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BACKGROUND: Pregnancy may be associated with adverse outcome in women with congenital heart disease (CHD). However, data regarding the outcome of pregnancy in women with CHD who receive care in cardiac-obstetric expert units are limited. METHODS: We retrospectively analyzed baseline characteristics and outcome of pregnancy in 67 females with CHD who received medical care in our tertiary center for 61 singleton and 6 twin pregnancies between 2009 and 2018. RESULTS: According to the modified World Health Organization (mWHO) risk scale for pregnancy, CHD lesions in 39 enrolled women (58%) were classified as mWHO class I or II, and in 28 females (42%) as mWHO class III or IV. Preterm births were more frequent in mWHO classes III or IV (P=0.003). Cardiac signs and complications occurred more often in mWHO classes III or IV than in women with cardiac lesions assigned to mWHO classes I or II (42.9% vs. 7.7%, P=0.002). N-terminal pro B-type natriuretic peptide (NT-proBNP) levels during pregnancy were higher in mWHO classes III or IV than in mWHO classes I or II (median 269.0 vs. 115.5 pg/mL, P=0.019). Presence of functional NYHA class III [odds ratio (OR) per standard deviation (SD) 8.8, 95% confidence interval (CI): 2.2–57.2, P=0.008] and mWHO classes III/IV (OR per SD 3.4, 95% CI: 1.2–9.9, P=0.018) prior to pregnancy were identified as independent predictors of adverse cardiac outcome of pregnancy. CONCLUSIONS: Adverse cardiac events and preterm deliveries should be anticipated in pregnant women with CHD, especially in those with mWHO classes III or IV. Therefore, these pregnancies should be under close surveillance and managed in specialized, multidisciplinary tertiary referral centers. Preconception counseling including individualized risk assessment is strongly recommended in women with CHD.

Aims Cardiac involvement in COVID-19 is associated with adverse outcome. However, it is unclear whether cell-specific consequences are associated with cardiac SARS-CoV-2 infection. Therefore, we investigated heart tissue utilizing in situ hybridization, immunohistochemistry, and RNA-sequencing in consecutive autopsy cases to quantify virus load and characterize cardiac involvement in COVID-19. Methods and results In this study, 95 SARS-CoV-2-positive autopsy cases were included. A relevant SARS-CoV-2 virus load in the cardiac tissue was detected in 41/95 deceased (43%). Massive analysis of cDNA ends (MACE)-RNA-sequencing was performed to identify molecular pathomechanisms caused by the infection of the heart. A signature matrix was generated based on the single-cell dataset ‘Heart Cell Atlas’ and used for digital cytometry on the MACE-RNA-sequencing data. Thus, immune cell fractions were estimated and revealed no difference in immune cell numbers in cases with and without cardiac infection. This result was confirmed by quantitative immunohistological diagnosis. MACE-RNA-sequencing revealed 19 differentially expressed genes (DEGs) with a q-value, Graphical Abstract

Background Cryoballoon (CB)-based pulmonary vein isolation (PVI) currently requires to verify occlusion of each pulmonary vein (PV) using fluoroscopy and dye injection. Objective The current study evaluated whether the novel CB-occlusion tool integrated into the wide-band dielectric imaging system KODEX-EPD reliably verifies occlusion of PV according to a novel dye-injection based algorithm. Methods Consecutive patients suffering from symptomatic atrial fibrillation (AF) underwent CB-based PVI using the KODEX-EPD and the novel occlusion-tool (group I). To confirm accurate display of the PVs, selective PV-angiography was performed in the first half of the patients of group I (group Ia) in addition to a three-dimensional left atrial (LA) map using a spiral mapping catheter (Achieve, SMC1, Medtronic, MN, USA). PV-angiographies were waived for the following patients (group Ib). Procedural duration and radiation exposure were compared to a control group of patients undergoing conventional CB-based PVI. Results CB-based PVI was successful in 50/50 patients of group I (mean age 63±11 years, 18 paroxysmal (36%)) and 25/25 patients of group II (66±10 years, 9 paroxysmal (60%)). Concordance of PV-occlusion as assessed by either PV-occlusion-angiography or KODEX-EPD, was documented in 237/272 (87%) occlusion-analyses among 198 PVs (95% for left superior PV, 93% for left inferior PV, 86% for right inferior PV and 77% for right superior PV). In the final evaluation phase (group Ib) LA fluoroscopy times and dose area products were comparable to the conventional CB-ablation group (10.5±5 vs 8.8±4 minutes (p=0.23) and 403±425 vs 321±202 cGycm2 (p=0.44), whereas the amount of dye could be significantly reduced (group Ib: 31±10 ml vs group II: 70±20 ml, p Conclusion The novel KODEX-EPD PV-occlusion tool allows for accurate PV-occlusion assessment in the majority of PVs and a high acute success rate. The system has the potential to reduce dye and radiation exposure. This should be evaluated in controlled clinical trials. Funding Acknowledgement Type of funding sources: None.

Background A growing number of patients are currently treated for severe mitral regurgitation (MR) using a transcatheter mitral valve repair (TMVr). In clinical routine, the potential risk of elevated post-procedural mitral valve pressure gradient (MPG) may prohibit optimal MR reduction driven by the avoidance of additional clip implantations. Thus, the unfavorable impact on survival and functional outcome of increased MPG in patients undergoing TMVr is currently debatable. Methods In this single-center, prospective study, survival and functional outcome of 780 consecutive patients with severe MR undergoing TMVr between September 2008 and January 2020 were investigated. After exclusion of patients with unsuccessful procedure and those lost to follow-up, data of 676 patients with a median follow-up time of 5.26 (5.11, 5.51) years were analyzed. MPG was determined by transthoracic echocardiography at discharge and considered elevated in excess of 4.5 mmHg. Kaplan-Meier analysis as well as multivariable Cox regression models were performed for the impact on elevated MPG on 5-year outcomes for the subgroups of functional MR (FMR) and degenerative MR (DMR). The primary outcome measure was a combined endpoint of death or rehospitalization for congestive heart failure. Results Among 676 patients undergoing TMVr (mean age 74.6±8.5 years, 59.0% male, median STS Score 3.9 [interquartile range 2.5; 6.0]), 179 (26.4%) patients had elevated MPG >4.5 mmHg. FMR was present in 426 (63.0%) patients. In the overall patient cohort, Kaplan-Meier and Cox Regression analyses could not demonstrate significant differences for the combined endpoint (p=0.99). In contrast, subgroup analysis according to MR etiology indicated a significant adverse influence of elevated MPG on the combined endpoint as well as functional outcome in patients with DMR, but not with FMR (Figure 1). After adjustment, multivariate Cox Regression analysis showed an inferior prognosis in patients with DMR and elevated MVPG >4.5 mmHg (hazard ratio 1.79 [1.17, 2.72], p=0.0069, Figure 2). Conclusions TMVr-patients with DMR and measurable elevated post-procedural MVPG face an inferior prognosis and reduced functional outcomes compared to patients with FMR. Funding Acknowledgement Type of funding sources: None. Figure 1Figure 2

Background Discrimination among patients with type 1 myocardial infarction (T1MI), type 2 myocardial infarction (T2MI), and myocardial injury is difficult. Objectives The aim of this study was to investigate the discriminative value of a 29-biomarker panel in an emergency department setting. Methods Patients presenting with suspected myocardial infarction (MI) were recruited. The final diagnosis in all patients was adjudicated on the basis of the fourth universal definition of MI. A panel of 29 biomarkers was measured, and multivariable logistic regression analysis was used to evaluate the associations of these biomarkers with the diagnosis of MI or myocardial injury. Biomarkers were chosen using backward selection. The model was internally validated using bootstrapping. Results Overall, 748 patients were recruited (median age 64 years), of whom 138 had MI (107 T1MI and 31 T2MI) and 221 had myocardial injury. In the multivariable model, 4 biomarkers (apolipoprotein A-II, N-terminal prohormone of brain natriuretic peptide, copeptin, and high-sensitivity cardiac troponin I) remained significant discriminators between T1MI and T2MI. Internal validation of the model showed an area under the curve of 0.82. For discrimination between MI and myocardial injury, 6 biomarkers (adiponectin, N-terminal prohormone of brain natriuretic peptide, pulmonary and activation-regulated chemokine, transthyretin, copeptin, and high-sensitivity troponin I) were selected. Internal validation showed an area under the curve of 0.84. Conclusions Among 29 biomarkers, 7 were identified to be the most relevant discriminators between subtypes of MI or myocardial injury. Regression models based on these biomarkers allowed good discrimination. (Biomarkers in Acute Cardiac Care [BACC]; NCT02355457 )

1AbstractBackgroundAnalyses in hospitalized patients and small autopsy series suggest that severe SARS-CoV-2 infection may affect the heart. We investigated heart tissue by in situ hybridization, immunohistochemistry and RNA sequencing in consecutive autopsy cases to quantify virus load and characterize cardiac involvement in COVID-19.MethodsLeft ventricular tissue from 95 deceased with diagnosed SARS-CoV-2 infection undergoing autopsy was analyzed and clinical data were collected. RNA was isolated to examine virus load of SARS- CoV-2 and its replication in the heart. A virus load >1000 copies per µg RNA was defined as relevant. Viral RNA and inflammatory cells were assessed using histology. RNA sequencing and gene ontology (GO) enrichment were performed in 10 cases with high cardiac virus load and 10 age-matched cases without cardiac infection.ResultsA relevant SARS-CoV-2 virus load was detected in 41 out of 95 deceased (43%). The median cardiac virus load was 7952 copies per µg RNA (IQR 2507, 32 005). In situ hybridization revealed SARS- CoV-2 RNA primarily in the interstitium or interstitial cells. Virus detection was not associated with increased inflammatory cells. Relevant cardiac infection was associated with increased expression of the entry factor TMPRSS2. Cardiac virus replication was found in 14/95 hearts (15%). Remarkably, cardiac virus replication was associated with shorter time between diagnosis and death. RNA sequencing revealed clear activation of immune response pathways to virus infection and destruction of cardiomyocytes. Hearts with high virus load showed activation of the GO term “extracellular exosomes”.ConclusionSARS-CoV-2 infection including virus replication and distinct transcriptomic alterations without signs of myocarditis demonstrate a cardiac involvement. In this autopsy series, cardiac replication of SARS-CoV-2 was associated with early death.

Background The discrimination of patients with type 1 myocardial infarction (T1MI) from patients with type 2 MI (T2MI) is often challenging in the emergency department. Earlier we presented a discrimination model, which based on clinical variables, as well as on troponin concentrations. In the present analyses we sought to investigate the discriminative power of 28 biomarkers in patients with T1MI and T2MI. Methods Patients presenting to the emergency department with symptoms suggestive of MI were recruited. The final diagnosis of all patients was adjudicated by two physicians in a blinded fashion and based on the fourth universal definition of MI. For the present analyses only patients with T1MI and T2MI were used. In total 28 biomarkers were measured in blood samples collected directly at admission. A multivariable logistic regression model for T1MI vs T2MI as the dependent variable was used and the predictors were chosen via backward step-down selection. Results In total 138 patients (107 T1MI and 31 T2MI) were available for the analyses. The median age of the study population was 65 years and 66.7% were males. Hypertension was present in 77.4% and dyslipidemia in 41.3%. In the multivariable model four biomarkers (apolipoprotein A-II, n-terminal prohormone of brain natriuretic peptide, copeptin and high-sensitivity troponin I) were significant discriminators between T1MI and T2MI (Table 1). Internal validation of the model via bootstrap shows a for overoptimism corrected area under the curve of 0.82. Conclusion Using a multibiomarker approach discrimination between T1MI and T2MI could be improved. External validation of our findings is warranted. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Research fellowship by the Deutsche Forschungsgemeinschaft

Aim Evidence on non-ischaemic cardiogenic shock (CS) is scarce. The aim of this study was to investigate differences in presentation characteristics, use of treatments and outcomes in patients with ischaemic vs. non-ischaemic CS. Methods Patients with CS admitted to a tertiary care hospital between October 2009 and October 2017 were identified and stratified as ischaemic CS/non-ischaemic CS based on the presence/absence of acute myocardial infarction. Missing data was handled by chained equation multiple imputation. Logistic and Cox regression models were fitted to investigate the association of non-ischaemic CS with presentation characteristics (adjusted for all baseline variables), and use of treatments as well as30-day in-hospital mortality (adjusted for relevant confounders including age, sex, prior cardiac arrest, haemodynamics, pH and lactate). Results A total of 978 patients were enrolled in this study; median age was 70 (interquartile range 58, 79) years and 70% were male. 505 patients (43%) had non-ischaemic CS. Patients with non-ischaemic CS were more likely younger and female; were less likely to be active smokers or to have diabetes, but more likely to have chronic renal disease and history of myocardial infarction; and were more likely to present with unfavourable haemodynamics and with mechanical ventilation. Regarding use of treatments, patients with non-ischaemic CS were more likely to be treated with catecholamines [odds ratio (OR) 1.58, 95% confidence interval (CI) 1.11–2.27, p0.01], but less likely to be treated with extracorporeal membrane oxygenation (OR 0.66, 95% CI 0.48–0.92, p=0.02) or percutaneous left ventricular assist devices (OR 0.51, 0.35–0.74, p Conclusion In this large study, non-ischaemic CS accounted for almost 50% of all CS cases. Non-ischaemic CS was not only associated with relevant differences in presentation characteristics and use of treatments, but also with a worse prognosis. These findings highlight the need for effective treatment strategies for patients with non-ischaemic CS. Figure 1 Funding Acknowledgement Type of funding source: None

Background In the Universal Definition of Myocardial Infarction (MI) myocardial injury was introduced as a specific diagnosis in patients with elevated troponin concentrations, but without evidence of acute myocardial ischemia. However, their differentiation within the acute setting might be challenging. Therefore, we sought to investigate a multibiomarker panel in these patients and determine the discriminative capacity to differentiation MI from myocardial injury. Methods We use a cohorts of acute patients presenting to the emergency department. All final diagnoses were adjudicated by two physicians in a blinded fashion and based on the fourth universal definition of MI. In case of disagreement a third physician referred. For the present analyses only patients diagnosed with MI or myocardial injury were used. A panel of 28 biomarkers was measured in blood samples collected directly at admission. Spearman correlations were calculated. A multivariable logistic regression model using MI as the dependent variable was used and the predictors were chosen via backward step-back selection. Odds ratios (OR) were calculated for each predictor. Results We included 359 patients; 138 were diagnosed as having MI and 221 has having myocardial injury. The median age of the study population was 73 years and 59.1% were males. Hypertension was diagnosed in 80.4%, dyslipidemia in 45.4% and diabetes in 19.0%.The biomarker panel showed a wide range of correlations (Figure 1). In the multivariable model five logarithmized biomarkers (N-terminal prohormone of brain natriuretic peptide [OR 0.62], pulmonary and activation-regulated chemokine [OR 0.51], tumor-necrosis-factor-receptor 2 [OR 2.22], copeptin [OR 1.59] and high-sensitivity troponin I [OR 1.80]) were significant discriminators between MI and myocardial injury. Internal validation of the model via bootstrap shows a for overoptimism corrected area under the curve of 0.84. Conclusion In the multivariable model five biomarkers were discriminators between MI and myocardial injury. Spearman correlations Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Research fellowship by the Deutsche Forschungsgemeinschaft

BACKGROUND: The therapeutic success in patients with congenital heart disease (CHD) leads to a growing number of adults with CHD (adult CHD [ACHD]) who develop end-stage heart failure. We aimed to determine patient characteristics and outcomes of ACHD listed for heart transplantation. METHODS: Using data from all the patients with ACHD in 20 transplant centers in the Eurotransplant region from 1999 to 2015, we analyzed patient characteristics, waiting list, and post-transplantation outcomes. RESULTS: A total of 204 patients with ACHD were listed during the study period. The median age was 38 years, and 62.3% of the patients were listed in high urgency (HU), and 37.7% of the patients were in transplantable (T)-listing status. A total of 23.5% of the patients died or were delisted owing to clinical worsening, and 75% of the patients underwent transplantation. Median waiting time for patients with HU-listing status was 4.18 months and with T-listing status 9.07 months. There was no difference in crude mortality or delisting between patients who were HU status listed and T status listed (p = 0.65). In multivariable regression analysis, markers for respiratory failure (mechanical ventilation, hazard ratio [HR]: 1.41, 95% CI: 1.11-1.81, p = 0.006) and arrhythmias (anti-arrhythmic medication, HR: 1.42, 95% CI: 1.01-2.01, p = 0.044) were associated with a higher risk of death or delisting. In the overall cohort, post-transplantation mortality was 26.8% after 1 year and 33.4% after 5 years. CONCLUSIONS: Listed patients are at high risk of death without differences in the urgency of listing. Respiratory failure requiring invasive ventilation and possibly arrhythmias requiring anti-arrhythmic medication indicate worse outcomes on waiting list. (C) 2020 International Society for Heart and Lung Transplantation. All rights reserved.

Aim: Evidence on non-ischemic cardiogenic shock (CS) is scarce. The aim of this study was to investigate differences in patient characteristics, use of treatments and outcomes in patients with non-ischemic vs. ischemic CS. Methods: Patients with CS admitted between October 2009 and October 2017 were identified and stratified as non-ischemic/ischemic CS based on the absence/presence of acute myocardial infarction. Logistic/Cox regression models were fitted to investigate the association between non-ischemic CS and patient characteristics, use of treatments and 30-day in-hospital mortality. Results: A total of 978 patients were enrolled in this study, median age was 70 (interquartile range 58, 79) years and 70% were male. Of these, 505 patients (52%) had non-ischemic CS. Patients with non-ischemic CS were more likely to be younger and female, were less likely to be active smokers, to have diabetes or decreased renal function, but more likely to have a history of myocardial infarction, and they were more likely to present with unfavorable hemodynamics and with mechanical ventilation. Regarding treatments, patients with non-ischemic CS were more likely to be treated with catecholamines, but less likely to be treated with extracorporeal membrane oxygenation or percutaneous left-ventricular assist devices. After adjustment for multiple relevant confounders, non-ischemic CS was associated with a significant increase in the risk of 30-day in-hospital mortality (hazard ratio 1.14, 95% confidence interval 1.04&ndash, 1.24, p &lt, 0.01). Conclusion: In this large study, non-ischemic CS accounted for more than 50% of all CS cases. Non-ischemic CS was not only associated with relevant differences in patient characteristics and use of treatments, but also with a worse prognosis. These findings highlight the need for effective treatment strategies for patients with non-ischemic CS.

Background: Right ventricular dysfunction is a major determinant of outcome in pulmonary arterial hypertension (PAH). We aimed to identify echocardiographic right heart parameters associated with adverse outcome and to develop a non-invasive, echocardiography-based risk score for PAH patients. Methods and Results: In 254 PAH patients we analyzed functional status, laboratory results, and echocardiographic parameters. We included these parameters to estimate all-cause death or lung transplantation using Cox regression models. The analyses included a conventional model using guideline-recommended variables and an extended echocardiographic model. Based on the final model a 12-point risk score was derived, indicating the association with the primary outcome within five years. During a median follow-up time of 4.2 years 74 patients died or underwent lung transplantation. The conventional model resulted in a C-Index of 0.539, whereas the extended echocardiographic model improved the discrimination (C-index 0.639, p-value 0.017). Ultimately, the newly developed risk score included WHO functional class, 6-min walking distance, N-terminal brain natriuretic peptide concentrations, pericardial effusion, right atrial area, tricuspid annular plane systolic excursion, and fractional area change. Conclusion: Integrating right heart function assessed by echocardiography improves prediction of death or lung transplantation in PAH patients. Independent validation of this finding is warranted.