Risk factors for unfavorable prognosis and progression of chronic heart failure in COVID-19 pneumonia

was conducted. Subsequently, the data of 90 patients with chronic heart failure (CHF) and COVID-19 pneumonia from January – February 2021 were collected at Lviv Clinical Hospital of Emergency Medical Care. The following indices were evaluated: anthropometric and demographic data, complications, treatment results, results of clinical, laboratory, and instrumental examinations, and dynamic NT-proBNP. Results. CHF is recorded in 42.9% of hospitalized patients with COVID-19 and is accompanied by lower values of blood oxygen level (p=0.0474), hemoglobin (p=0.0090), prothrombin time (p=0.0196), prothrombin index (p=0.0196) and higher indicators of glucose (p=0.0032), creatinine (p=0.00001), interleukin-6 (p=0.0041). CHF decompensation is associated with lower values of body temperature (p=0.0047) and blood oxygen saturation (p=0.0076), while hemoglobin level (p=0.0026), higher creatinine values (p=0.0034), interleukin-6 (p=0.0300), aspartate aminotransferase (p=0.0035), troponin I (p=0.0061); are associated with the development of myocardial infarction (p=0.0014), acute arrhythmias (p=0.0011), hypertensive crisis (p=0.0096) and increased mortality (OR=5.72; 95). % CI: 1.84, 17.81; p=0.0026). Conclusions. CHF is common and often fatal in patients with COVID-19, especially in decompensated CHF. Low blood oxygen saturation


Introduction
Heart failure (HF) is a disease with unfavorable prognosis, its appearance often indicates the final phase of the underlying disease [1,2].Mortality due to HF is similar or even higher than mortality from various types of cancer.Modern advances in treatment have improved the quality of life and survival of patients with HF [3].However, the emergence of the coronavirus disease pandemic, a new disease that affected humanity and caused significant morbidity and mortality worldwide, has made patients with HF particularly vulnerable.The prevalence of cardiovascular disease (CVD) in patients with coronavirus disease 2019 (COVID-19) has been reported to range from 4% to 40%, and there is increasing evidence that its presence is associated with adverse outcomes, including but not limited to hospitalization in the intensive care unit and increased mortality [4,5].The aim of this study was to investigate risk factors of an unfavorable prognosis and progression of heart failure in hospitalized patients with chronic heart failure (CHF) and COVID-19 pneumonia.

Study Population
A retrospective analysis of 555 medical records of inpatients treated at Lviv Clinical Hospital of Emergency Medical Care from November 2020 to February 2021 diagnosed with COVID-19 pneumonia was conducted.All patients were hospitalized based on clinical criteria for patients with suspected/confirmed COVID-19: 1) respiratory rate <10 or >30 or 2) saturation ≤ 92% or 3) impaired consciousness (according to the AVPU scale, all except A) or decompensated HF corresponding to a moderate or severe course of COVID-19.The criteria for including patients in the retrospective analysis was a diagnosis of COVID-19-associated pneumonia, confirmed using laboratory and instrumental methods (blood tests, such as complete blood count, serum biomarkers -C-reactive protein (CRP) and procalcitonin, sputum test, chest computed tomography (CT) scan, pulse oximetry); detected genome of SARS-CoV-2 virus in swabs from the nasopharynx and oropharynx using the polymerase chain reaction method and/or detection of IgM antibodies to SARS-CoV coronavirus-1 and the level of suspicion of COVID-19 infection according to the CO-RADS scale corresponding to 5 points; complicated epidemiological anamnesis.The aim of this phase of the study was to determine the prevalence of CHF, mortality and key factors for unfavorable prognosis among hospitalized patients with CHF and COVID-19 pneumonia.Given that the study was retrospective, estimating the prevalence of decompensated CHF among patients with coronavirus disease based on available medical records was complicated.
The next step of the work was planned as a single-center prospective controlled study and aimed to research the prevalence of decompensated CHF among hospitalized patients with COVID-19 pneumonia, risk factors for decompensation, as well as mortality in patients with decompensated CHF and COVID-19 pneumonia.The data were collected from 90 patients with a history of CHF admitted to Lviv Clinical Hospital of Emergency Medical Care in January -February 2021 with a diagnosis of COVID-19 pneumonia.COVID-19 pneumonia was diagnosed using the criteria mentioned above.The diagnosis of chronic heart failure (CHF) was established based on the "2016 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure: Working Group on the Diagnosis and Treatment of Acute and Chronic Heart Failure of the European Society of Cardiology (ESC)" [6].CHF progression was diagnosed based on an increase in the value of N-terminal natriuretic pro-peptide B-type (NT-proBNP) by 100% or more from its initial concentration determined at the time of hospitalization [7] and the recommended limit values of natriuretic peptide for diagnosing acute heart failure of the Heart Failure Association of the European Society of Cardiologists.
All patients were over 18 and signed informed consent to participate in the study.Exclusion criteria: Patients without a confirmed diagnosis of pneumonia, those suspected of being infected with COVID-19 according to the CO-RADS scale of 1-4 points, individuals with other etiological pneumonia (bacterial, hypostatic), pulmonary tuberculosis, severe accompanying diabetes, patients with immunosuppressive conditions, severe chronic pathology of the respiratory system, end-stage renal failure, recently experienced acute coronary syndrome, coronary artery bypass grafting, recent (within one month) hospitalization for CHF, as well as patients with shock or sepsis.
The following parameters were evaluated: patient's age, sex, presence of complications and treatment results (discharge/death).Complaints, case history, physical examination results, and additional laboratory and instrumental examination methods were studied.
Demographic, clinical and anamnestic data were analyzed during hospitalization, and laboratory and instrumental examinations were conducted in 1-3 days.
Echocardiography was mandatory in the prospective study on days 1-5.Two-dimensional echocardiographic images were recorded: 1) the inferior vena cava during inhaling and exhaling from the subcostal transducer position; and 2) the left ventricular outflow tract from the parasternal long-axis position.Continuous and pulsed wave spectral Doppler images of the tricuspid regurgitation, pulmonic regurgitation, mitral regurgitation and transaortic systolic flow signals were obtained from multiple transducer positions.Images of the inferior vena cava were obtained from the subcostal transducer position.Mean right atrial pressure (RAP) was estimated from the inferior vena cava diameter and its degree of respirophasic change.Pulmonary artery systolic pressure (PASP) was calculated as the sum of the estimated RAP and the gradient between the peak right ventricular systolic pressure and the estimated RAP.This gradient was estimated by applying the modified Bernoulli equation to the peak velocity of the continuous wave Doppler tricuspid regurgitation signal (VTR Max): PASP = RAP + 4VTR Max2.Pulmonary artery diastolic pressure (PADP) was calculated as the sum of the estimated RAP and the gradient between the pulmonary artery end-diastolic pressure and the right ventricular end-diastolic pressure, which is equal to the RAP at this time in the cardiac cycle.This gradient was estimated from the end-diastolic velocity of the continuous wave Doppler pulmonic regurgitation signal (VPR end-diastolic2): PADP = RAP + 4VPR end-diastolic2.Pulmonary artery mean pressure (PAMP) was calculated by adding one-third of the pulmonary artery pulse pressure to the estimated PADP: PAMP = PADP + 1/3(PASP − PADP).Left atrial pressure (LAP) at the time of aortic valve opening, an estimate of mean LAP was calculated as the difference between the diastolic aortic pressure (AoDP) and the pressure gradient between the left ventricle and left atrium at the time of aortic valve opening.This pressure gradient was determined from the peak velocity of the continuous wave Doppler mitral regurgitation signal at the time of aortic valve opening (VMR-AVO2): LAP = AoDP − 4VMR-AVO.The transpulmonary gradient (TPG) was calculated as PAMP minus LAP.Pulmonary vascular resistance (PVR) was calculated as TPG divided by cardiac output.The PVR index (PVRI) was calculated as TPG divided by the cardiac index.
After signed informed consent was obtained, NT-proBNP levels were measured in blood samples during hospitalization and repeatedly on the 5th-7th day or when symptoms exacerbated.NT-proBNP was measured by the immunofluorescence method in the biochemical laboratory of Lviv Emergency Hospital.
The study was conducted after the approval of the Ethical Commission on Experimental Development and Research of Danylo Halytsky Lviv National Medical University (No. 10 dated 12/16/2019).All patients signed an informed consent to participate in the study.The study complies with the principles listed in the Declaration of Helsinki.

Statistical analysis
Categorical variables are shown as rates and percentages, and continuous variables as the mean ± standard deviation (SD) or median and interquartile range (IQR) as appropriate.Means for continuous variables were compared using independent group t-tests when data were normally distributed; otherwise, Mann-Whitney tests were performed.The normality of distributions was assessed using the Shapiro-Wilk test.Proportions for categorical variables were compared using the chi-squared test or Fisher's exact test, as appropriate.The receiver operating characteristic curve (ROC) was drawn to calculate the area under the curve (AUC) and evaluate the diagnostic value of the marker for heart failure.Correlation analysis between variables, continuous variables that presented normal distribution was analyzed through Pearson correlation, and variables that did not present normal distribution were analyzed by Spearman correlation.The multivariate conditional logistic regression model was constructed using significant variables in the univariate analysis.All data were analyzed using Statistica 6.0.A two-sided P-value of <0.05 indicated statistically significant differences in all analyses.

Results
According to the results of the retrospective analysis, the percentage of patients who were treated at the Municipal Non-Profit Enterprise "Lviv Clinical Emergency Care Hospital" with a combination of COVID-19 pneumonia and CHF from September -November 2020 was 42.9% of cases (HF group, n = 238).Baseline patient characteristics are shown in Table 1.Patients in the CHF group had more severe presentations of COVID-19, as indicated by lower levels of oxygen saturation at admission (90.0 (86.0; 93.0) vs 92.0 (89.0; 93.0); P=0.0474).
It was difficult to distinguish the clinical features of decompensation of CHF on COVID-19 pneumonia due to the typical symptoms of shortness of breath and the results of physical examination (wet wheezing) for both diseases.
Although echocardiography is the gold standard for left ventricular dysfunction, it was not performed in most patients.Also, there was no predetermined "dry NT-proBNP concentration" in most patients, as indicated in the guidelines of the Heart Failure Association of the European Society of Cardiology regarding the use of NT limit values for diagnosing acute HF [7].Therefore, we proposed to perform an assessment of HF decompensation in hospitalized patients with COVID-19 pneumonia based on dynamic measurement of NT-proBNP values in blood serum, particularly during hospitalization, on the 5-7th day of treatment and/or when disease symptoms worsened, especially in cases of increasing shortness of breath.To assess the accuracy of the proposed method, NT-proBNP values obtained in dynamics were compared with HF assessment results using the Doppler echocardiography mentioned.By design, Doppler echocardiographic thresholds (ratio of mitral peak low velocity in early diastole to peak low velocity in late diastole E/A ratio≥2, transpulmonary gradient TPG ≥13 mm Hg; pulmonary vascular resistance PVR ≥3.5 Wood units; and pulmonary vascular resistance index PVRI ≥6.5 Wood units × m2) established for patients with decompensated HF [8].
We additionally contacted patients with CHF and COVID-19, and if the duration of their hospitalization did not exceed seven days, we offered to perform additional analysis of blood samples for NT-proBNP and echocardiogram to verify that they have decompensated HF.A repeated blood test was taken after signing the informed consent.This way, we recruited 85 patients.There were no patients who refused additional blood sample.Afterwards, five more patients were included in the study.
Therefore, 90 patients with CHF were included in the prospective analysis.The receiver operating characteristic curve (ROC) was drawn to calculate the area under the curve (AUC) to evaluate the diagnostic value NT-proBNP for diagnosing decompensated HF (Fig. 1).
During the study period, 21 (23.3%)patients with confirmed COVID-19 infection met the inclusion criteria for decompensated СHF.The average duration of hospitalization and observation of patients was 16.56 ±0.83 days.A total of 9 patients (42.86%) died during hospitalization (OR=5.72;95% CI: 1.84, 17.81; p=0.0026).The mean ± SD age of the cohort was 70.14±11.24years, and 9 (42.86%) were male.Of those, 10 (47.62%) had some degree of left ventricular systolic dysfunction prior to COVID-19 diagnosis.The remaining 11 had HF with preserved ejection fraction and other significant echocardiographic abnormalities such as left ventricular hypertrophy or moderate-to-severe valvular disease.Four had pathological findings such as significant aortic valve stenosis and 2 -pericardial effusion.Baseline patient characteristics are shown in Table 2.All patients with COVID-19 pneumonia had shortness of breath.However, oxygen saturation at the first measurement was significantly lower in patients who developed decompensated CHF (p=0.0076) and had a lower body temperature (p=0.00001).Only six (28.57%) patients had peripheral edema during hospitalization.
Changes in the coagulation potential (decrease in prothrombin index in patients with decompensated CHF), which developed along with the previous antithrombotic therapy in patients with a high cardiovascular risk, were recorded.At the same time, D-dimers in both groups did not differ significantly (р=0.6970).

Discussion
In this study, we examined the prevalence and prognostic implications of HF in patients with COVID-19.The prevalence of CHF among patients with COVID-pneumonia who were admitted to Lviv Clinical Hospital of Emergency Medical Care with a diagnosis of COVID-pneumonia in September -November 2020 constituted 42.9% of cases, and mortality during hospital stay equaled 23.95% of cases without a statistically significant gender difference (p = 0.0644).
In our retrospective study, we encountered high diagnostic uncertainty in the assessment of decompensated CHF in COVID-19 pneumonia after clinical evaluation.The most common manifestation of HF is dyspnea, a complaint that is neither specific nor sensitive for predicting the presence of HF exacerbation.In addition, physical signs of HF, such as bilateral basal end-inspiratory crackles, were present in both diseases and increased jugular venous pressure and leg edema have limited sensitivity.Similar limitations were found in other studies, and they also concerned electrocardiography and chest radiography [9].
In a planned prospective analysis based on studying the dynamics of the NT-proBNP level, we showed that in approximately every 4-5 patients with CHF, COVID-19 pneumonia contributed to the development of decompensation.Among the factors associated with the deterioration of cardiac function was a decrease in blood oxygen saturation along with the occurrence of atypical pneumonia and respiratory failure, the development of acute myocardial infarction, arrhythmia, and, much more rarely -a hypertensive crisis.In patients with decompensated CHF IQR, Q3-Q1 of high-sensitivity troponin was significantly higher compared to the level in patients with compensated HF, which probably could indicate an increase in the processes of myocardiocytolysis in these patients along with Covid 19.Among other results of laboratory screening, lower hemoglobin values (p=0.0016) and increased creatinine (p=0.0011) were detected in patients with CHF.According to the results of several meta-analyses, both of these indicators belong to the determining predictors of an unfavorable cardiovascular prognosis, in-hospital mortality in both systolic and diastolic HF, and low body temperature [10,11,12,13].
On the other hand, a significant increase in IL-6, a key mediator of the cytokine storm, was recorded in patients with decompensated HF [14].According to published studies 15, 16, it is the cytokine storm that is most destructive in the case of COVID-19, rather than direct damage by SARS [17].An elevation of IL-6 values greater than the previously determined 95th percentile of normal values at baseline in patients with HF by more than 50% was also associated with an unfavorable clinical prognosis in the extensive BIOSTAT-CHF cohort study [18].
Changes in the coagulation potential (decrease in prothrombin index in patients with decompensated CHF), which developed along with the previous antithrombotic therapy in patients with a high cardiovascular risk, were recorded.At the same time, a clinical paradox was observed -with low values of the prothrombin index, PE occurred more often (p=0.0344) in patients with decompensated heart failure, despite concomitant antithrombotic therapy, while the values of D-dimers in both groups did not differ significantly (p > 0.05).
Mortality in patients with decompensated CHF was extremely high -42.86%(p=0.0027)(OR=5.72;95% CI: 1.84, 17.81; p=0.0026).In our opinion, the increased mortality was influenced by a number of prognostically unfavorable clinical and laboratory factors of cardiovascular risk and risk factors associated with the coronavirus disease (the development of a hyper-inflammatory immune response, respiratory failure and, possibly, the direct effect of the virus on the cardiovascular system).Thus, it is vital in the management of CHF and COVID-19 to influence manageable risk factors for decompensation in all patients with CHF and coronavirus disease and timely diagnosis of CHF decompensation, which is complicated in routine clinical practice.For these reasons, the determination of NT-proBNP is useful not only at the time of the patient's diagnosis/hospitalization but also dynamically during the patient's follow-up.
In conclusions: CHF is common in patients with COVID-19 pneumonia and is often fatal, especially in patients with decompensated CHF.Factors contributing to the decompensation of HF in patients with COVID-19 are a decrease in blood oxygen saturation during COVID-19, myocardial infarction, arrhythmias, and hypertensive crisis.In such patients, there is an increase in troponin I, AST, and markers of an unfavorable cardiovascular prognosis -decreased hemoglobin, increased creatinine and the pro-inflammatory cytokine -IL-6.Direct correlations of NT-proBNP with the levels of IL-6 (r=0.31,p=0.003), troponins (r=0.39,p=0.000), age (r=0.46,p=0.000), creatinine values (r=-0.60,p=0.000) and inversely proportional between NT-proBNP and hemoglobin (-r=0.37,p=0.002) have been established.
COVID-19 patients with decompensated heart failure should be identified early and actively treated to improve outcomes in this patient cohort.Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.

Institutional Review Board
Statement: The study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethical Commission on Experimental Development and Research of Danylo Halytsky Lviv National Medical University (No. 10 dated 12/16/2019).

Table 1 Baseline characteristics, vital signs, laboratory data and clinical outcomes in COVID-19 patients with and without a previous history of chronic heart failure
Among patients with CHF, hypertension was observed in 86.14% of cases, coronary heart disease -in 72.29%, diabetes -in 28.99%, and a history of myocardial infarction -in 23.11%.Atrial fibrillation was the most prevalent rhythm abnormality recorded in 45 patients (18.09%).Premature complexes were recorded in 41 patients (17.23%) and bundle branch blocks in 10 (4.2%) patients.Mortality in patients with CHF and СOVID-19 pneumonia was 23.94%, as opposed to 9.15% in patients without CHF (p<0.00001)(OR=3.13;95% CI: 1.93; 5.08; p= 0.000004).

Table 2 Baseline characteristics, vital signs, laboratory data and clinical outcomes in patients with COVID-19 with and without the development of Advanced heart failure (AHF) during admission
85.7% of CHF patients had a history of ischemic heart disease, and 23.3% of them had a myocardial infarction in the past.During hospitalization, 33.3% of patients were diagnosed with diabetes, 76.19% with hypertension, and 38.1% with arrhythmia.The hypertensive crisis was a possible predictor of cardiac decompensation in 9.5% of patients and heart arrhythmic disorders in 14.29%.