Heart failure in the course of a pandemic
Authors: Dimitrios Farmakis, Mandeep R. Mehra, John Parissis, Gerasimos Filippatos
Journal: European Journal of Heart Failure (2020)

This article refers to ‘Management of heart failure patients with COVID-19: a joint position paper of the Chinese Heart Failure Association & National Heart Failure Committee and the Heart Failure Association of the European Society of Cardiology’ by Y. Zhang et al., published in Eur J Heart Fail 2020;22:941–956. The coronavirus disease 2019 (COVID-19) outbreak, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has already affected millions of people and resulted in hundred thousand deaths worldwide in the course of less than 6 months. Patients with cardiovascular disease, including heart failure (HF), are more susceptible to serious COVID-19,1, 2 while HF may be particularly prevalent in critically ill COVID-19 patients.3 As a result, HF represents a potential risk factor for COVID-19 increasing its propensity and severity. On the other hand, COVID-19 seems to provoke cardiac injury and potentially HF.4 Therefore, a structured approach to the care of HF patients with suspected or confirmed COVID-19, and COVID-19 patients with suspected or confirmed HF is warranted. In this context, the Heart Failure Association of the European Society of Cardiology and the Chinese Heart Failure Association & National Heart Failure Committee have developed a position statement to address this need, providing diagnostic and therapeutic guidance and describing a HF care pathway.5 There are a number of implications of COVID-19 in HF, including COVID-19 as a potential cause of HF in the form of either new-onset HF due to SARS-CoV-2-associated cardiac injury or HF decompensation in patients with pre-existing HF, SARS-CoV-2 interference with the renin–angiotensin–aldosterone system (RAAS) and its inhibition and the handling of HF patients with suspected or confirmed diagnosis of COVID-19 in the outpatient and inpatient setting (Figure 1). SARS-CoV-2 enters host cells by using angiotensin-converting enzyme 2 (ACE2) on the surface of these cells as a functional receptor.6 ACE2 is a membrane-bound peptidase that cleaves angiotensin II to angiotensin (1–7) but also angiotensin I to angiotensin (1–9) and other peptides. Besides pulmonary alveolar epithelial cells, ACE2 is broadly present in various additional tissues, including intestinal, testicular, adipose and kidney cells, as well as the myocardium.7 Given the expression of ACE2 in the myocardium, it has been postulated that SARS-CoV-2 may directly attack the heart causing cardiac injury and myocarditis.1 Plasma concentration of circulating ACE2 has been shown to be higher in men than women, which may actually explain the higher incidence and worse prognosis of COVID-19 in men.8 In this context, it has been shown that ACE2 is expressed in myocardial pericytes that are in close vicinity and communication with myocardial capillary cells, affecting their integrity and function.7 Thus, the pericyte-capillary cell-cardiomyocyte interaction provides a potential mechanism for cardiac involvement in COVID-19. Evidence supporting direct infection of endothelial cells has also become apparent.9 Cardiac biomarker elevation is encountered in 8% to 12% of COVID-19 patients,10 but it is particularly prevalent among those with severe COVID-19, being associated with adverse outcomes. In a cohort of 416 patients hospitalized with COVID-19 in Wuhan, China, high-sensitivity cardiac troponin I (hs-cTnI) increase above the 99th percentile of normal was found in 19.7% of cases, being associated with more severe disease, higher complication rate and three to fourfold higher mortality rates.4 Similarly, in a retrospective cohort of 113 deceased and 161 recovered COVID-19 patients in China, hs-cTnI elevation was observed in 72% of deceased and 14% of recovered patients and an N-terminal pro B-type natriuretic peptide elevation was found in 85% of deceased and 18% of recovered patients.11 In another retrospective cohort of 187 patients with confirmed COVID-19 in China, 28% exhibited cardiac troponin T (cTnT) elevation that was associated with higher mortality; mortality rates reached 69.4% in patients with both cTnT elevation and coexisting cardiovascular disease vs. 7.6% in those with neither of the two.2 In all the above studies, biomarker elevation was significantly more frequent in patients with cardiovascular comorbidities. In a meta-analysis of four studies with a total of 341 patients, cardiac troponin values were significantly higher in patients with severe COVID-19 compared to those without (standardized mean difference 25.6 ng/L; 95% confidence interval 6.8–44.5 ng/L).12 A significant elevation of cardiac biomarkers in the context of COVID-19 may be explained by different mechanisms, including HF decompensation due to the viral infection in patients with pre-existing HF, an acute coronary syndrome, including a type I or type II myocardial infarction, triggered by the infection, increased myocardial stress due to hypoxia in the context of severe lung infection, a severe systemic inflammatory reaction or cytokine storm observed in advanced stages of COVID-19, or a potential direct myocardial injury or myocarditis caused by SARS-CoV-2.1, 13 It may also be the result of the stress of critical illness, akin to a Takotsubo cardiomyopathy.14 A number of sporadic cases of acute myocarditis complicated by acute HF has been reported in patients with COVID-19.15-18 However, most of these cases concerned clinically suspected myocarditis, not confirmed by endomyocardial biopsy. In one of the cases, the diagnosis of myocarditis was confirmed by endomyocardial biopsy, which revealed T-cell infiltration, interstitial oedema and foci of necrosis, but molecular analysis showed absence of SARS-CoV-2 genome.18 The above patients were successfully managed with HF medications in combination with various drugs being tested for COVID-19. However, there is not yet any widely accepted regimen for the treatment of COVID-19. Infectious and febrile states, particularly viral respiratory tract infections, represent a significant cause of HF decompensation and hospitalization.19 In the Atherosclerosis Risk in Communities (ARIC) study, a population-based study on 451 588 adults, a 5% monthly increase in influenza activity was associated with an adjusted 24% increase in HF hospitalizations.20 In this context, COVID-19 represents a potential trigger for HF decompensation. The role of ACE2 as a functional receptor for SARS-CoV-2 and as a potential determinant of virus infectivity may have implications in the treatment of heart disease with RAAS inhibitors, including angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs). Cardiovascular disease including HF, hypertension as well as diabetes mellitus increase ACE2 levels and the same may be true for RAAS inhibitors.21 It has thus been postulated that RAAS inhibition in patients with the above conditions could increase the susceptibility to COVID-19 or worsen its course.22 However, there is currently no clinical evidence supporting this hypothesis while two recently published studies showed that background therapy with ACEi or ARB does not increase the propensity, severity or mortality of COVID-19.23, 24 On the other hand, the actual effects of inhibitors on the different components of RAAS, including ACE2, are complex, partly uncertain and seem to differ among drug classes (ACEi ARB, mineralocorticoid receptor antagonists, renin inhibitors).25 At the same time, SARS-CoV-2 downregulates ACE2, which may lead to accumulation of unopposed angiotensin II that may in turn mediate lung injury, an effect that could be mitigated by RAAS inhibition.26 ACE2 dysregulation may have further detrimental effects on myocardial recovery and response to stress, while experimental evidence suggests that administration of recombinant ACE2 may be beneficial for viral lung injury as well as cardiovascular disorders.25 In view of the above, several scientific societies have issued statements that strongly recommend the continuation of RAAS inhibition therapy in patients with arterial hypertension or HF, given the lack of any evidence supporting a detrimental effect of these drugs in COVID-19 as well as the potential risks associated with their withdrawal.27, 28 The overall care of HF faces several challenges during the period of COVID-19 pandemic (Table 1). Adaptations of HF care are necessary means to minimize the transmission of SARS-CoV-2 but also to respond to the overload of healthcare systems during the pandemic. Routine visits to outpatient HF clinics should preferably be postponed in the absence of aggravating or worrying symptoms. In fact, many HF clinics have stopped accepting routine patient visits. To address this situation, virtual HF clinics offering remote patient consultation have been developed coupled with changes in the organization of established HF clinic networks.29, 30 In the presence of aggravating HF symptoms or symptoms suggestive of COVID-19, the patient should call the treating physician on the phone rather than visiting a medical facility, except for emergency cases. The physician will advise the patient whether a visit to hospital or clinic is necessary. In the case that such a visit is not deemed necessary, the patient with flu-like symptoms will practice self-isolation and social distancing measures staying at home for at least 14 days, according to physician's advice and national or local guidance. If a visit to hospital or clinic is deemed necessary, there should ideally be a triage site for accepting patients, particularly those with flu-like symptoms, that would provide an initial evaluation and decide whether SARS-CoV-2 testing is necessary. In any case, national and local guidelines and practices for the handling of COVID-19 suspected and confirmed cases should be followed. This also applies to hospitalized HF patients, in whom several issues remain challenging such as the diagnosis, differential diagnosis and treatment of a possible respiratory tract infection in patients presenting with dyspnoea, the handling of ventilation in the presence of respiratory distress or hypoxia, the performance of invasive procedures, the need for hospitalization of confirmed cases in dedicated wards, and many others. As previously mentioned, there is currently no evidence that treatment with RAAS inhibitors or other HF medications is harmful for patients with suspected or confirmed COVID-19 and, therefore, HF regimens should be followed as previously. Treatment of COVID-19 should comply with national or local guidelines, as the applied regimens differ and are continuously being updated. The potential interactions with HF patient background medication is of concern, including the risk of QT prolongation and arrhythmogenesis by chloroquine/hydroxychloroquine and azithromycin combination, or the interaction between antiviral agents with antithrombotic agents. The position statement of the European and Chinese Heart Failure Associations on the management of patients with HF and COVID-19 provides detailed information on drug–drug interactions along with useful algorithms for inpatient and outpatient management of HF patients with suspected or confirmed COVID-19.5 The inevitable reallocation of personnel and resources towards the management of the COVID-10 pandemic may pose a risk of suboptimal management of non-COVID-19 patients, including those with HF. An alarming increase of non-COVID-19 deaths has actually been noticed in areas with particularly high COVID-19 burden across Europe. In these areas, the total mortality increase was more than twice the number of deaths attributed to COVID-19.31 Therefore, the early adoption of a structured and evidenced-based approach to HF management in the course of the COVID-19 pandemic, with frequent updates incorporating the rapidly growing knowledge, is of utmost importance not only for the effective management of COVID-19 but also for the preservation of the overall HF care during this unprecedented era. Such a well structured plan may further be used as a blueprint for future epidemics of the same or similar respiratory viruses or other equivalent healthcare crises. The figure was created using artwork provided by Servier Medical Art, licensed under a Creative Commons Attribution 3.0 Unported License. Conflict of interest: D.F.: lecture honoraria or consulting fees from Abbott Laboratories, Bayer, Boehringer Ingelheim, Menarini, Novartis, Orion Pharma and Roche Diagnostics. M.R.M.: committee member in trials sponsored by Abbott, Medtronic, Janssen and Mesoblast; consulting fees from Baim Institute for Clinical Research, Portola, Bayer and Triple Gene; advisory board fees from Leviticus, NupulseCV and FineHeart; unpaid advisor to Riovant. J.P.: honoraria from Orion Pharma, Roche Diagnostics, Novartis, Pfizer and Servier. G.F.: committee member in trials and registries sponsored by Novartis, Vifor, Medtronic, Servier and Boehringer Ingelheim.