key: cord-0964260-4xfv7te7 authors: Hadzibegovic, Sara; Lena, Alessia; Churchill, Timothy W.; Ho, Jennifer E.; Potthoff, Sophia; Denecke, Corinna; Rösnick, Lukas; Heim, Katrin Moira; Kleinschmidt, Malte; Sander, Leif Erik; Witzenrath, Martin; Suttorp, Norbert; Krannich, Alexander; Porthun, Jan; Friede, Tim; Butler, Javed; Wilkenshoff, Ursula; Pieske, Burkert; Landmesser, Ulf; Anker, Stefan D.; Lewis, Gregory D.; Tschöpe, Carsten; Anker, Markus S. title: Heart Failure with preserved ejection fraction according to the HFA‐PEFF score in COVID‐19 patients: clinical correlates and echocardiographic findings date: 2021-05-01 journal: Eur J Heart Fail DOI: 10.1002/ejhf.2210 sha: 61c6f45ef1ec92284169126496215314b47c7080 doc_id: 964260 cord_uid: 4xfv7te7 AIMS: Viral‐induced cardiac inflammation can induce heart failure with preserved ejection fraction (HFpEF) like syndromes. COVID‐19 can lead to myocardial damage and vascular injury. We hypothesised that COVID‐19 patients frequently develop a HFpEF‐like syndrome, and designed this study to explore this. METHODS AND RESULTS: Cardiac function was assessed in 64 consecutive, hospitalized, and clinically stable COVID‐19 patients from April – November 2020 with left ventricular ejection fraction (LVEF) ≥50% (age 56±19 years, females: 31%, severe COVID‐19 disease: 69%). To investigate likelihood of HFpEF presence, we used the HFA‐PEFF score. A low (0‐1 points), intermediate (2‐4 points), and high (5‐6 points) HFA‐PEFF score was observed in 42%, 33%, and 25% of patients, respectively. In comparison, 64 subjects of similar age, sex, and comorbidity status without COVID‐19, showed these scores in 30%, 66%, and 4%, respectively (between groups: p=0.0002). High HFA‐PEFF scores were more frequent in COVID‐19 patients than controls (25% vs. 4%, p=0.001). In COVID‐19 patients, HFA‐PEFF score significantly correlated with age, estimated glomerular filtration rate, high sensitivity troponin T (hsTnT), haemoglobin, QTc interval, LVEF, mitral E/A ratio, and H(2)FPEF score (all p<0.05). In multivariate, ordinal regression analyses, higher age and hsTnT were significant predictors of increased HFA‐PEFF scores. Patients with myocardial injury (hsTnT ≥14 ng/L: 31%) vs. patients without myocardial injury, showed higher HFA‐PEFF scores (median 5 [IQR 3–6] vs. 1 [0–3], p<0.001) and more often showed LV diastolic dysfunction (75% vs. 27%, p<0.001). CONCLUSION: Hospitalised COVID‐19 patients frequently show high likelihood of presence of HFpEF that is associated with cardiac structural and functional alterations, and myocardial injury. Detailed cardiac assessments including echocardiographic determination of LV diastolic function and biomarkers should become routine in the care of hospitalised COVID‐19 patients. This article is protected by copyright. All rights reserved. COVID-19 is known to lead to myocardial damage and vascular injury in many patients. We hypothesised that a substantial proportion of patients with COVID-19 develop heart failure with preserved ejection fraction (HFpEF), and designed this study for further investigation. The clinical manifestations of COVID-19 disease range from none or mild symptoms to acute respiratory distress syndrome (ARDS) and death 1 . Despite respiratory symptoms, patients also present with chest pain, arrhythmias, palpitations, severe peripheral oedema and acute heart failure 2,3 . In particular, COVID-19 patients with cardiac disease compared to patients without cardiac disease more often have thromboembolic events 4 and demonstrate a higher mortality 5, 6 . In May 2020 Tavazzi et al. reported the first case of acute cardiac injury with the finding of SARS-CoV-2 particles and low-grade inflammation within the myocardium but not accompanied by cardiomyocyte necrosis 7 . Whether myocardial alterations are caused by direct viral damage to the heart or vasculature or by infection-related cytokine storm is still under debate 8 . Principally, viral-induced cardiac inflammatory alterations are known to be able to trigger myocarditis induced HFpEF and HFrEF, respectively 9 . There is growing interest in identifying COVID-19 patients at risk of developing viral-related heart failure and cardiovascular (CV) impairments 10 . From April to November 2020, we prospectively enrolled clinically stable COVID-19 patients at one of our COVID-19 wards (at the Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité-Universitätsmedizin, Campus Virchow-Klinikum, Berlin, Germany) into the observational Cohort Study Pa-COVID-19. 11 All patients gave written informed consent. The study was approved by the ethics committee of the Charité-Universitätsmedizin Berlin (EA2/066/20) and conducted in accordance with the Declaration of Helsinki. This article is protected by copyright. All rights reserved. We consecutively recruited 71 clinically stable COVID-19 patients in the first days following their admission to one of our COVID-19 wards at the Charité (average number of days since first symptoms until echocardiography and biomarker assessment 11 days [IQR [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] ). Six patients were found to have a reduced systolic left ventricular function (left ventricular ejection fraction [LVEF] < 50%, mean LVEF 35 ± 6%) and were therefore excluded from this analysis. Three patients had a transthoracic echocardiogram in the 12 months before their SARS-CoV-2 infection, with one patient showing pre-existing right ventricular dysfunction (TAPSE 12 mm, RV S' 0.06 m/s) with LVEF 50%, who was therefore excluded from the analysis. The final study cohort reported on here consists of 64 COVID-19 patients with an LVEF ≥ 50% without prior known heart failure. To compare the HFA-PEFF scores of the COVID-19 patients with that of patients without COVID-19, we included a control group of 64 patients from the Massachusetts General Hospital Cardiopulmonary Exercise Testing (CPET) cohort. Controls were consecutive patients with exertional dyspnoea and preserved ejection fraction (LVEF≥50%) but without a prior diagnosis of heart failure who were referred for clinically-indicated CPET and also had available echocardiographic and biomarker assessments to calculate HFA-PEFF scores 12 . From this sample of 121 individuals, we group-matched 64 controls for sex (primary matching criterion), age, and comorbidity distribution with the COVID-19 patient cohort. All patients gave written informed consent. The study was approved by the Massachusetts General Hospital's institutional review board (2010P001704) and conducted in accordance with the Declaration of Helsinki. All patients received a standard blood sample from an antecubital vein, and a 12channel resting electrocardiogram (ECG) and a transthoracic echocardiography (VIVID E95, GE Healthcare) were performed. Data on patients' clinical condition, comorbidities and drug therapy were collected from all patients, directly of from their history and medical records. Myocardial injury was defined as a high sensitivity troponin T (hsTnT) value exceeding the 99 th percentile of a normal reference population (≥ 14 ng/L) 13, 14 . Accepted Article 6 A complete standard echocardiographic examination, including gray-scale images for 2D strain analysis was performed. Offline analyses were conducted with a standard imaging software (EchoPAC SW 203, GE Healthcare). Left ventricular (LV) ejection fraction was calculated using the biplane Simpson´s method 15 , left atrial end-systolic volumes were obtained in the apical 4-chamber view according to Simpson's method. Post-processing analysis with speckle-tracking was conducted in the apical 4chamber, 2-chamber, and long axis views at a frame rate of 50 to 70 frames/s using automated function imaging (AFI). Global longitudinal strain (GLS) was calculated as the mean of all segmental strain values in the 3 apical views. Linear LV measurements as well as LV mass calculation were performed according to the recommendations of the American Society of Echocardiography and the European Association of Cardiovascular Imaging 16 . LV mass index and left atrium index were obtained by adjustment for body surface area according to DuBois formula. LV diastolic function was evaluated using: 1) the ratio of early transmitral flow velocity (E) to late transmitral flow velocity (A); 2) the mean (E/e' mean) of transmitral E to early diastolic medial LV tissue velocity (e′ septal) and the transmitral E to the early diastolic LV tissue velocity of the lateral wall (e' lateral). Right ventricular function was defined by the measurement of the tricuspid annular plane systolic excursion (TAPSE), and the tricuspid lateral annular systolic velocity (RV S′). Pulmonary artery systolic pressure (PASP) was obtained from the peak velocity of the tricuspid regurgitation jet derived by continuous wave Doppler, using the modified Bernoulli equation, plus the estimated right atrial pressure, obtained from the inferior vena cava size and its collapsibility. The HFA-PEFF score was calculated according to the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) recommendations. 17 It is composed of 4 steps (pre-test assessment, echocardiography and natriuretic peptide diagnostic score, functional testing, and final aetiology). According to the HFA-PEFF score the patients were divided into three risk groups for heart failure with preserved ejection fraction (HFpEF) probability: low (0-1 points, HFpEF unlikely), intermediate (2) (3) (4) HFpEF uncertain) , and high (5-6, HFpEF diagnosis). This article is protected by copyright. All rights reserved. The H 2 FPEF score was calculated according to Reddy et al. 18 , and derives from the integration of 4 clinical characteristics and 2 echocardiographic parameters. According to this score the diagnosis of HFpEF is ruled out with 0-1 points and highly likely in patients with 6-9 points. The probability of HFpEF is intermediate when the score is between 2-5 points. For statistical analyses we used IBM Statistical Package for the Social Sciences (SPSS) version 26.0 (IBM Co., Armonk, NY, USA). The collected data were presented as mean ± standard deviation or number of patients and percentage. Where mean ± standard deviation was not appropriate to summarize the distributions, median and interquartile range (IQR) were reported. We used unpaired t-test/ANOVA as parametric and Mann-Withney U-Test / Kruskal-Wallis test as nonparametric hypothesis tests. For the analysis of the contingency tables, we preferably used Chi-squared tests. If the contingency tables contained at least one cell assignment smaller than five, the Fisher´s Exact test was chosen 19 . We correlated the HFA-PEFF score with clinical relevant parameters from ECG, echocardiography, and blood parameters using rank based Spearman correlation (none of these clinical relevant parameters were used to calculate the HFA-PEFF score). All significant parameters from Spearman correlation analysis were included in a multivariate, ordinal regression analysis with logit link. Prior to multivariate, ordinal regression analysis, six missing "mitral E/A ratios" were imputed using the expectation maximization (EM) algorithm. For the two significant parameters from multivariate regression analysis (hsTnT and age) we conducted receiver operating characteristics (ROC) analysis for predicting a high HFA-PEFF score (5-6 points). The optimal cut-off value was chosen by maximizing Youden's index using the R package maxstat. 20,21 A p-value < 0.05 was considered statistically significant in all analyses. To compare the frequencies of HFA-PEFF scores (in the categories low, middle and high as well as low/middle and high) in COVID-19 patients and controls, chisquare tests were used. This article is protected by copyright. All rights reserved. The final study population included 64 COVID-19 patients. The mean age was 56 ± 19 years and 20 (31%) patients were females. 44 (69%) patients had severe COVID-19 pneumonia according to the current WHO definition 22 . Detailed baseline characteristics are shown in Table 1 . A total of 3 (5%) patients died during the hospitalization. All other patients were discharged by December 7 th , 2020 at the latest, with a median hospitalization duration of 10 days (inter quartile range 5-15 days). In our study we found that 42% of COVID-19 patients (n=27) had a low HFA-PEFF score, 33% (n=21) an intermediate score, and 25% (n=16) a high HFA-PEFF score ( Figure 1 ). All COVID-19 patients with a high HFA-PEFF score (n=16 [25%], "5-6 points") had arterial hypertension and 6 of these patients had atrial fibrillation ( Table 1) . Patients with high HFA-PEFF score ("5-6 points") had higher levels of hsTnT (+400% vs. "0-1 points on the HFA-PEFF score" and +213% vs. "2-4 points on the HFA-PEFF score", ANOVA p-value <0.001), lower levels of haemoglobin (-12% vs. "0-1 points" and -6% vs. "2-4 points", ANOVA p-value =0.032), lower estimated glomerular filtration rate (eGFR) (-31% vs. "0-1" points" and -20% vs. "2-4 points", ANOVA p-value <0.001), lower LVEF (-5% vs. "0-1 points" and -3% vs. "2-4 points", ANOVA p-value =0.014), and more often severe COVID-19 disease, diastolic dysfunction or right ventricular dysfunction. Among the 64 controls with mean age 5916 years and 39% female, 19 (30%) showed a low HFA-PEFF score, 42 (66%) had an intermediate score, and 3 (4%) had a high HFA-PEFF score (Figure 1 ). The frequency distribution of low/middle/high HFA-PEFF scores was different between COVID-19 patients and controls (chisquare p-value = 0.0002) and high HFA-PEFF scores were more frequent in COVID-19 patients than controls (25% vs. 4%, chisquare p-value = 0.001). Additionally, COVID-19 patients showed higher NT-proBNP values (+101%, p=0.002), and lower LVEF (-3%, p=0.013, Table 2 ). Spearman correlation analysis showed a positive association between the HFA-PEFF score and the following clinical parameters: age, eGFR, hsTnT, haemoglobin, leukocytes, QTc interval, LVEF, mitral E/A ratio, and additionally with the H 2 FPEF score. None of these parameters were used for the calculation of the HFA-PEFF score ( Table 3 ). In multivariate ordinal regression analyses, including the This article is protected by copyright. All rights reserved. aforementioned significant clinical parameters, age and hsTnt were significant predictors of the HFA-PEFF score (Table 4, Figure 2 ). If one of these parameters increased by one unit, the HFA-PEFF score increased by 0.06 points (age) or 0.13 points (hsTnt). Nagelkerke's R Square 23 was 0.60, indicative for a substantial goodness-of-fit of the multivariate model according to Cohen. 24 A chi-square was performed to test the difference between the -2 log-likelihood (-2LL) for the interceptonly model and the final model. The statistically significant chi-square statistic (p<0.0001) indicates that the final model gives a significant improvement over the baseline intercept-only model. Correlation coefficient between predicted response category and measured HFA-PEFF score was 0.72 (Spearman's rho). According to Landis and Koch 25 , this is a substantial agreement. For the two significant parameters from multivariate regression analysis (age and hsTnT), we conducted receiver operating characteristics (ROC) analysis for calculating the best cut-offs for predicting a high HFA-PEFF score (5-6 points; age: area under the curve 0.93 [0.87-1.00]; hsTnT: area under the curve 0.94 [0.89-1.00], p < 0.001). The best cut-off for predicting a high HFA-PEFF score regarding age was ≥62 years (sensitivity 94%, specificity 79%) and for hsTnT ≥10 ng/L (sensitivity 100%, specificity 79%, Figure 3 ). Patients with vs. without myocardial injury had higher HFA-PEFF scores (median 5 [IQR 3-6] vs. 1 [IQR 0-3], p<0.001), elevated levels of NT-proBNP (+455%, p<0.001) eGFR (-30%, p<0.001, Table 5 ). In echocardiographic examination, patients with myocardial injury demonstrated lower LVEF, more often diastolic dysfunction, and right ventricular dysfunction. In this study we describe for the first time using the HFA-PEFF score that a substantial proportion of COVID-19 patients showed higher risk of heart failure with preserved ejection fraction (HFpEF). The prevalence of a high HFA-PEFF score was increased in COVID-19 patients in comparison to controls. In multivariate, ordinal regression analyses, age, and hsTnT were significantly associated with a raised HFA-PEFF score. Amongst patients with biochemical evidence for myocardial injury, This article is protected by copyright. All rights reserved. HFA-PEFF score was higher and LV diastolic dysfunction and reduced global longitudinal strain were more prevalent. Based on these results using the HFA-PEFF algorithm during the acute phase of infection may facilitate the identification of COVID-19 patients with acute cardiac abnormalities compatible with HFpEF-like syndrome, as is also known for other inflammatory viral diseases. 26 In the last months, great efforts have been made to accomplish better characterization of the CV profile of COVID-19 patients, to define which factors may reveal CV complications, and how to manage CV care of these patients 27 . So far, CV risk factors like advanced age, male sex, arterial hypertension, and previous coronary artery disease have been frequently reported in COVID-19 patients admitted to hospital 28, 29, 30 . The presence of arterial hypertension in 43% of our patients is slightly higher than in other large, multi-centre studies conducted in China and United States where hypertension was observed in 24% 1 and 35% 31 of patients with COVID-19. HFpEF is a severe medical problem with currently limited therapeutic options. The HFA-PEFF score was recently developed to improve the diagnosis of HFpEF 17 . It has been validated in two different independent cohorts of 258 and 459 HFpEF patients 32 , describing a specificity of 93% and positive predictive value of 98% to rule in HFpEF with a high score, and a sensitivity of 99% and a negative predictive value of 73% to rule out HFpEF with a low score. The diagnostic accuracy in patients with ≥5 points was 0.90 (0.84-0.96, area under the curve of the ROC curve). Accordingly, we reasonably hypothesized the score might be helpful in the assessment of HFpEF been observed in about 20% of COVID-19 patients 37 . It has been shown that higher concentrations of cardiac biomarkers (NT-proBNP, hsTnI, hsTnT) correlate with severity of infection 38, 39 . A non-specific increase of cardiac enzymes in COVID-19 patients may reveal not only a predisposition of these patients to cardiac injury 40 , but also other cardiac dysfunctions 41 . In our study hsTnT was observed as a strong predictor of higher HFA-PEFF score. Accordingly, increased hsTnT in COVID-19 patients may help identifying COVID-19 induced cardiac diastolic aberrations. Whether myocardial injury is only temporary is unclear and therefore clinical follow-up studies of patients with myocardial injury are needed. Cardiac magnetic resonance (CMR) analysing and endomyocardial biopsy studies showed that in some COVID-19 or post-COVID-19 patients an ongoing cardiac inflammation can be detected 42,43,44 . This is in agreement with several echocardiographic parameters, detectable in those patients 4546 . The time for cardiac depolarization and repolarization (QTc interval) was prolonged in COVID-19 patients with an intermediate or high HFA-PEFF score. In general, a QTc prolongation is associated with a higher risk for ventricular arrhythmias and sudden cardiac death 47 . Arrhythmias and QTc prolongation are known to occur in COVID-19 patients. 48 Our finding does not necessarily belong directly to key features of LV diastolic dysfunction in COVID-19 induced HFpEF, but could be an indicator of cardiac damage induced by COVID-19 induced cardiac inflammatory stress responses as known for myocarditis and ischemia, respectively 49 . Guo et al. 50 have shown in 187 hospitalized COVID-19 patients that malignant arrhythmias occurred in 7% of patients and were more frequently in patients with vs. without myocardial injury (12% vs. 5%, p<0.001). Hence, the HFA-PEFF score could also be useful and important in detecting COVID-19 patients more vulnerable to malignant arrhythmias. In this COVID-19 cohort, the in-hospital mortality rate was at 5% (3/64 patients). There are several reasons for this low mortality: first of all, the overall mortality rate during the study period in patients in Germany with a SARS-CoV-2 infection was also low at about 2-5% 51 . Secondly, even though all our patients were hospitalized, we only included clinically stable patients on a normal COVID-19 ward and examined no patients in an intermediate or intensive care unit. Lastly, as explained in the methods section, six patients with LVEF <50% and one patient with previously known right ventricular dysfunction were excluded from the study (two of these seven patients died during hospitalisation). If these patients would have been included in the analysis, the in-hospital mortality rate would have been at 7%. This in-hospital mortality rate is comparable to that found by others in Germany 52 , when looking at hospitalized COVID-19 patients not treated in an intensive care unit (156 deaths in 1,856 patients, i.e. 8%). Limitations: Our main limitation is the relatively small sample size of 64 COVID-19 patients, but all patients were included prospectively and with detailed echocardiography assessment, which is more complicated to perform in COVID-19 patients than usual, due to the required protection measures for the investigator. Only few patients had ever received an echocardiogram before their current COVID-19 hospitalization (n=3) and hence a comparison to previous echocardiograms was not possible. The reason for this is that in none of the included 64 COVID-19 patients, HFpEF had ever been suspected or diagnosed before. We could only apply step 2 of the HFA-PEFF algorithm in all patients. Since the HFA-PEFF score has not been used in COVID-19 patients before, we did not rule out patients with step 1 (i.e. pretest assessment), and could not apply step 3 (i.e. stress echocardiography for patients with intermediate scores to secure a final diagnosis of HFpEF) and step 4 (i.e. identify the specific aetiology for HFpEF). The HFA-PEFF score algorithm was assessed during the acute phase of COVID-19 infection. For this setting, the score has not been originally developed. Nevertheless, we believe that our results are representative for the CV profile of clinically stable COVID-19 patients treated in a normal COVID-19 ward despite the small sample size. We cannot know for sure from our analysis, whether HFpEF and COVID-19 are truly related and whether some of the COVID-19 patients already had an elevated HFA-PEFF score before their COVID-19 infection, also given that patients with high HFA-PEFF score were older and all suffered from arterial hypertension, but compared to our control group (with similar age, sex, and comorbidity status), a high HFA-PEFF score was seen more often in COVID-19 patients than controls. It is possible, that patients had Normal distributed variables are presented as means ± SD, non-paramentric variables as median (interquartile range) and nominal variables as %. The abbreviations are explained in Table 1 . Link function: Logit. Correlation coefficient between predicted response category and measured HFA-PEFF score: 0.72 (Spearman's rho). *the Estimate gives the increase or decrease of the HFA-PEFF score, if the given parameter increased by one unit. The abbreviations are explained in Table 1 . Accepted Article 15 Normal distributed variables are presented as means ± SD, non-parametric variables as median (interquartile range) and nominal variables as %. The abbreviations are explained in Table 1 . This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. Zhong NS; China Medical Treatment Expert Group for Covid-19. 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