Prophylactic rivaroxaban in the early post-discharge period reduces the rates of hospitalization for atrial fibrillation and incidence of sudden cardiac death during long-term follow-up in hospitalized COVID-19 survivors.

Introduction: While acute Coronavirus disease 2019 (COVID-19) affects the cardiovascular (CV) system according to recent data, an increased CV risk has been reported also during long-term follow-up (FU). In addition to other CV pathologies in COVID-19 survivors, an enhanced risk for arrhythmic events and sudden cardiac death (SCD) has been observed. While recommendations on post-discharge thromboprophylaxis are conflicting in this population, prophylactic short-term rivaroxaban therapy after hospital discharge showed promising results. However, the impact of this regimen on the incidence of cardiac arrhythmias has not been evaluated to date. Methods: To investigate the efficacy of this therapy, we conducted a single center, retrospective analysis of 1804 consecutive, hospitalized COVID-19 survivors between April and December 2020. Patients received either a 30-day post-discharge thromboprophylaxis treatment regimen using rivaroxaban 10 mg every day (QD) (Rivaroxaban group (Riva); n = 996) or no thromboprophylaxis (Control group (Ctrl); n = 808). Hospitalization for new atrial fibrillation (AF), new higher-degree Atrioventricular-block (AVB) as well as incidence of SCD were investigated in 12-month FU [FU: 347 (310/449) days]. Results: No differences in baseline characteristics (Ctrl vs Riva: age: 59.0 (48.9/66.8) vs 57 (46.5/64.9) years, p = n.s.; male: 41.5% vs 43.7%, p = n.s.) and in the history of relevant CV-disease were observed between the two groups. While hospitalizations for AVB were not reported in either group, relevant rates of hospitalizations for new AF (0.99%, n = 8/808) as well as a high rate of SCD events (2.35%, n = 19/808) were seen in the Ctrl. These cardiac events were attenuated by early post-discharge prophylactic rivaroxaban therapy (AF: n = 2/996, 0.20%, p = 0.026 and SCD: n = 3/996, 0.30%, p < 0.001) which was also observed after applying a logistic regression model for propensity score matching (AF: χ 2-statistics = 6.45, p = 0.013 and SCD: χ 2-statistics = 9.33, p = 0.002). Of note, no major bleeding complications were observed in either group. Conclusion: Atrial arrhythmic and SCD events are present during the first 12 months after hospitalization for COVID-19. Extended prophylactic Rivaroxaban therapy after hospital discharge could reduce new onset of AF and SCD in hospitalized COVID-19 survivors.

Impact of cavotricuspid isthmus ablation for typical atrial flutter and heart failure in the elderly-results of a retrospective multi-center study.

Introduction: While in the CASTLE-AF trial, in patients with atrial fibrillation and heart failure with reduced ejection fraction, interventional therapy using pulmonary vein isolation was associated with outcome improvement, data on cavotricuspid isthmus ablation (CTIA) in atrial flutter (AFL) in the elderly is rare. Methods: We included 96 patients between 60 and 85 years with typical AFL and heart failure with reduced or mildly reduced ejection fraction (HFrEF/HFmrEF) treated in two medical centers. 48 patients underwent an electrophysiological study with CTIA, whereas 48 patients received rate or rhythm control and guideline-compliant heart failure therapy. Patients were followed up for 2 years, with emphasis on left ventricular ejection fraction (LVEF) over time. Primary endpoints were cardiovascular mortality and hospitalization for cardiac causes. Results: Patients with CTIA showed a significant increase in LVEF after 1 (p < 0.001) and 2 years (p < 0.001) in contrast to baseline LVEF. Improvement of LVEF in the CTIA group was associated with significantly lower 2-year mortality (p = 0.003). In the multivariate regression analysis, CTIA remained the relevant factor associated with LVEF improvement (HR: 2.845 CI:95% 1.044-7.755; p = 0.041). Elderly patients (≥ 70 years) further benefited from CTIA, since they showed a significantly reduced rehospitalization (p = 0.042) and mortality rate after 2 years (p = 0.013). Conclusions: CTIA in patients with typical AFL and HFrEF/HFmrEF was associated with significant improvement of LVEF and reduced mortality rates after 2 years. Patient age should not be a primary exclusion criterion for CTIA, since patients ≥70 years also seem to benefit from intervention in terms of mortality and hospitalization.

Effects of Angiotensin Receptor-Neprilysin Inhibitors (ARNIs) on the Glucose and Fat Metabolism Biomarkers Leptin and Fructosamine.

(1) Background: Heart failure with reduced ejection fraction (HFrEF) remains a major health burden. Angiotensin-Receptor-Neprilysin-Inhibitors (ARNIs) are an established HFrEF therapy which increases natriuretic peptide levels by inhibiting neprilysin. Leptin is a lipid metabolism parameter, which is also involved in glucose metabolism and is suggested to correlate with HF burden. While the hormone also seems to interact with neprilysin, potential associations with ARNI therapy have not been investigated yet. (2) Methods: To study this issue, we measured levels of leptin and fructosamine in consecutive 72 HFrEF patients before initiation of ARNI therapy and 3-6 months after initiation of therapy in two European centers. Biomarker levels were correlated with clinical parameters including ejection fraction, LVEF, and NYHA class. (3) Results: During a follow-up of up to 6 months, clinical parameters improved significantly (LVEF: 30.2 ± 7.8% to 37.6 ± 10.0%, (p < 0.001) and a significant improvement of the mean NYHA class with initial 32 patients in NYHA III or IV and 8 patients in NYHA class III/IV during the follow up (p < 0.001). The initial NT-proBNP levels of 2251.5 ± 2566.8 pg/mL significantly improved to 1416.7 ± 2145 pg/mL, p = 0.008) during follow up. ARNI therapy was also associated with an increase in leptin levels (17.5 ± 23.4 µg/L to 22.9 ± 29.3, p < 0.001) and furthermore, affected glucose metabolism indicated by elevation of fructosamine values (333.9 ± 156.8 µmol/L to 454.8 ± 197.8 µmol/L, p = 0.013). (4) Conclusion: while in the early phase of therapy, ARNI promotes clinical improvement of HFrEF, and it also seems to affect fat and glucose parameters, indicating significant metabolic implications of this therapy regime.

Investigation of hs-TnI and sST-2 as Potential Predictors of Long-Term Cardiovascular Risk in Patients with Survived Hospitalization for COVID-19 Pneumonia.

Introduction: COVID-19 survivors reveal an increased long-term risk for cardiovascular disease. Biomarkers like troponins and sST-2 improve stratification of cardiovascular risk. Nevertheless, their prognostic value for identifying long-term cardiovascular risk after having survived COVID-19 has yet to be evaluated. Methods: In this single-center study, admission serum biomarkers of sST-2 and hs-TnI in a single cohort of 251 hospitalized COVID-19 survivors were evaluated. Concentrations were correlated with major cardiovascular events (MACE) defined as cardiovascular death and/or need for cardiovascular hospitalization during follow-up after hospital discharge [FU: 415 days (403; 422)]. Results: MACE was a frequent finding during FU with an incidence of 8.4% (cardiovascular death: 2.8% and/or need for cardiovascular hospitalization: 7.2%). Both biomarkers were reliable indicators of MACE (hs-TnI: sensitivity = 66.7% & specificity = 65.7%; sST-2: sensitivity = 33.3% & specificity = 97.4%). This was confirmed in a multivariate proportional-hazards analysis: besides age (HR = 1.047, 95% CI = 1.012−1.084, p = 0.009), hs-TnI (HR = 4.940, 95% CI = 1.904−12.816, p = 0.001) and sST-2 (HR = 10.901, 95% CI = 4.509−29.271, p < 0.001) were strong predictors of MACE. The predictive value of the model was further improved by combining both biomarkers with the factor age (concordance index hs-TnI + sST2 + age = 0.812). Conclusion: During long-term FU, hospitalized COVID-19 survivors, hs-TnI and sST-2 at admission, were strong predictors of MACE, indicating both proteins to be involved in post-acute sequelae of COVID-19.

Early antithrombotic post-discharge therapy using prophylactic DOAC or dipyridamole improves long-term survival and cardiovascular outcomes in hospitalized COVID-19 survivors.

Introduction: Cardiovascular events are common in COVID-19. While the use of anticoagulation during hospitalization has been established in current guidelines, recommendations regarding antithrombotic therapy in the post-discharge period are conflicting. Methods: To investigate this issue, we conducted a retrospective follow-up (393 ± 87 days) of 1,746 consecutive patients, hospitalized with and surviving COVID-19 pneumonia at a single tertiary medical center between April and December 2020. Survivors received either 30-day post-discharge antithrombotic treatment regime using prophylactic direct oral anticoagulation (DOAC; n = 1,002) or dipyridamole (n = 304), or, no post-discharge antithrombotic treatment (Ctrl; n = 440). All-cause mortality, as well as cardiovascular mortality (CVM) and further cardiovascular outcomes (CVO) resulting in hospitalization due to pulmonary embolism (PE), myocardial infarction (MI) and stroke were investigated during the follow-up period. Results: While no major bleeding events occured during follow-up in the treatment groups, Ctrl showed a high but evenly distributed rate all-cause mortality. All-cause mortality (CVM) was attenuated by prophylactic DOAC (0.6%, P < 0.001) and dipyridamole (0.7%, P < 0.001). This effect was also evident for both therapies after propensity score analyses using weighted binary logistic regression [DOAC: B = -3.33 (0.60), P < 0.001 and dipyridamole: B = -3.04 (0.76), P < 0.001]. While both treatment groups displayed a reduced rate of CVM [DOAC: B = -2.69 (0.74), P < 0.001 and dipyridamole: B = -17.95 (0.37), P < 0.001], the effect in the DOAC group was driven by reduction of both PE [B-3.12 (1.42), P = 0.012] and stroke [B = -3.08 (1.23), P = 0.028]. Dipyridamole significantly reduced rates of PE alone [B = -17.05 (1.01), P < 0.001]. Conclusion: Late cardiovascular events and all-cause mortality were high in the year following hospitalization for COVID-19. Application of prophylactic DOAC or dipyridamole in the early post-discharge period improved mid- and long-term CVO and all-cause mortality in COVID-19 survivors.

Cardiovascular Biomarkers for Prediction of in-hospital and 1-Year Post-discharge Mortality in Patients With COVID-19 Pneumonia.

Aims: While COVID-19 affects the cardiovascular system, the potential clinical impact of cardiovascular biomarkers on predicting outcomes in COVID-19 patients is still unknown. Therefore, to investigate this issue we analyzed the prognostic potential of cardiac biomarkers on in-hospital and long-term post-discharge mortality of patients with COVID-19 pneumonia. Methods: Serum soluble ST2, VCAM-1, and hs-TnI were evaluated upon admission in 280 consecutive patients hospitalized with COVID-19-associated pneumonia in a single, tertiary care center. Patient clinical and laboratory characteristics and the concentration of biomarkers were correlated with in-hospital [Hospital stay: 11 days (10; 14)] and post-discharge all-cause mortality at 1 year follow-up [FU: 354 days (342; 361)]. Results: 11 patients died while hospitalized for COVID-19 (3.9%), and 11 patients died during the 1-year post-discharge follow-up period (n = 11, 4.1%). Using multivariate analysis, VCAM-1 was shown to predict mortality during the hospital period (HR 1.081, CI 95% 1.035;1.129, p = 0.017), but not ST2 or hs-TnI. In contrast, during one-year FU post hospital discharge, ST2 (HR 1.006, 95% CI 1.002;1.009, p < 0.001) and hs-TnI (HR 1.362, 95% CI 1.050;1.766, p = 0.024) predicted mortality, although not VCAM-1. Conclusion: In patients hospitalized with Covid-19 pneumonia, elevated levels of VCAM-1 at admission were associated with in-hospital mortality, while ST2 and hs-TnI might predict post-discharge mortality in long term follow-up.

Gender-Specific Differences in the Intensive Care Treatment of COVID-19 Patients.

BACKGROUND: Gender-specific differences in the outcome of COVID-19 patients requiring intensive care treatment have been reported. However, a potential association with ICU therapy remains elusive. METHODS: A total of 224 consecutive patients (63 women) treated for severe COVID-19 disease requiring mechanical ventilation were screened for the study. After propensity score matching for gender, 40 men and 40 women were included in the study. Comparative analysis was conducted for laboratory parameters, ICU therapy and complications (pulmonary embolism, thrombosis, stroke, and ventricular arrhythmias), and outcome (mortality). RESULTS: Male patients had significantly higher levels of CRP (p = 0.012), interleukin-6 (p = 0.020) and creatinine (p = 0.027), while pH levels (p = 0.014) were significantly lower compared to females. Male patients had longer intubation times (p = 0.017), longer ICU stays (p = 0.022) and higher rates of catecholamine dependence (p = 0.037). Outcome, complications and ICU therapy did not differ significantly between both groups. CONCLUSION: The present study represents the first matched comparison of male and female COVID-19 patients requiring intensive care treatment. After propensity matching, male patients still displayed a higher disease severity. This was reflected in higher rates of vasopressors, duration of ICU stay and duration of intubation. In contrast, no significant differences were observed in mortality rates, organ replacement therapy and complications during ICU stay.

Sustained Impairment in Cardiopulmonary Exercise Capacity Testing in Patients after COVID-19: A Single Center Experience.

Background: Following COVID-19, patients often present with ongoing symptoms comparable to chronic fatigue and subjective deterioration of exercise capacity (EC), which has been recently described as postacute COVID-19 syndrome. Objective: To objectify the reduced EC after COVID-19 and to evaluate for pathologic limitations. Methods: Thirty patients with subjective limitation of EC performed cardiopulmonary exercise testing (CPET). If objectively limited in EC or deteriorated in oxygen pulse, we offered cardiac stress magnetic resonance imaging (MRI) and a follow-up CPET. Results: Eighteen male and 12 female patients were included. Limited relative EC was detected in 11/30 (36.7%) patients. Limitation correlated with reduced body weight-indexed peak oxygen (O2) uptake (peakV̇O2/kg) (mean 74.7 (±7.1) % vs. 103.6 (±14.9) %, p < 0.001). Reduced peakV̇O2/kg was found in 18/30 (60.0%) patients with limited EC. Patients with reduced EC widely presented an impaired maximum O2 pulse (75.7% (±5.6) vs. 106.8% (±13.9), p < 0.001). Abnormal gas exchange was absent in all limited EC patients. Moreover, no patient showed signs of reduced pulmonary perfusion. Using cardiac MRI, diminished biventricular ejection fraction was ruled out in 16 patients as a possible cause for reduced O2 pulse. Despite noncontrolled training exercises, follow-up CPET did not reveal any exercise improvements. Conclusions: Deterioration of EC was not associated with ventilatory or pulmonary vascular limitation. Exercise limitation was related to both reduced O2 pulse and peakV̇O2/kg, which, however, did not correlate with the initial severity of COVID-19. We hypothesize that impaired microcirculation or limited peripheral O2 utilization might be causative for prolonged deterioration of EC following acute COVID-19 infection.

Dexamethasone Improves Cardiovascular Outcomes in Critically Ill COVID-19, a Real World Scenario Multicenter Analysis.

BACKGROUND: Severe COVID-19 pneumonia requiring intensive care treatment remains a clinical challenge to date. Dexamethasone was reported as a promising treatment option, leading to a reduction of mortality rates in severe COVID-19 disease. However, the effect of dexamethasone treatment on cardiac injury and pulmonary embolism remains largely elusive. METHODS: In total 178 critically ill COVID-19 patients requiring intensive care treatment and mechanical ventilation were recruited in three European medical centres and included in the present retrospective study. One hundred thirteen patients (63.5%) were treated with dexamethasone for a median duration of 10 days (IQR 9-10). Sixty five patients (36.5%) constituted the non-dexamethasone control group. RESULTS: While peak inflammatory markers were reduced by dexamethasone treatment, the therapy also led to a significant reduction in peak troponin levels (231 vs. 700% indicated as relative to cut off value, p = 0.001). Similar, dexamethasone resulted in significantly decreased peak D-Dimer levels (2.16 mg/l vs. 6.14 mg/l, p = 0.002) reflected by a significant reduction in pulmonary embolism rate (4.4 vs. 20.0%, p = 0.001). The antithrombotic effect of dexamethasone treatment was also evident in the presence of therapeutic anticoagulation (pulmonary embolism rate: 6 vs. 34.4%, p < 0.001). Of note, no significant changes in baseline characteristics were observed between the dexamethasone and non-dexamethasone group. CONCLUSION: In severe COVID-19, anti-inflammatory effects of dexamethasone treatment seem to be associated with a significant reduction in myocardial injury. Similar, a significant decrease in pulmonary embolism, independent of anticoagulation, was evident, emphasizing the beneficial effect of dexamethasone treatment in severe COVID-19.

A new player in the game: treatment with antagomiR-21a-5p significantly attenuates histological and echocardiographic effects of experimental autoimmune myocarditis.

AIMS: Myocarditis is associated with formidable symptoms and increased risk of adverse outcomes. Current approaches mostly rely on symptomatic treatments, warranting novel concepts for clinical practice. The aim of this study was to investigate the microRNA (miRNA) expression profile of Balb/c mice with experimental autoimmune myocarditis (EAM), choose a representative miRNA to antagonize after review of available literature and test its effects on myocardial inflammation in vitro and in vivo. METHODS AND RESULTS: Phase 1: EAM was induced in 12 male Balb/c mice, 10 animals served as controls. After sacrifice, next-generation sequencing (NGS) of the miRNA expression profile was performed. Based on these results, H9C2 cells and human ventricular cardiac fibroblasts exposed to lipopolysaccharide (LPS) were treated with the selected candidate antagomiR-21a-5p. Phase 2: EAM was induced in 48 animals. Thereof, 24 animals were either treated with antagomiR-21a-5p or negative control oligonucleotide in a nanoparticle formulation. Transthoracic echocardiography (TTE) was performed on Days 0, 7, 14, and 21. Histopathological examination was performed after sacrifice. Phase 1: EAM resulted in a significant up-regulation of 27 miRNAs, including miR-21a-5p (log2FC: 2.23, adj. P = 0.0026). Transfection with antagomiR-21a-5p resulted in a significant reduction of TNFα, IL-6, and collagen I in vitro. Phase 2: Treatment with antagomiR-21a-5p, formulated in polymeric nanoparticles for systemic injection, significantly attenuated myocardial inflammation (P = 0.001) and fibrosis (P = 0.013), as well as myocardial 'hypertrophy' on TTE. CONCLUSIONS: Silencing of miR-21a-5p results in a significant reduction of the expression of pro-inflammatory cytokines in vitro, as well as a significant attenuation of inflammation, fibrosis and echocardiographic effects of EAM in vivo.

Higher Incidence of Stroke in Severe COVID-19 Is Not Associated With a Higher Burden of Arrhythmias: Comparison With Other Types of Severe Pneumonia.

Aims: Thromboembolic events, including stroke, are typical complications of COVID-19. Whether arrhythmias, frequently described in severe COVID-19, are disease-specific and thus promote strokes is unclear. We investigated the occurrence of arrhythmias and stroke during rhythm monitoring in critically ill patients with COVID-19, compared with severe pneumonia of other origins. Methods and Results: This retrospective study included 120 critically ill patients requiring mechanical ventilation in three European tertiary hospitals, including n =60 COVID-19, matched according to risk factors for the occurrence of arrhythmias in n = 60 patients from a retrospective consecutive cohort of severe pneumonia of other origins. Arrhythmias, mainly atrial fibrillation (AF), were frequent in COVID-19. However, when compared with non-COVID-19, no difference was observed with respect to ventricular tachycardias (VT) and relevant bradyarrhythmias (VT 10.0 vs. 8.4 %, p = ns and asystole 5.0 vs. 3.3%, p = ns) with consequent similar rates of cardiopulmonary resuscitation (6.7 vs. 10.0%, p = ns). AF was even more common in non-COVID-19 (AF 18.3 vs. 43.3%, p = 0.003; newly onset AF 10.0 vs. 30.0%, p = 0.006), which resulted in a higher need for electrical cardioversion (6.7 vs. 20.0%, p = 0.029). Despite these findings and comparable rates of therapeutic anticoagulation (TAC), the incidence of stroke was higher in COVID-19 (6.7.% vs. 0.0, p = 0.042). These events also happened in the absence of AF (50%) and with TAC (50%). Conclusions: Arrhythmias were common in severe COVID-19, consisting mainly of AF, yet less frequent than in matched pneumonia of other origins. A contrasting higher incidence of stroke independent of arrhythmias also observed with TAC, seems to be an arrhythmia-unrelated disease-specific feature of COVID-19.

Analysis of Selected Cardiovascular Biomarkers in Takotsubo Cardiomyopathy and the Most Frequent Cardiomyopathies.

Introduction: Among the causes of de novo diagnosed cardiomyopathy, Takotsubo cardiomyopathy (TTC) plays a minor role, with an occurrence of 50,000-100,000 cases per annum in the United States. In clinical practice, a differentiation of a TTC toward an ischemic cardiomyopathy (ICMP) or a dilatative cardiomyopathy (DCMP) appears to be challenging, especially in a subacute setting or in atypical types of TTC. Methods: To investigate this issue, we analyzed serum levels of sST2, GDF-15, suPAR, HFABP, and clinical parameters including echocardiography in 51 patients with TTC, 52 patients with ischemic cardiomyopathy (ICMP) and 65 patients with dilated cardiomyopathy (DCMP). Results: sST-2 seemed to be the most promising biomarker for prediction of a TTC in differential diagnosis to an ICMP (AUC: 0.879, p = < 0.001, Cut off values: 12,140.5 pg/ml) or to a DCMP (AUC: 0.881, p = < 0.001, cut off value: 14521.9 pg/ml). GDF-15 evidenced a slightly lower AUC for prediction of a TTC in differential diagnosis to an ICMP (AUC: 0.626, p = 0.028) and to a DCMP (AUC: 0.653, p = 0.007). A differential diagnostic value was found for H-FABP in the prediction of a DCMP compared to TTC patients (AUC: 0.686, p = < 0.001). In propensity score matching for left ventricular ejection fraction, sex, and cardiovascular risk factors, differences in the plasma levels of sST2 and H-FABP in the matched cohort of TTC vs. DCMP remained statistically significant. In the matched cohort of TTC vs. ICMP, differences in sST2 also remained statistically significant Conclusion: As medical therapy, long term prognosis, interval of follow-ups, rehabilitation program and recommendations differ completely between TTC and ICMP/DCMP, biomarkers for differential diagnosis, or rather for confirmation of diagnosis, are warranted in cases of cardiomyopathies with unsure origin. sST-2, GDF-15 and H-FABP might facilitate the classification.

Soluble suppression of tumorigenicity 2 as outcome predictor after cardiopulmonary resuscitation: an observational prospective study.

Prognostication after cardiopulmonary resuscitation (CPR) is complex. Novel biomarkers like soluble suppression of tumorigenicity 2 (sST2) may provide an objective approach. A total of 106 post-CPR patients were included in this single-center observational prospective study. Serum sST2 levels were obtained 24 h after admission. Individuals were assigned to two groups: patients below and above the overall cohort's median sST2 concentration. Primary outcome was a combined endpoint at 6 months (death or Cerebral Performance Category > 2); secondary endpoint 30-day mortality. A uni- and multivariate logistic regression analysis were conducted. Elevated sST2-levels were associated with an increased risk for the primary outcome (OR 1.011, 95% CI 1.004-1.019, p = 0.004), yet no patients with poor neurological outcome were observed at 6 months. The optimal empirical cut-off for sST2 was 46.15 ng/ml (sensitivity 81%, specificity 53%, AUC 0.69). Levels above the median (> 53.42 ng/ml) were associated with higher odds for both endpoints (death or CPC > 2 after 6 months: 21% vs. 49%, OR 3.59, 95% CI 1.53-8.45, p = 0.003; death after 30 days: 17% vs. 43.3%, OR 3.75, 95% CI 1.52-9.21, p = 0.003). A positive correlation of serum sST2 after CPR with mortality at 30 days and 6 months after cardiac arrest could be demonstrated.

J-waves in acute COVID-19: A novel disease characteristic and predictor of mortality?

BACKGROUND: J-waves represent a common finding in routine ECGs (5-6%) and are closely linked to ventricular tachycardias. While arrhythmias and non-specific ECG alterations are a frequent finding in COVID-19, an analysis of J-wave incidence in acute COVID-19 is lacking. METHODS: A total of 386 patients consecutively, hospitalized due to acute COVID-19 pneumonia were included in this retrospective analysis. Admission ECGs were analyzed, screened for J-waves and correlated to clinical characteristics and 28-day mortality. RESULTS: J-waves were present in 12.2% of patients. Factors associated with the presence of J-waves were old age, female sex, a history of stroke and/or heart failure, high CRP levels as well as a high BMI. Mortality rates were significantly higher in patients with J-waves in the admission ECG compared to the non-J-wave cohort (J-wave: 14.9% vs. non-J-wave 3.8%, p = 0.001). After adjusting for confounders using a multivariable cox regression model, the incidence of J-waves was an independent predictor of mortality at 28-days (OR 2.76 95% CI: 1.15-6.63; p = 0.023). J-waves disappeared or declined in 36.4% of COVID-19 survivors with available ECGs for 6-8 months follow-up. CONCLUSION: J-waves are frequently and often transiently found in the admission ECG of patients hospitalized with acute COVID-19. Furthermore, they seem to be an independent predictor of 28-day mortality.

Analysis of Metabolic Markers in Patients with Chronic Heart Failure before and after LVAD Implantation.

Chronic heart failure (HF) is a clinical syndrome characterized by functional impairments of the myocardium. Metabolic and clinical changes develop with disease progression. In an advanced state, left ventricular assist devices (LVADs) are implanted for mechanical unloading. Our study aimed to assess the effects of LVAD implantation on the metabolic phenotypes and their potential to reverse the latter in patients with advanced HF. Plasma metabolites were analyzed by LC-MS/MS in 20 patients with ischemic cardiomyopathy (ICM), 20 patients with dilative cardiomyopathy (DCM), and 20 healthy controls. Samples were collected in HF patients before, 30 days after, and >100 days after LVAD implantation. Out of 188 measured metabolites, 63 were altered in HF. Only three metabolites returned to pre-LVAD concentrations 100 days after LVAD implantation. Pre-LVAD differences between DCM and ICM were mainly observed for amino acids and biogenic amines. This study shows a reversal of metabolite abnormalities in HF as a result of LVAD implantation. The etiology of the underlying disease plays an essential role in defining which specific metabolic parameter is altered in HF and reversed by LVAD implantation. Our findings provide a detailed insight into the disease pattern of ICM and DCM and the potential for reversibility of metabolic abnormalities in HF.

Myocardial injury in severe COVID-19 is similar to pneumonias of other origin: results from a multicentre study.

AIMS: COVID-19, a respiratory viral disease causing severe pneumonia, also affects the heart and other organs. Whether its cardiac involvement is a specific feature consisting of myocarditis, or simply due to microvascular injury and systemic inflammation, is yet unclear and presently debated. Because myocardial injury is also common in other kinds of pneumonias, we investigated and compared such occurrence in severe pneumonias due to COVID-19 and other causes. METHODS AND RESULTS: We analysed data from 156 critically ill patients requiring mechanical ventilation in four European tertiary hospitals, including all n = 76 COVID-19 patients with severe disease course requiring at least ventilatory support, matched to n = 76 from a retrospective consecutive patient cohort of severe pneumonias of other origin (matched for age, gender, and type of ventilator therapy). When compared to the non-COVID-19, mortality (COVID-19 = 38.2% vs. non-COVID-19 = 51.3%, P = 0.142) and impairment of systolic function were not significantly different. Surprisingly, myocardial injury was even more frequent in non-COVID-19 (96.4% vs. 78.1% P = 0.004). Although inflammatory activity [C-reactive protein (CRP) and interleukin-6] was indifferent, d-dimer and thromboembolic incidence (COVID-19 = 23.7% vs. non-COVID-19 = 5.3%, P = 0.002) driven by pulmonary embolism rates (COVID-19 = 17.1% vs. non-COVID-19 = 2.6%, P = 0.005) were higher. CONCLUSIONS: Myocardial injury was frequent in severe COVID-19 requiring mechanical ventilation, but still less frequent than in similarly severe pneumonias of other origin, indicating that cardiac involvement may not be a specific feature of COVID-19. While mortality was also similar, COVID-19 is characterized with increased thrombogenicity and high pulmonary embolism rates.

COVID-19 among heart transplant recipients in Germany: a multicenter survey.

AIMS: Heart transplantation may represent a particular risk factor for severe coronavirus infectious disease 2019 (COVID-19) due to chronic immunosuppression and frequent comorbidities. We conducted a nation-wide survey of all heart transplant centers in Germany presenting the clinical characteristics of heart transplant recipients with COVID-19 during the first months of the pandemic in Germany. METHODS AND RESULTS: A multicenter survey of all heart transplant centers in Germany evaluating the current status of COVID-19 among adult heart transplant recipients was performed. A total of 21 heart transplant patients with COVID-19 was reported to the transplant centers during the first months of the pandemic in Germany. Mean patient age was 58.6 ± 12.3 years and 81.0% were male. Comorbidities included arterial hypertension (71.4%), dyslipidemia (71.4%), diabetes mellitus (33.3%), chronic kidney failure requiring dialysis (28.6%) and chronic-obstructive lung disease/asthma (19.0%). Most patients received an immunosuppressive drug regimen consisting of a calcineurin inhibitor (71.4%), mycophenolate mofetil (85.7%) and steroids (71.4%). Eight of 21 patients (38.1%) displayed a severe course needing invasive mechanical ventilation. Those patients showed a high mortality (87.5%) which was associated with right ventricular dysfunction (62.5% vs. 7.7%; p = 0.014), arrhythmias (50.0% vs. none; p = 0.012), and thromboembolic events (50.0% vs. none; p = 0.012). Elevated high-sensitivity cardiac troponin T- and N-terminal prohormone of brain natriuretic peptide were significantly associated with the severe form of COVID-19 (p = 0.017 and p < 0.001, respectively). CONCLUSION: Severe course of COVID-19 was frequent in heart transplanted patients. High mortality was associated with right ventricular dysfunction, arrhythmias, thromboembolic events, and markedly elevated cardiac biomarkers.

Characterization of dendritic cells in human and experimental myocarditis.

AIMS: Dendritic cells (DCs) are central mediators of adaptive immunity, and there is growing evidence of their role in myocardial inflammatory disease. We hypothesized that plasmacytoid and myeloid DCs are involved in the mechanisms of myocarditis and analysed these two main subtypes in human myocarditis subjects, as well as in a murine model of experimental autoimmune myocarditis (EAM). METHODS AND RESULTS: Circulating DCs were analysed by flow cytometry in patients with acute myocarditis, dilated cardiomyopathy, and controls. Myocardial biopsies were immunostained for the presence of DCs and compared with non-diseased controls. In a mouse model of acute myocarditis induced through synthetic cardiac myosine peptide injection, effects of immunomodulation including DC inhibition through MCS-18 versus placebo treatment were tested at the peak of inflammation (Day 21), as well as 1 week later (partial recovery). Circulatory pDCs and mDCs were significantly reduced in myocarditis patients compared with controls (P < 0.01 for both) and remained so even after 6 months of follow-up. Human myocarditis biopsies showed accumulation of pDCs (two-fold CD304+/three-fold CD123+, all P < 0.05) compared with controls. Myocardial pDCs and mDCs accumulated in EAM (P for both <0.0001). MCS-18 treatment reduced pDC levels (P = 0.009), reduced myocardial inflammation (myocarditis score reduction from 2.6 to 1.8, P = 0.026), and improved ejection fraction (P = 0.03) in EAM at Day 21 (peak of inflammation). This effect was not observed during the partial recovery of inflammation on Day 28. CONCLUSIONS: Circulating DCs are reduced in human myocarditis and accumulate in the inflamed myocardium. MCS-18 treatment reduces DCs in EAM, leading to amelioration of inflammation and left ventricular remodelling during the acute phase of myocarditis. Our data further elucidate the role of DCs and their specific subsets in acute inflammatory cardiomyopathies.

Expression of the Novel Cardiac Biomarkers sST2, GDF-15, suPAR, and H-FABP in HFpEF Patients Compared to ICM, DCM, and Controls.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) remains an ongoing therapeutic and diagnostic challenge to date. In this study we aimed for an analysis of the diagnostic potential of four novel cardiovascular biomarkers, GDF-15, H-FABP, sST2, and suPAR in HFpEF patients compared to controls as well as ICM, and DCM. METHODS: In total, we included 252 stable outpatients and controls (77 DCM, 62 ICM, 18 HFpEF, and 95 controls) in the present study. All patients were in a non-decompensated state and on a stable treatment regimen. Serum samples were obtained and analyzed for GDF-15 (inflammation, remodeling), H-FABP (ischemia and subclinical ischemia), sST2 (inflammation, remodeling) and suPAR (inflammation, remodeling) by means of ELISA. RESULTS: A significant elevation of GDF-15 was found for all heart failure entities compared to controls (p < 0.005). Similarly, H-FABP evidenced a significant elevation in all heart failure entities compared to the control group (p < 0.0001). Levels of sST2 were significantly elevated in ICM and DCM patients compared to the control group and HFpEF patients (p < 0.0001). Regarding suPAR, a significant elevation in ICM and DCM patients compared to the control group (p < 0.0001) and HFpEF patients (p < 0.01) was observed. An AUC analysis identified H-FABP (0.792, 95% CI 0.713-0.870) and GDF-15 (0.787, 95% CI 0.696-0.878) as paramount diagnostic biomarkers for HFpEF patients. CONCLUSION: Based on their differences in secretion patterns, novel cardiovascular biomarkers might represent a promising diagnostic tool for HFpEF in the future.