Cardiovascular Complications in Patients with Heart Failure and COVID-19: CARDIO COVID 19-20 Registry

Since early 2020, different studies have shown an increased prevalence of COVID-19 and poorer prognosis in older adults with cardiovascular comorbidities. This study aimed to assess the impact of heart failure (HF) on cardiovascular complications, intensive care unit (ICU) admissions, and in-hospital mortality in patients hospitalized with COVID-19. The CARDIO COVID 19-20 registry includes 3260 hospitalized patients with a COVID-19 serological diagnosis between May 2020 and June 2021 from Latin American countries. A history of HF was identified in 182 patients (5.6%). In patients with and without previous HF, the incidence of supraventricular arrhythmia was 16.5% vs. 6.3%, respectively (p = 0.001), and that of acute coronary syndrome was 7.1% vs. 2.7%, respectively (p = 0.001). Patients with a history of HF had higher rates of ICU admission (61.5% vs. 53.1%, respectively; p = 0.031) and in-hospital mortality (41.8% vs. 24.5%, respectively; p = 0.001) than patients without HF. Cardiovascular mortality at discharge (42.1% vs. 18.5%, respectively; p < 0.001) and at 30 days post-discharge (66.7% vs. 18.0%, respectively) was higher for patients with a history of HF than for patients without HF. In patients hospitalized with COVID-19, previous history of HF was associated with a more severe cardiovascular profile, with increased risk of cardiovascular complications, and poor in-hospital and 30-day outcomes.


Introduction
According to the World Health Organization, SARS-CoV-2 infection (COVID-19) became a pandemic, with over 762 million reported cases worldwide as of April 2023 [1], changing the dynamics of morbidity and mortality worldwide and putting a financial strain on healthcare systems in several countries.Since early 2020, different studies have shown an increased prevalence of COVID-19 and poorer prognosis in older adults with cardiovascular comorbidities [2], with later reports and descriptions affirming these initial findings [3][4][5][6].Only a few of these focused on analyzing the impact of heart failure (HF) on outcomes after COVID-19 events [7,8], some of which proved that HF is an independent risk factor for mortality [9].Using the available clinical data collected by 14 Latin American countries from patients hospitalized with COVID-19 and recorded in the CARDIO COVID [19][20] Registry from May 2020 to June 2021, the aim of this study was to evaluate the impact of HF as a comorbidity on intensive care unit (ICU) admissions, the incidence of cardiovascular complications, and in-hospital mortality in patients with COVID-19.

Materials and Methods
The CARDIO COVID 19-20 Registry sought to determine the presence of comorbidities and cardiovascular complications in patients with COVID-19 who were admitted to Latin American hospitals between May 2020 and June 2021.The registry recruited 3260 adult patients with a COVID-19 diagnosis confirmed using reverse-transcription polymerase chain reaction (RT-PCR) or antigen tests for SARS-CoV-2 at 44 institutions in 14 Latin American countries, including Argentina, Brazil, Chile, Colombia, Costa Rica, Ecuador, El Salvador, Guatemala, Mexico, Panama, Paraguay, Peru, the Dominican Republic, and Venezuela.HF diagnoses, along with information about other comorbidities, were taken from medical histories and clinical records.Cardiovascular complications were documented during hospitalization, including arrhythmia, deep vein thrombosis (DVT), pulmonary embolism (PE), arterial thrombosis, decompensated heart failure (DHF), acute coronary syndrome (for acute coronary syndrome, we classified it as 1.Acute Myocardial Infarction with elevation of ST segment, or 2. Acute Myocardial Infarction without elevation of ST segment), and myocarditis (defined as the evidence of this diagnosis obtained from the clinical records of the recruited patients, and based on the wide range of clinical presentations of this condition, the diagnosis should be differentiated from acute coronary syndrome with atherosclerotic lesions, other causes that can explain abnormal serological biomarkers (pulmonary embolism, acute coronary syndrome, decompensated heart failure, among others), and other conditions explaining new-onset acute decompensated heart failure).Demographic variables such as past medical history of cardiovascular complications, comorbidities, treatment regimens administered during hospitalization, and outcomes were also registered.The full study design, patient recruitment, eligibility criteria, and evaluations were published elsewhere [10].The Ethics Committee of the Fundación Valle del Lili in Cali, Colombia, approved the registry protocol.

Data Collection
The subject of analysis for this study included 182 patients who had a previous diagnosis of HF (the definition of HF/history of HF was based on the information obtained from clinical records, which included the registered diagnosis of the entity and the evidence in the clinical record of the previous use of specific HF medication for this condition).The Research Electronic Data Capture (REDCap) electronic database system was used to collect information.Demographic information (i.e., age, sex, ethnicity, education, smoking, and pregnancy status), comorbidities before admission (cardiovascular and non-cardiovascular), previous cardiovascular treatment, laboratory test results at admission, clinical findings on admission, cardiovascular complications during hospitalization, echocardiography and other diagnostic cardiovascular tests, cardiovascular procedures, as well as COVID-19 treatments carried out during hospitalization, laboratory test results at discharge, and outcomes both during hospitalization and 30 days after discharge were analyzed.

Main Outcomes
Primary clinical outcomes were ICU admission, in-hospital all-cause mortality, readmission, and 30-day discharge mortality.These variables were documented at the time of discharge.All patients were followed until 30 days after discharge to evaluate rehospitalization or mortality through phone calls.

Statistical Analysis 2.3.1. Univariate and Bivariate Analysis
If the measurements followed a normal distribution, data are reported using mean values and the corresponding standard deviation (SD).If not, medians with a corresponding interquartile range (IQR) are used.
Categorical variables are presented as frequencies and percentages.When data were normally distributed, the independent samples t-test was used to compare the means of continuous variables.Otherwise, the Mann-Whitney test was used.Pearson's Chi-square test and Fisher's exact test were used to compare proportions between groups.To compare, in terms of mortality, patients who developed DHF and had a history of HF vs. those who developed DHF but had no history of HF, a t-test was performed to compare the proportions of the two independent populations.The results were considered statistically significant if the p-value < 0.05.All descriptive statistical analysis was performed using the R program (Version 4.2.2).

Multivariate Analysis
The predictor variables of mortality and ICU admission in patients with a history of HF and a diagnosis of COVID-19 were determined using a logistic regression model.The multivariate analysis was completed using Python 3.11.1 (compatible version).For the regression analysis, we filtered the variables analyzed, considering the missing data.If a variable had 20% or more missing data, we did not include it in the analysis.Moreover, we did not include variables that were not clinically relevant.

Results
A total of 182 out of 3260 recruited patients (5.58%) had a previous diagnosis of HF.The median ages of patients with and without a diagnosis of HF were 71 and 60 years, respectively (Table 1).

Outcomes from Patients with HF
Table 5 shows the variables associated with increased mortality and ICU admission in patients with HF according to the logistic regression model.Notably, the prediction models used were highly accurate (0.76 and 0.85 for ICU admission and mortality models, respectively).Even though it was not statistically significant, arterial hypertension is included in the table due to its clinical value.HF history was also associated with a higher risk of death (p = 0.001) and ICU admission (p = 0.031).Inotropic support and invasive mechanical ventilation (IMV) were strongly related to hospital mortality (p = 0.027 and p = 0.019, respectively).
Mortality and ICU admission according to left ventricular ejection fraction (LVEF) are presented in Table 6.

Discussion
Our study shows that having HF is associated with increased cardiovascular complications and in-hospital mortality in patients with COVID-19, findings consistent with the reports of other works and from the analyses of large registries [11].
Tomasoni et al. [6], in their multicenter registry including 692 patients (Cardio-COVID-Italy), found a HF prevalence of 13%; this population was typically older, and with a higher proportion of cardiovascular risk factors such as arterial hypertension, dyslipidemia, diabetes mellitus, coronary heart disease, and AF, compared to those without HF.There were no reports of supraventricular arrhythmias, and ventricular arrhythmias were present in 5.6% of individuals with HF.
In the CAPACITY COVID Registry, an international registry of 3011 patients, Linschoten et al. [11] reported a 5.3% prevalence of HF, with 349 patients requiring hospitalization for cardiovascular problems.They characterized arrhythmias and conduction disorders as the most frequent cardiac complications, identified in 73.9% of cases, with supraventricular tachycardia accounting for 54.2% of these.Acute coronary syndrome, on the contrary, was only diagnosed in 4.3% of cases, with PE and myocarditis also being uncommon.As per our registry, arterial hypertension, diabetes mellitus, and dyslipidemia were the most prevalent comorbidities in the HF population, being present in 72.5%, 46.2%, and 34.1% of patients, respectively.The findings on ventricular arrhythmias from the trial by Tomasoni et al. [6] are comparable to our study.
Tomasoni et al. [6] also reported higher mortality in individuals with previous HF, a finding differing from that documented by Linschoten et al. [11] but similar to our findings.In a multivariate Cox regression model, the risk of death associated with HF remained elevated after adjusting for clinical variables related to COVID-19 and the severity of the HF such as oxygen saturation, lymphocyte count, and plasma troponin (hazard ratio adjusted for death, 2.25; 95% CI, 1.26-4.02;p = 0.006).Interestingly, in our registry, cardiovascular mortality in the general population was 20.5%, compared to 18.5% in patients without HF and 42.1% in patients with HF.
Kim et al. [13] recently reported the findings of the Korean nationwide COVID-19 registry, which included 212,678 patients, and aimed to investigate the relationship between HF and the susceptibility to severe COVID-19 sequelae.The primary composite outcome included IMV, ICU admission, and mortality.Only 310 (4.1%) of the total number of patients had a history of HF.Following propensity score matching, HF comorbidity was revealed to be independently associated with the primary composite outcome (OR: 1.99; 95% CI: 1.42-2.79;p < 0.001) and notably with mortality (OR: 2.02; 95% CI: 1.36-3.00;p < 0.001).This supports previous published data and is in accordance with our findings [6].
In general, there are several reports associating HF history with a higher risk of complications and a worse prognosis.A study from Spain, including 3080 patients with COVID-19 [14], found that the 152 (4.9%) patients who had a history of HF were more likely to develop acute DHF as a cardiovascular complication during their hospitalization compared to the non-HF group (11.2% vs. 2.1%; p < 0.001) and, as a consequence, had a higher mortality risk (46.8% vs. 19.7%;p <0.001) [14,15].
Angeli et al. [16] documented a synergistic effect of HF and CAD in 954 consecutive patients hospitalized for SARS-CoV-2 in five Italian hospitals.They found a significant 35.6% mortality rate in the group with HF and CAD (OR: 6.9; p < 0.0001).Also described was the risk of mortality in patients with CAD and HF combined, which was consistently higher than the sum of risks related to either disorder.In our study, we found a high prevalence of CAD in the HF population (44.4%).Our analysis did not focus specifically on the relationship of these two comorbidities.However, the high prevalence of CAD in our population could be related to the statistically significant higher mortality rate found in patients with HF vs. patients without HF (41.8% vs. 24.5%,respectively; p < 0.001).Also, similar to our study, 44% of the population that Angeli et al. [16] analyzed that had a history of HF also had a history of CAD.Additionally, they cited numerous studies that have evaluated the detrimental prognostic effect of CAD or HF in patients with COVID-19, including monocenter, and multicenter studies from Italy, as well as from Sweden, specifically a registry that showed that CAD is a powerful and independent predictor of death in patients with non-valvular HF.In view of the above, the population in our study that had a history of both CAD and HF could have had higher mortality and, finally, have contributed greatly to the mortality rate found.
Our findings are also consistent with the results of a systematic review and metaanalysis that synthetized evidence from 18 studies worldwide, including 21,640 patients and demonstrating that HF was related to higher rates of hospital admission following COVID-19 infection [17] as well as poorer COVID-19 outcomes (defined by mortality or incidence of severe COVID-19 disease, ICU admission, and requirement of IVM), and a higher mortality rate [15].
In a study published by Raisi-Estabragh et al. [18], based on the UK Biobank, 17,871 patients with COVID-19 were evaluated from the time of infection to up to 30 days of followup between March 2020 and 2021.Their analyses revealed that 3% of patients in the COVID-19 group had some form of cardiovascular disease compared to 0.5% in a control group, this condition being more prevalent in individuals who were hospitalized.They also found that they more frequently developed complications such as venous thromboembolism (VTE), atrial fibrillation, and HF.COVID-19-induced cardiovascular complications are not restricted to the acute phase of the disease, since significant findings have been documented up to one year after infection, even in patients who did not require hospitalization [19].
In 2022, a large-scale study was carried out that included 153,760 patients diagnosed with COVID-19 belonging to the United States Department of Veterans Affairs.This was controlled by two groups: a contemporary cohort of 5,637,647 and a historical cohort (before COVID-19) of 5,859,411 patients, all with a 12-month follow-up [19].Two main conclusions were drawn from this study: First, even in patients who did not require hospitalization during the acute stage of the disease, the chance of developing cardiovascular problems increased substantially.Second, during the acute phase of the disease, the risk of developing cardiovascular complications rose progressively in direct proportion to the severity of the clinical presentation.The most prevalent cardiovascular complications in this study were supraventricular arrhythmias and HF, demonstrating that the risk of developing the latter was 72% higher in the group that had a history of COVID-19 infection than in the group that did not.
Wang et al. [20] conducted another study, emphasizing the need for a long-term follow-up (up to 12 months) in these patients, after having evaluated the development of cardiovascular complications in patients who survived COVID- Those results support the hypothesis that HF is a risk factor for poor outcomes in COVID-19 patients, a problematic situation even in the long term, providing valuable evidence for public health systems and healthcare services in the up-coming years, and hopefully helping to develop adequate strategies for the management of these problems, as they could eventually result in a post-pandemic health system crisis [21].

Limitations
The limitations of this study can be traced back to the information collection, as some data were incomplete due to the isolation measures in place to contain the pandemic at that time.Additionally, a non-random sampling of the population was conducted, including only medical institutions equipped with hospitalization, ICU, and specific paraclinical facilities as requirements for filling the variables in the registry.However, despite the mentioned limitations, the described findings are valuable and enable an initial appreciation of the clinical course of COVID-19 patients.They should encourage healthcare personnel towards early detection of cardiovascular complications, which are associated with a more severe disease course, increased risk of ICU admission, and mortality.

Conclusions
In the Latin American population, patients with HF who are hospitalized for COVID-19 have more myocardial injury (changes in troponin, D-dimer, and peptide), increased risk of developing cardiovascular complications, higher ICU admission rates, and higher general and cardiovascular in-hospital mortality rates.At the 30-day follow-up, there was no statistically significant difference in all-cause mortality when compared to the group without HF.
19 using data from the US Collaborative Network in the TriNetX database.A total of 4,131,717 individuals with this condition were recruited from a cohort of 42 million adults registered between January 2019 and March 2022.Their analyses concluded that COVID-19 survivors were at an increased risk of the development of cerebrovascular complications such as strokes (HR = 1.52 [1.43 − 1.62]), arrhythmias including atrial fibrillation and flutter (HR = 2407 [2296 − 2523]), myocarditis (HR = 4406 [2890 − 6716]), and HF (HR = 2296 [2200 − 2396]) in the long term.

Table 1 .
Demographic characteristics and comorbidities of patients with COVID-19 according to the presence/absence of HF.

Table 2 .
Clinical and paraclinical characteristics of patients with COVID-19 according to the presence/absence of HF.

Table 5 .
Variables associated with mortality and ICU admission in patients with HF according to the logistic regression model.

Table 6 .
Mortality and ICU admission percentages of patients with HF according to LVEF values.
ICU: intensive care unit.n: number of patients.LVEF: left ventricular ejection fraction.