1. Introduction
The SARS-CoV-2 pandemic has caused a high number of hospitalizations and mortality worldwide. Patients with pre-existing cardiovascular (CV) disease [
1,
2] show a worse prognosis than those without pre-existing CV diseases; with a reported mortality 5 to 10 times higher [
3].
SARS-CoV-2 infection has been associated with direct viral injury of cardiomyocytes, microvascular dysfunction, small vessels thrombotic complications and systemic inflammation; all of which could cause cardiac injury and precipitate an acute cardiovascular syndrome [
4] (i.e., acute heart failure, myocarditis, pericarditis, vasculitis, cardiac arrhythmias and cardiac arrest) [
5].
Heart failure (HF) decompensation is one of the main causes of hospitalization worldwide and is associated with high in-hospital mortality [
6,
7]. Respiratory infections trigger up to 10% of total HF hospital admissions, being the most common non-cardiovascular cause for hospitalization [
8]. In addition, respiratory viral and bacterial infections worsen prognosis of HF patients [
9]. Notably, previous SARS-CoV and Middle East Respiratory Syndrome (MERS) coronavirus epidemics have also been associated with acute heart failure [
10].
The age and CV comorbidities are associated with poor prognosis in SARS-Cov-2 infection. There is scarce data about the prognosis of coronavirus 2019 (COVID-19) disease in patients with pre-existing HF. New date is emerging about the impact of chronic heart failure (CHF) in patients with COVID-19 [
11,
12]. Recent studies have shown that mortality could reach 40% in patients with CHF [
11]. Some of these studies did not analyze CHF as a separate entity; and others only included patients with advanced HF [
13,
14,
15]. However, it remains unclear if CHF, in an elderly population with high comorbidity, is associated per se with a higher mortality [
16]. Therefore, the aim of this study was to analyze the prevalence and prognosis of CHF in a cohort of patients with SARS-Cov-2 infection.
4. Discussion
Several aspects of this study are worth highlighting. In the present study, 5% of patients with COVID-19 had pre-existing CHF. This was an elderly population with a high comorbidity. During hospital stay, 21% of CHF had an AHF decompensation and half of the patients died. An NT-proBNP > 2598 pg/mL had an excellent sensitivity in predicting mortality in patients with previous diagnosis of HF.
Notably, given the epidemiological relevance of CHF [
16], few studies have analyzed the prevalence and prognosis of CHF in patients with SARS-CoV-2 infection [
11,
12]. Prevalence of CHF in the setting of SARS-CoV-2 infection has been described to be between 4.1% to 36.5%, these differences might be due to the different populations analyzed [
11,
12,
13,
14,
18]. Although this prevalence seems low, it is possible that CHF patients were especially careful in self-isolating due to their baseline high risk; thus, their risk of infection could be lower than in the general population. More than 65% of patients had heart failure with preserved ejection fraction (HFpEF), probably because HFpEF is more prevalent in the general population, especially in older patients [
19]. Moreover, these results are in line with previous studies of COVID in CHF patients, even though other cohorts included a much younger population [
11].
As expected, patients with CHF were older and had more CV comorbidities compared to non-CHF patient. Comorbidities, CV risk factors and older age have been associated with poor prognosis during COVID-19 disease [
1,
20,
21,
22]. Thus, it may be difficult to assess the role CHF per se played in mortality. To minimize this limitation, first we did a propensity score matching for age and gender. Second, we carried out a survival analysis with Cox proportional hazard models. Our results showed that 30-day mortality in CHF patients was remarkably high, almost double in comparison with non-CHF patients (51.2% vs. 29.1%). Similar mortality rate (40 to 63%) has been described in other series [
11,
12,
13,
14], which reflects the extremely poor prognosis in this population. The presence of CHF was independently associated with all-cause death in our cohort (HR 2.3 CI95% (1.26–4.2),
p = 0.007), confirming similar results recently published by Álvarez et al. [
11]. Interestingly, several treatments have been studied in COVID [
23,
24,
25,
26]. At the time this cohort was recruited, several anti-viral treatments, hydroxychloroquine plus azithromycin and tocilizumab were used, which have now been abandoned due to lack of efficacy. Moreover, although anticoagulation seems to play a role in COVID treatment [
27,
28], its use was not standardized and the protocols describing the indications and optimal doses varied throughout the study. We did not see a difference in prognosis according to the treatment received.
Viral infections are common causes of HF exacerbations [
29]. Acute HF decompensation associated to SARS-CoV-2 infection can occur as the first clinical manifestation of the infection even in patients without previous CV disease [
30]. Moreover, AHF developed during SARS-CoV-2 infection has been associated with an increased risk of mortality [
12,
31]. In the present study, around 4% of patients without previous history of HF had an acute episode of HF during hospitalization; this could be caused by myocardial involvement of virus infection in a cohort of elderly patients with high CV comorbidity [
32]. Similar findings were described in a study by Rey et al. regarding the prevalence of AHF in patients with COVID-19 disease [
12]. AHF was remarkably more frequent in patients with previous CHF affecting almost 1 out of 4 CHF patients (21 vs. 3.5%,
p < 0.019). Notably, CHF patients who develop an acute HF decompensation during hospitalization for COVID19 disease had an in-hospital mortality of 44%. One challenge in identifying HF decompensation is that clinical manifestations, as well as radiological findings, can be difficult to distinguish from respiratory infection. That requires a high degree of suspicion and the use of special image technics as computed tomography or lung ultrasound [
33] in order to promptly initiate HF medication to optimize loading conditions, especially when there is associated respiratory or hemodynamic compromise. In our cohort all CV deaths were due to HF decompensation refractory to treatment.
There are several factors that could explain this high mortality other than the older age and the presence of comorbidities. First, previous studies have demonstrated that HF confers a proinflammatory status to patients that may weaken the immunological response to virus infections [
34]. Second, SARS-CoV-2 infection has been associated with markedly elevated proinflammatory mediators and cytokine profile similar to the cytokine release syndrome [
4]. Moreover, SARS-CoV-2 infection has been associated with direct myocardial injury that might worsen previous cardiac diseases such as CHF [
3,
35] and prevent achieving the higher hemodynamic demands associated with infection [
4,
36]. Finally, SARS-CoV-2 infection has been associated with angiotensin-converting enzyme 2 (ACE2) signaling pathways [
36]. Patients with CHF have an upregulated renin-angiotensin-aldosterone system [
34]. Binding ACE2 may have special impact in these patients and explains the deleterious impact on survival.
The usefulness of cardiac troponin and NT-proBNP as prognostic markers in CHF is well recognized [
37]. Similarly, biochemical markers of myocardial injury have been associated with higher mortality in SARS-CoV-2 infection suggesting their potential role as a risk stratification tool [
18,
32,
38,
39]. There is scarce data about the prognostic value of these biomarkers in CHF patients with COVID-19. Dong et al. has described severe myocardial injury in patients with end-stage HF during COVID-19 and its association with disease progression and mortality [
15]. In our HF cohort, 84% of patients had Hs-TnT measurement above normal values, probably due to preceding myocardial injury and more susceptible myocardium to virus insult. Although troponin values should be interpreted with caution in CHF population due to chronic myocardial injury [
18], it seems to be a relationship between Hs-TnT on admission and prognosis. In fact, Hs-TnT levels below normal range were associated with better prognosis in the present study. Considering that the Hs-TnT cut-off value identified by ROC curves was rather low and associated with low sensitivity and specificity, we consider that the easiest approach would be to consider any patients with Hs-TnT above > 14 ng/L as a high-risk patient. The majority of previous studies focused on troponin release as the biomarker associated with acute myocardial injury in non-selected populations [
4,
18]. A recent study that focused on CHF patients admitted to hospital with SARS-CoV2 infection shows an association between increased troponin concentrations and in-hospital mortality in this specific population. However, NT-proBNP was not significantly associated with mortality [
11]. The prognostic value of NT-proBNP in viral respiratory infections has been previously described [
40]. A recent study conducted in a non-selected population of patients admitted to hospital with SARS-CoV2 infection underlined that a NT-proBNP level > 300 pg/mL on admission was an independent predictor of mortality or need for mechanical ventilation. The authors also emphasize that the NT-proBNP even improved the prognostic accuracy of Hs-TnT for the outcomes analyzed [
32]. In patients with severe COVID-19, an NT-proBNP > 88.64 pg/mL on admission was independently associated with in-hospital mortality suggesting its usefulness as a specific index of COVID19 disease severity [
41]. The overall median NT-proBNP described in the present study was high in both groups probably due to old age and high prevalence of CV risk factors and disease in our population. As expected, NT-proBNP levels were higher in CHF patients. However, a cut-off of NT-ProBNP > 2598 ng/dL on admission was strongly associated with poor prognosis in CHF patients infected with SARS-CoV-2.
The present clinical study has certain limitations. This is a single center study with a relatively small sample size; therefore, these results would benefit from a validation cohort. Biomarkers results should be interpreted with caution because we only focused on a single measurement on admission without being systematically collected in all patients. Finally, given the difficulty in establishing a HF diagnosis in the setting of acute respiratory failure and pulmonary infiltrates, it is possible that episodes of acute HF were not identified.