidence, that neither the use of ACE-i and/or ARB are associated with a greater risk of infection from SARS-CoV-2, or of severity or death in Covid-19 patients. A separate mention is necessary for a population-based casecontrol study carried out in the Lombardy region of Italy, one of the hardest hit by the pandemic in Europe 10 . In this study 6,272 cases of SARS-CoV-2 infection confirmed between 21 February and 11 March 2020 identified through the Regional Health Authority register were matched by sex, age and municipality (1:5) with 30,759 controls registered with the same Health Authority. All were aged 40 years or older. Information on selected drug use and patients' clinical characteristics were obtained from the Regional Healthcare database on healthcare utilisation. More than half of the selected participants had high blood pressure. In this highly controlled comparison, the use of ACE-i and ARB did not show any association with Covid-19 prevalence, severity or fatality, and no sex difference. Finally, in two studies there was a suggestion that the treatment with ACE-i/ARB would be associated with a lower rate of severity 14 or mortality 34 . This proposition, whilst highly speculative, finds some theoretical corroboration in a possible down-regulation of ACE2 activity in the lungs and trials with ARB as a treatment in patients with Covid-19 are underway (NCT04312009 and NCT04311177).

Can we formulate evidence-based answers to the questions set in the introduction? With a necessary cautionary note that the evidence around the links between Covid-19 and CV disease is accruing at a fast pace, to date we can conclude that:

(a) the greater susceptibility of individuals with underlying CV risk factors or overt disease to develop more severe Covid-19 with higher mortality rate is likely to be confounded, in part, by age and the type of co-morbidities. However, patients with heart failure or chronic kidney disease might show an excess risk and vigilance and further research is necessary to establish a causality link. to enter the cell (endocytosis) and replicate. Blockade of the AT 1 R by ARB will increase Ang II circulating levels that will shed the membrane-bound ACE2 resulting in an increase in the levels of soluble ACE2 that will not mediate the entry of the virus in to the cell. Results did not confirm concerns regarding a potential harmful association of ACE-I or ARB with in-hospital death.

[1] Large sample size. [2] International representation of patients.

[1] Cannot exclude confounding. [2] No pre-specified hypothesis, hence increased probability of chance finding. [3] Cause-effect relationship between therapy and survival should not be inferred. 

Clinical characteristics of Coronavirus Disease 2019 in China

Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis

Potential effects of Coronaviruses on the cardiovascular system. A review

Presenting characteristics, comorbidities and outcomes among 5700 patients hospitalized with COVID-19 in the New York City Area

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study

Association of cardiovascular disease and myocardial injury with outcomes of patients hospitalized with 2019-coronavirus disease (COVID-19)

Association of Renin-Angiotensin system inhibitors with severity or risk of death in patients with hypertension hospitalized for Coronavirus Disease 2019 (COVID-19) infection in Wuhan, China

Renin-Angiotensin-Aldosterone System blockers and the risk of Covid-19

RAAs inhibitors and outcome in patients with SARS-CoV-2 pneumonia. A case series study

Cardiovascular disease, drug therapy and mortality in Covid-19

Association of use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with testing positive for Coronavirus Disease 2019 (COVID-19)

Renin-angiotensin-system inhibitors improve the clinical outcome of COVID-19 patients with hypertension

Renin-Angiotensin-Aldosterone system inhibitors and risk of Covid-19

Cardiac injury in patients with corona virus disease 2019

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Association of blood glucose control and outcomes in patients with covid-19 and pre-existing type 2 diabetes

Hypertension and its severity or mortality in Coronavirus Disease 2019 (COVID-19): a pooled analysis

Diabetes mellitus is associated with increased mortality and severity of disease in COVID-19 pneumonia. A systematic review, meta-analysis, and metaregression

Inpatient and outpatient infection as a trigger of cardiovascular disease: the ARIC study

Underlying disorders and their impact on the host response to infection

A close-up on COVID-19 and cardiovascular diseases

A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury

COVID-19 and the cardiovascular system

Renin-Angiotensin-Aldosterone system inhibitors in patients with Covid-19

At present there is no evidence to abandon renin-angiotensin system blockers

Risk for all-cause mortality lower in the ACEi/ARB group vs non-ACE-i/ARB group (adjusted HR 0.42; 95%CI 0.19-0.92; P=0.03). In a propensity score-matched analysis followed by adjusting imbalanced variables, lower risk of Covid-19 mortality in patients who received ACE-i/ARB vs those who did not receive ACEi/ARB

Compared to use of other antihypertensive drugs, ACEI/ARB was associated with decreased mortality

Among hospitalized Covid-19 patients with hypertension, inpatient use of ACE-i/ARB was associated with lower risk of all-cause mortality compared with ACEi/ARB non-users

May not reflect outpatient management

Antihypertensive drugs not matched or adjusted when comparing ACEi/ARB and non-ACE-i/ARB groups. [5] Not retrieving pre-hospital selfmedications