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The acute and long-lasting side effects of modern multimodal tumour therapy significantly impair quality of life and survival of patients afflicted with malignancies. The key components of this therapy include radiotherapy, conventional chemotherapy, immunotherapy and targeted therapies. In addition to established tumour therapy strategies, up to 30 new therapies are approved each year with only incompletely characterised side effects. This consensus paper discusses the risk factors that contribute to the development of a potentially adverse reaction to tumour therapy and, in addition, defines specific side effect profiles for different treatment groups. The focus is on novel therapeutics and recommendations for the surveillance and treatment of specific patient groups.

Cardiac arrhythmias remain a common challenge and are associated with significant morbidity and mortality. Effective and safe rhythm control strategies are a primary, yet unmet need in everyday clinical practice. Despite significant pharmacological and technological advances, including catheter ablation and device-based therapies, the development of more effective alternatives is of significant interest to increase quality of life and to reduce symptom burden, hospitalizations and mortality. The mechanistic understanding of pathophysiological pathways underlying cardiac arrhythmias has advanced profoundly, opening up novel avenues for mechanism-based therapeutic approaches. Current management of arrhythmias, however, is primarily guided by clinical and demographic characteristics of patient groups as opposed to individual, patient-specific mechanisms and pheno-/genotyping. With this state-of-the-art paper, the Working Group on Cellular Electrophysiology of the German Cardiac Society aims to close the gap between advanced molecular understanding and clinical decision-making in cardiac electrophysiology. The significance of cellular electrophysiological findings for clinical arrhythmia management constitutes the main focus of this document. Clinically relevant knowledge of pathophysiological pathways of arrhythmias and cellular mechanisms of antiarrhythmic interventions are summarized. Furthermore, the specific molecular background for the initiation and perpetuation of atrial and ventricular arrhythmias and mechanism-based strategies for therapeutic interventions are highlighted. Current "hot topics" in atrial fibrillation are critically appraised. Finally, the establishment and support of cellular and translational electrophysiology programs in clinical rhythmology departments is called for to improve basic-science-guided patient management.

Background COVID-19 has been associated with a high prevalence of myocardial injury and increased cardiovascular morbidity. Copeptin, a marker of vasopressin release, has been previously established as a risk marker in both infectious and cardiovascular disease. Methods This prospective, observational study of patients with laboratory-confirmed COVID-19 infection was conducted from June 6th to November 26th, 2020 in a tertiary care hospital. Copeptin and high-sensitive cardiac troponin I (hs-cTnI) levels on admission were collected and tested for their association with the primary composite endpoint of ICU admission or 28-day mortality. Results A total of 213 eligible patients with COVID-19 were included of whom 55 (25.8%) reached the primary endpoint. Median levels of copeptin and hs-cTnI at admission were significantly higher in patients with an adverse outcome (Copeptin 29.6 pmol/L, [IQR, 16.2–77.8] vs 17.2 pmol/L [IQR, 7.4–41.0] and hs-cTnI 22.8 ng/L [IQR, 11.5–97.5] vs 10.2 ng/L [5.5–23.1], P

Background Atrial fibrillation (AF) is the most common age-related cardiac arrhythmia. The etiology underlying AF is still largely unknown. At the intersection of the innate immune system and hemostasis, immunothrombosis may be a possible cause of atrial remodeling, and therefore be an underlying cause of AF. Methods From 1990 to 2014, we followed participants aged 55 and over, free from AF at inclusion. Immunothrombosis factors fibrinogen, von Willebrand factor, ADAMTS13, and neutrophil extracellular traps (NETs) levels were measured at baseline. Participants were followed until either onset of AF, loss-to-follow-up, or reaching the end-date of 01-01-2014. Cox proportional hazard modelling was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for cardiovascular risk factors. Results We followed 6174 participants (mean age 69.1 years, 57% women) for a median follow-up time of 12.8 years. 364 men (13.7%, incidence rate 13.0/1000 person-years) and 365 women (10.4%, incidence rate 8.9/1000 person-years) developed AF. We found no significant association between markers of immunothrombosis and new-onset AF after adjusting for cardiovascular risk factors [HR 1.00 (95% CI 0.93–1.08) for fibrinogen, 1.04 (0.97–1.12) for von Willebrand factor, 1.00 (1.00–1.01) for ADAMTS13, and 1.01 (0.94–1.09) for NETs]. In addition, we found no differences in associations between men and women. Conclusion We found no associations between markers of immunothrombosis and new-onset AF in the general population. Inflammation and immunothrombosis may be associated with AF through other cardiovascular risk factors or predisposing conditions of AF. Our findings challenge the added value of biomarkers in AF risk prediction. Graphic abstract

Introduction The effect of valve type on outcomes in transfemoral transcatheter aortic valve replacement (TF-TAVR) has recently been subject of debate. We investigate outcomes of patients treated with balloon-expanding (BE) vs. self-expanding (SE) valves in in a cohort of all these procedures performed in Germany in 2018. Methods All patients receiving TF-TAVR with either BE (N = 9,882) or SE (N = 7,413) valves in Germany in 2018 were identified. In-hospital outcomes were analyzed for the endpoints in-hospital mortality, major bleeding, stroke, acute kidney injury, postoperative delirium, permanent pacemaker implantation, mechanical ventilation > 48 h, length of hospital stay, and reimbursement. Since patients were not randomized to the two treatment options, logistic or linear regression models were used with 22 baseline patient characteristics and center-specific variables as potential confounders. As a sensitivity analysis, the same confounding factors were taken into account using the propensity score methods (inverse probability of treatment weighting). Results Baseline characteristics differed substantially, with higher EuroSCORE (p p p p = 0.617] major bleeding [aOR 0.91 (0.73;1.14), p = 0.400], stroke [aOR 1.13 (0.88;1.46), p = 0.347], acute kidney injury [OR 0.97 (0.85;1.10), p = 0.621], postoperative delirium [aOR 1.09 (0.96;1.24), p = 0.184], mechanical ventilation > 48 h [aOR 0.98 (0.77;1.25), p = 0.893], length of hospital stay (risk adjusted difference in days of hospitalization (SE instead of BE): − 0.05 [− 0.34;0.25], p = 0.762) and reimbursement [risk adjusted difference in reimbursement (SE instead of BE): − €72 (− €291;€147), p = 0.519)] There is, however, an increased risk of PPI for SE valves (aOR 1.27 [1.15;1.41], p Conclusions We find broadly equivalent outcomes in contemporary TF-TAVR procedures, regardless of the valve type used. Incidence of major complications is very low for both types of valve.

Background Recent randomized controlled trials have sparked debate about the optimal treatment of patients suffering from left main coronary artery disease. The present study analyzes outcomes of left main stenting versus coronary bypass grafting (CABG) in a nationwide registry in patients with chronic coronary syndrome (CCS). Methods All cases suffering from CCS and left main coronary artery disease treated either with CABG or stent, were identified within the database of the German bureau of statistics. Logistic or linear regression models were used with 20 baseline patient characteristics as potential confounders to compare both regimens. Results In 2018, 1318 cases with left main stenosis were treated with CABG and 8,920 with stent. Patients assigned for stenting were older (72.58 ± 9.87 vs. 68.63 ± 9.40, p p p = 0.748; aOR stroke: 0.59 [0.27; 1.32], p = 0.199). Stent implantation was associated with a reduced risk of relevant bleeding (aOR 0.38 [0.24; 0.61], p p = 0.002), and postoperative delirium (aOR 0.16 [0.11; 0.22], p p p Conclusion Left main stenting is a safe and effective treatment option for CCS-patients suffering from left main coronary artery disease at reasonable economic cost. Graphic abstract

Objectives To evaluate associations of omega-3 fatty acid (O3-FA) blood levels with cardiometabolic risk markers, functional capacity and cardiac function/morphology in patients with heart failure with preserved ejection fraction (HFpEF). Background O3-FA have been linked to reduced risk for HF and associated phenotypic traits in experimental/clinical studies. Methods This is a cross-sectional analysis of data from the Aldo-DHF-RCT. From 422 patients, the omega-3-index (O3I = EPA + DHA) was analyzed at baseline in n = 404 using the HS-Omega-3-Index® methodology. Patient characteristics were; 67 ± 8 years, 53% female, NYHA II/III (87/13%), ejection fraction ≥ 50%, E/e′ 7.1 ± 1.5; median NT-proBNP 158 ng/L (IQR 82–298). Pearson’s correlation coefficient and multiple linear regression analyses, using sex and age as covariates, were used to describe associations of the O3I with metabolic phenotype, functional capacity, echocardiographic markers for LVDF, and neurohumoral activation at baseline/12 months. Results The O3I was below ( 11%) than the target range in 374 (93%), 29 (7%), and 1 (0.2%) patients, respectively. Mean O3I was 5.7 ± 1.7%. The O3I was inversely associated with HbA1c (r = − 0.139, p = 0.006), triglycerides-to-HDL-C ratio (r = − 0.12, p = 0.017), triglycerides (r = − 0.117, p = 0.02), non-HDL-C (r = − 0.101, p = 0.044), body-mass-index (r = − 0.149, p = 0.003), waist circumference (r = − 0.121, p = 0.015), waist-to-height ratio (r = − 0.141, p = 0.005), and positively associated with submaximal aerobic capacity (r = 0.113, p = 0.023) and LVEF (r = 0.211, p β = 15.614, p β = 0.399, p = 0.005) and LVEF (β = 0.698, p = 0.007) at 12 months. Conclusions Higher O3I was associated with a more favorable cardiometabolic risk profile and predictive of higher submaximal/maximal aerobic capacity and lower BMI/truncal adiposity in HFpEF patients. Graphic abstract Omega-3 fatty acid blood levels are inversely associated with cardiometabolic risk factors in HFpEF patients. Higher O3I was associated with a more favorable cardiometabolic risk profile and aerobic capacity (left) but did not correlate with echocardiographic markers for left ventricular diastolic function or neurohumoral activation (right). An O3I-driven intervention trial might be warranted to answer the question whether O3-FA in therapeutic doses (with the target O3I 8–11%) impact on echocardiographic markers for left ventricular diastolic function and neurohumoral activation in patients with HFpEF. This figure contains modified images from Servier Medical Art (https://smart.servier.com) licensed by a Creative Commons Attribution 3.0 Unported License.

Background Thrombi and spontaneous echo contrast (SEC) in the left atrial appendage (LAA) are associated with thromboembolic events and poor prognosis. There are very few data on long-term outcome, especially with the use of direct acting anticoagulants (DOAC). Methods In this retrospective study, all transoesophageal echocardiographies performed at a tertiary care university hospital from 2015 to 2020 were analyzed. All patients with thrombus or SEC in the LAA were included. Medical history, laboratory, echocardiographic parameters and medication at discharge were documented. The primary endpoint of the study was a composite endpoint (all-cause mortality, non-fatal stroke or transient ischaemic attack [TIA], non-fatal systemic embolization, non-fatal major bleeding and non-fatal myocardial infarction). Results Of a total of 4062 transoesophageal echocardiographies, thrombi were detected in 51 patients (1.2%) and SEC in 251 patients (6.2%). These patients formed the final study cohort (n = 302). During a mean follow-up period of 956 ± 663 days, 87 patients (29%) suffered the primary point. The following baseline characteristics predicted the primary endpoint: age, haemoglobin, a previous coronary artery bypass grafting, dialysis and choice of anticoagulation. Prescription of apixaban at discharge was associated with lower rate of adverse events (hazard ratio 0.564, confidence interval 0.331–0.960; p = 0.035) while prescription of dabigatran was associated with higher rate of adverse events (hazard ratio 3.091, confidence interval 1.506–6.347; p = 0.002). Conclusion Even in the DOAC era, the occurrence of thrombus or SEC in the LAA is associated with a high rate of MACCE. Our study suggests that the choice of DOAC therapy may have an impact on long-term survival. Graphic abstract

Aims Left bundle branch block (LBBB) is the most common conduction disorder after transcatheter aortic valve replacement (TAVR) with an increased risk of atrioventricular (AV) block. The aim of the current study was to identify non-invasive predictors for infranodal conduction delay in patients with LBBB. Methods We analyzed consecutive patients undergoing TAVR with pre-existing or new-onset LBBB between August 2014 and August 2020. His ventricular (HV) interval measurement was performed on day 1 after TAVR. Baseline, procedural, as well as surface and intracardiac electrocardiographic parameters were included. Infranodal conduction delay was defined as HV interval > 55 ms. Results Of 825 patients screened after TAVR, 151 patients (82 ± 6 years, 39% male) with LBBB were included. Among these, infranodal conduction delay was observed in 25%. ΔPR (difference in PR interval after and before TAVR), PR and QRS duration after TAVR were significantly longer in the group with HV prolongation. In a multivariate analysis in patients with sinus rhythm (n = 123), ΔPR (OR per 10 ms increase: 1.52; 95%CI: 1.19–2.01; p = 0.002) was the only independent factor associated with infranodal conduction delay. A change in PR interval by 20 ms yielded a specificity of 83% and a sensitivity of 46%, with a negative predictive value of 84% and a positive predictive value of 45% to predict HV prolongation. Conclusions Simple analysis of surface ECG and a calculated ΔPR Graphical abstract

Objectives We assessed possible myocardial involvement in previously cardiac healthy post-COVID patients referred for persisting symptoms with suspected myocarditis. Background Prior studies suggested myocardial inflammation in patients with coronavirus-induced disease 2019 (COVID-19). However, the prevalence of cardiac involvement among COVID patients varied between 1.4 and 78%. Methods A total of 56 post-COVID patients without previous heart diseases were included consecutively into this study. All patients had positive antibody titers against SARS-CoV-2. Patients were referred for persistent symptoms such as chest pain/discomfort, shortness of breath, or intolerance to activity. All patients underwent standardized cardiac assessment including electrocardiogram (ECG), cardiac biomarkers, echocardiography, and cardiac magnetic resonance (CMR). Results 56 Patients (46 ± 12 years, 54% females) presented 71 ± 66 days after their COVID-19 disease. In most patients, the course of COVID-19 was mild, with hospital treatment being necessary in five (9%). At presentation, patients most often reported persistent fatigue (75%), chest pain (71%), and shortness of breath (66%). Acute myocarditis was confirmed by T1/T2-weighed CMR and elevated NTpro-BNP levels in a single patient (2%). Left ventricular ejection fraction was 56% in this patient. Additional eight patients (14%) showed suspicious CMR findings, including myocardial edema without fibrosis (n = 3), or non-ischemic myocardial injury suggesting previous inflammation (n = 5). However, myocarditis could ultimately not be confirmed according to 2018 Lake Louise criteria; ECG, echo and lab findings were inconspicuous in all eight patients. Conclusions Among 56 post-COVID patients with persistent thoracic complaints final diagnosis of myocarditis could be confirmed in a single patient using CMR. Graphic abstract

Objectives This study aimed to determine if changes in myeloperoxidase (MPO) levels correlate with response to cardiac resynchronization therapy (CRT) and the potential role of MPO as a predictor of response to CRT. Background CRT is a well-established treatment option in chronic heart failure (CHF) with 50–80% of patients benefiting. Inflammation and oxidative stress play a key role in CHF pathophysiology. Previous studies have demonstrated increased levels of MPO in CHF patients, but the correlation with CRT response remains incompletely understood. Methods Fifty-three patients underwent CRT implantation. During follow-up, patients were divided into two groups, responders and non-responders to CRT, based on improved physical capacity and NYHA classification. Levels of MPO and NT-pro-brain-natriuretic-peptide (NT-proBNP) were determined prior to implantation, 30 and 90 days after. Physical capacity, including a 6-min walking-test, NYHA class, and LVEF were evaluated at baseline and during follow-up. Results Thirty-four patients (64%) responded to CRT, showing improved physical capacity and LVEF. All responders revealed a significant decrease of MPO levels (503.8 ng/ml vs. 188.4 ng/ml; p p = 0.672) during follow-up. At baseline, physical capacity and NYHA class, as well as MPO levels differed significantly between both groups (p p = 0.005) and physical capacity (Spearman’s rho: − 0.335; p = 0.042). Conclusions Response to CRT and course of MPO levels correlate significantly. MPO levels differ between responders and non-responders prior to CRT, which may indicate an additional value of MPO as a predictor for CRT response. Further randomized studies are required to confirm our data in larger patient cohorts.

Background Higher body mass index (BMI) is associated with better outcome compared with normal weight in patients with HF and other chronic diseases. It remains uncertain whether the apparent protective role of obesity relates to the absence of comorbidities. Therefore, we investigated the effect of BMI on outcome in younger patients without co-morbidities as compared to older patients with co-morbidities in a large heart failure (HF) population. Methods In an individual patient data analysis from pooled cohorts, 5,819 patients with chronic HF and data available on BMI, co-morbidities and outcome were analysed. Patients were divided into four groups based on BMI (i.e. ≤ 18.5 kg/m2, 18.5–25.0 kg/m2; 25.0–30.0 kg/m2; 30.0 kg/m2). Primary endpoints included all-cause mortality and HF hospitalization-free survival. Results Mean age was 65 ± 12 years, with a majority of males (78%), ischaemic HF and HF with reduced ejection fraction. Frequency of all-cause mortality or HF hospitalization was significantly worse in the lowest two BMI groups as compared to the other two groups; however, this effect was only seen in patients older than 75 years or having at least one relevant co-morbidity, and not in younger patients with HF only. After including medications and N-terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin concentrations into the model, the prognostic impact of BMI was largely absent even in the elderly group with co-morbidity. Conclusions The present study suggests that obesity is a marker of less advanced disease, but does not have an independent protective effect in patients with chronic HF. Graphic abstract Categories of BMI are only predictive of poor outcome in patients aged > 75 years or with at least one co-morbidity (bottom), but not in those aged

Background A small aortic annulus is associated with increased risk of prosthesis–patient mismatch (PPM) after transcatheter aortic valve implantation (TAVI). Whether specific transcatheter heart valve (THV) designs yield superior hemodynamic performance in these small anatomies remains unclear. Methods Data from 8411 consecutive patients treated with TAVI from May 2012 to April 2019 at four German centers were retrospectively evaluated. A small aortic annulus was defined as multidetector computed tomography-derived annulus area 2. TAVI was performed with a balloon-expanding intra-annular (Sapien-3, n = 288), self-expanding intra-annular (Portico, n = 110), self-expanding supra-annular (Evolut, n = 179 and Acurate-Neo, n = 428) and mechanically expanding infra-annular (Lotus, n = 64) THV according to local practice. PPM was defined as indexed effective orifice area ≤ 0.85cm2/m2. Results A small annulus was found in 1069 (12.7%) patients. PPM was detected in 38.3% overall with a higher prevalence after implantation of a balloon-expanding intra-annular or mechanically expanding infra-annular THV compared to self-expanding intra- and supra-annular THV. Multivariable analysis linked self-expanding THV (Evolut: Odds ratio [OR] 0.341, Acurate-Neo: OR 0.436, Portico: OR 0.291), postdilatation (OR 0.648) and age (OR 0.968) to lower rates of PPM, while aortic valve calcification was associated with an increased risk (OR 1.001). Paravalvular regurgitation > mild was more frequent after TAVI with self-expanding THV (p = 0.04). Conclusion In this large contemporary multicenter patient population, a substantial number of patients with a small aortic anatomy were left with PPM after TAVI. Self-expanding supra- and intra-annular THV demonstrated superior hemodynamics in these patients at risk, however at the cost of higher rates of residual paravalvular regurgitation. Graphic abstract

Objective Despite growing evidence about myocardial injury in hospitalized COronaVIrus Disease 2019 (COVID-19) patients, the mechanism behind this injury is only poorly understood and little is known about its association with SARS-CoV-2-mediated myocarditis. Furthermore, definite evidence of the presence and role of SARS-CoV-2 in cardiomyocytes in the clinical scenario is still lacking. Methods We histologically characterized myocardial tissue of 40 patients deceased with severe SARS-CoV-2 infection during the first wave of the pandemic. Clinical data were also recorded and analyzed. In case of findings supportive of myocardial inflammation, histological analysis was complemented by RT-PCR and immunohistochemistry for SARS-CoV-2 viral antigens and in situ RNA hybridization for the detection of viral genomes. Results Both chronic and acute myocardial damage was invariably present, correlating with the age and comorbidities of our population. Myocarditis of overt entity was found in one case (2.5%). SARS-CoV-2 genome was not found in the cardiomyocytes of the patient with myocarditis, while it was focally and negligibly present in cardiomyocytes of patients with known viral persistence in the lungs and no signs of myocardial inflammation. The presence of myocardial injury was not associated with myocardial inflammatory infiltrates. Conclusions In this autopsy cohort of COVID-19 patients, myocarditis is rarely found and not associated with SARS-CoV-2 presence in cardiomyocytes. Chronic and acute forms of myocardial damage are constantly found and correlate with the severity of COVID-19 disease and pre-existing comorbidities. Graphic abstract

Background Heyde syndrome (HS) is known as the association of severe aortic stenosis (AS) and recurrent gastrointestinal bleeding (GIB) from angiodysplasia. Data on the prevalence of HS and results after TAVI remain scarce. Methods 2548 consecutive patients who underwent TAVI for the treatment of AS from 2008 to 2017 were evaluated for a history of GIB and the presence of HS. The diagnosis of HS was defined as a clinical triad of severe AS, a history of recurrent GIB, and an endoscopic diagnosis of angiodysplasia. These patients (Heyde) were followed to investigate clinical outcomes, bleeding complications and the recurrence of GIB and were compared to patients with GIB unrelated to HS (Non-Heyde). Results A history of GIB prior to TAVI was detected in 190 patients (7.5%). Among them, 47 patients were diagnosed with HS (1.8%). Heyde patients required blood transfusions more frequently compared to Non-Heyde patients during index hospitalization (50.0% vs. 31.9%, p = 0.03). Recurrent GIB was detected in 39.8% of Heyde compared to 21.2% of Non-Heyde patients one year after TAVI (p = 0.03). In patients diagnosed with HS and recurrent GIB after TAVI, the rate of residual ≥ mild paravalvular leakage (PVL) was higher compared to those without recurrent bleeding (73.3% vs. 38.1%, p = 0.05). Conclusion A relevant number of patients undergoing TAVI were diagnosed with HS. Recurrent GIB was detected in a significant number of Heyde patients during follow-up. A possible association with residual PVL requires further investigation to improve treatment options and outcomes in patients with HS. Graphic abstract

Aims Immunocompromised patients have been excluded from studies of SARS-CoV-2 messenger RNA vaccines. The immune response to vaccines against other infectious agents has been shown to be blunted in such patients. We aimed to analyse the humoral and cellular response to prime-boost vaccination with the BNT162b2 vaccine (Pfizer-BioNTech) in cardiothoracic transplant recipients. Methods and results A total of 50 transplant patients [1–3 years post heart (42), lung (7), or heart–lung (1) transplant, mean age 55 ± 10 years] and a control group of 50 healthy staff members were included. Blood samples were analysed 21 days after the prime and the boosting dose, respectively, to quantify anti-SARS-CoV-2 spike protein (S) immunoglobulin titres (tested by Abbott, Euroimmun and RocheElecsys Immunoassays, each) and the functional inhibitory capacity of neutralizing antibodies (Genscript). To test for a specific T-cell response, heparinized whole blood was stimulated with SARS-CoV-2 specific peptides, covering domains of the viral spike, nucleocapsid and membrane protein, and the interferon-γ release was measured (QuantiFERON Monitor ELISA, Qiagen). The vast majority of transplant patients (90%) showed neither a detectable humoral nor a T-cell response three weeks after the completed two-dose BNT162b2 vaccination; these results are in sharp contrast to the robust immunogenicity seen in the control group: 98% exhibited seroconversion after the prime dose already, with a further significant increase of IgG titres after the booster dose (average > tenfold increase), a more than 90% inhibition capability of neutralizing antibodies as well as evidence of a T-cell responsiveness. Conclusions The findings of poor immune responses to a two-dose BNT162b2 vaccination in cardiothoracic transplant patients have a significant impact for organ transplant recipients specifically and possibly for immunocompromised patients in general. It urges for a review of future vaccine strategies in these patients.

Objectives This study aimed to assess the clinical outcome of the bioprosthetic or native aortic scallop intentional laceration to prevent iatrogenic coronary obstruction (BASILICA) technique in a single-center patient cohort considered at high or prohibitive risk of transcatheter aortic valve implantation (TAVI)-induced coronary obstruction. Methods Between October 2019 and January 2021, a total of 15 consecutive patients (age 81.0 [78.1, 84.4] years; 53.3% female; EuroSCORE II 10.6 [6.3, 14.8] %) underwent BASILICA procedure prior to TAVI at our institution. Indications for TAVI were degeneration of stented (n = 12, 80.0%) or stentless (n = 1, 6.7%) bioprosthetic aortic valves, or calcific stenosis of native aortic valves (n = 2, 13.3%), respectively. Individual risk of TAVI-induced coronary obstruction was assessed by pre-procedural computed tomography analysis. Procedural and 30-day outcomes were documented in accordance with Valve Academic Research Consortium (VARC)-2 criteria. Results BASILICA was attempted for single left coronary cusp in 12 patients (80.0%), for single right coronary cusp in 2 patients (13.3%), and for both cusps in 1 patient (6.7%), respectively. The procedure was feasible in 13 patients (86.7%) resulting in effective prevention of coronary obstruction, whilst TAVI was performed without prior successful bioprosthetic leaflet laceration in two patients (13.3%). In one of these patients (6.7%), additional chimney stenting immediately after TAVI was performed. No all-cause deaths or strokes were documented after 30 days. Conclusion The BASILICA technique appears to be a feasible, safe and effective concept to avoid iatrogenic coronary artery obstruction during TAVI in both native and bioprosthetic valves of patients at high or prohibitive risk. ClinicalTrials.gov Identifier: NCT04227002 (Hamburg AoRtic Valve cOhoRt).

Background Very long-term outcomes according to diabetic status of patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI) with new-generation drug-eluting stents (DES) are scant. Both, the durable polymer zotarolimus-eluting stent (DP-ZES), the first DES to gain FDA-approval for specific use in patients with diabetes mellitus, and the polymer-free sirolimus- and probucol-eluting stent (PF-SES), with a unique design that enables effective drug release without the need of a polymer offer the potential to enhance clinical long-term outcomes especially in patients with diabetes mellitus. Methods We investigate 10-year clinical outcomes of the prespecified subgroups of patients with and without diabetes mellitus, randomly assigned to treatment with PF-SES versus DP-ZES in the ISAR-TEST 5 trial. The primary endpoint of interest was major adverse cardiac events (MACE), defined as the composite of all-cause death, any myocardial infarction or any revascularization. Further endpoints of interest were cardiac death, myocardial infarction related to the target vessel and target lesion revascularization as well as the individual components of the primary composite endpoint and the incidence of definite or probable stent thrombosis at 10 years. Results This analysis includes a total of 3002 patients randomly assigned to PF-SES (n = 2002) or DP-ZES (n = 1000). Prevalence of diabetes mellitus was high and comparable, 575 Patients (28.7%) in PF-SES group and 295 patients (29.5%) in DP-ZES group (P = 0.66). At 10 years 53.5% of patients with diabetes mellitus and 68.5% of patients without diabetes mellitus were alive. Regarding major adverse cardiac events, PF-SES as compared to DP-ZES showed comparable event rates in patients with diabetes mellitus (74.8% vs. 79.6%; hazard ratio 0.86; 95% CI 0.73–1.02; P = 0.08) and in patients without diabetes (PF-SES 62.5% vs. DP-ZES 62.2%; hazard ratio 0.99; 95% CI 0.88–1.11; P = 0.88). Conclusion At 10 years, both new-generation DES show comparable clinical outcome irrespective of diabetic status or polymer strategy. Event rates after PCI in patients with diabetes mellitus are considerable higher than in patients without diabetes mellitus and continue to accrue over time. Trial registration ClinicalTrials.gov, NCT00598533, Registered 10 January 2008, https://clinicaltrials.gov/ct2/show/NCT00598533?term=NCT00598533 Graphic abstract Kaplan-Meier estimates of endpoints of interest for patients with vs. without diabetes mellitus treated with PF-SES vs. DP-ZES. Bar graphs: Kaplan-Meier estimates as percentages. PF-SES: polymer-free sirolimus-eluting stent; DP-ZES: durable polymer zotarolimus-eluting stent; DM: diabetes mellitus. Comparison of event rates of individual endpoints in patients with and without diabetes mellitus treated with PF-SES vs. DP-ZES all without statistically significant differences. Comparison of event rates of individual endpoints in overall patients with vs. without diabetes mellitus significantly different (P ≤ 0.01 for all comparisons).

Background Sudden death (SD) and pump failure death (PFD) are the two leading causes of death in patients with heart failure and reduced ejection fraction (HFrEF). Objective Identifying patients at higher risk for mode-specific death would allow better targeting of individual patients for relevant device and other therapies. Methods We developed models in 7156 patients with HFrEF from the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial, using Fine-Gray regressions counting other deaths as competing risks. The derived models were externally validated in the Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure (ATMOSPHERE) trial. Results NYHA class and NT-proBNP were independent predictors for both modes of death. The SD model additionally included male sex, Asian or Black race, prior CABG or PCI, cancer history, MI history, treatment with LCZ696 vs. enalapril, QRS duration and ECG left ventricular hypertrophy. While LVEF, ischemic etiology, systolic blood pressure, HF duration, ECG bundle branch block, and serum albumin, chloride and creatinine were included in the PFD model. Model discrimination was good for SD and excellent for PFD with Harrell’s C of 0.67 and 0.78 after correction for optimism, respectively. The observed and predicted incidences were similar in each quartile of risk scores at 3 years in each model. The performance of both models remained robust in ATMOSPHERE. Conclusion We developed and validated models which separately predict SD and PFD in patients with HFrEF. These models may help clinicians and patients consider therapies targeted at these modes of death. Trial registration number PARADIGM-HF: ClinicalTrials.gov NCT01035255, ATMOSPHERE: ClinicalTrials.gov NCT00853658. Graphics abstract

Background During the COVID-19 pandemic, compulsory masks became an integral part of outdoor sports such as jogging in crowded areas (e.g. city parks) as well as indoor sports in gyms and sports centers. This study, therefore, aimed to investigate the effects of medical face masks on performance and cardiorespiratory parameters in athletes. Methods In a randomized, cross-over design, 16 well-trained athletes (age 27 ± 7 years, peak oxygen consumption 56.2 ± 5.6 ml kg−1 min−1, maximum performance 5.1 ± 0.5 Watt kg−1) underwent three stepwise incremental exercise tests to exhaustion without mask (NM), with surgical mask (SM) and FFP2 mask (FFP2). Cardiorespiratory and metabolic responses were monitored by spiroergometry and blood lactate (BLa) testing throughout the tests. Results There was a large effect of masks on performance with a significant reduction of maximum performance with SM (355 ± 41 Watt) and FFP2 (364 ± 43 Watt) compared to NM (377 ± 40 Watt), respectively (p ηp2 = 0.50). A large interaction effect with a reduction of both oxygen consumption (p ηp2 = 0.34) and minute ventilation (p ηp2 = 0.39) was observed. At the termination of the test with SM 11 of 16 subjects reported acute dyspnea from the suction of the wet and deformed mask. No difference in performance was observed at the individual anaerobic threshold (p = 0.90). Conclusion Both SM and to a lesser extent FFP2 were associated with reduced maximum performance, minute ventilation, and oxygen consumption. For strenuous anaerobic exercise, an FFP2 mask may be preferred over an SM.

Objectives Optimizing valve implantation depth (ID) plays a crucial role in minimizing conduction disturbances and achieving optimal functional integrity. Until now, the impact of intraprocedural fast (FP) or rapid ventricular pacing (RP) on the implantation depth has not been investigated. Therefore, we aimed to (1) evaluate the impact of different pacing maneuvers on ID, and (2) identify the independent predictors of deep ID. Methods 473 TAVR patients with newer-generation self-expanding devices were retrospectively enrolled and one-to-one propensity-score-matching was performed, resulting in a matching of 189 FP and RP patients in each cohort. The final ID was analyzed, and the underlying functional, anatomical, and procedural conditions were evaluated by univariate and multivariate analysis. Results The highest ID was reached under RP in severe aortic valve calcification and valve size 26 mm. Multivariate analysis identified left ventricular outflow (LVOT) calcification [OR 0.50 (0.31–0.81) p = 0.005*], a “flare” aortic root [OR 0.42 (0.25–0.71), p = 0.001*], and RP (OR 0.49 [0.30–0.79], p = 0.004*) as independent highly preventable predictors of a deep ID. In a model of protective factors, ID was significantly reduced with the number of protective criteria (0–2 criteria: − 5.7 mm ± 2.6 vs. 3–4 criteria − 4.3 mm ± 2.0; p Conclusion Data from this retrospective analysis indicate that RP is an independent predictor to reach a higher implantation depth using self-expanding devices. Randomized studies should prove for validation compared to fast and non-pacing maneuvers during valve delivery and their impact on implantation depth. Trail registration Clinical Trial registration: NCT01805739. Graphic abstract Study design: Evaluation of the impact of different pacing maneuvers (fast ventricular pacing—FP vs. rapid ventricular pacing—RP) on implantation depth (ID). After one-to-one-propensity-score-matching, independent protective and risk factors for a very deep ID beneath 6 mm toward the LVOT (®. AVC aortic valve calcification.

Background Transcatheter aortic valve implantation (TAVI) has become standard treatment for elderly patients with symptomatic severe aortic valve stenosis. The ACURATE neo AS study evaluates 30-day and 1-year clinical and hemodynamic outcomes in patients treated with the ACURATE neo2 valve. Methods The primary endpoint of this single-arm multicenter study is 30-day all-cause mortality. Other key endpoints include device performance, echocardiographic measures assessed by an independent core laboratory, and VARC-2 clinical efficacy and safety endpoints through 12 months. Results The study enrolled 120 patients (mean age 82.1 ± 4.0 years; 67.5% female, mean baseline STS score 4.8 ± 3.8%). The VARC-2 composite safety endpoint at 30 days occurred in 13.3% of patients. All-cause mortality was 3.3% at 30 days and 11.9% at 1 year. The 30-day stroke rate was 2.5% (disabling stroke 1.7%); there were no new strokes between 30 days and 12 months. The rate of permanent pacemaker implantation was 15.0% (18/120) at 30 days and 17.8% (21/120) at 1 year. No patients required re-intervention for valve-related dysfunction and there were no cases of valve thrombosis or endocarditis. Patients demonstrated significant improvement in mean aortic valve gradient (baseline 38.9 ± 13.1 mmHg, 1 year 7.8 ± 3.5 mmHg; P Conclusions One-year outcomes from the ACURATE neo AS study support the safety and performance of TAVI with the ACURATE neo2 valve. Graphic Abstract

Background Cardiovascular morbidity and mortality are closely linked to chronic kidney disease (CKD). Sex-specific long-term outcome data of patients with coronary artery disease (CAD) and CKD are scarce. Methods In the prospective observational multicenter Coronary Artery Disease and REnal F ailure (CAD-REF) Registry, 773 (23.1%) women and 2,579 (76.9%) men with angiographically documented CAD and different stages of CKD were consecutively enrolled and followed for up to 8 years. Long-term outcome was evaluated using survival analysis and multivariable Cox-regression models. Results At enrollment, women were significantly older than men, and suffered from more comorbidities like CKD, hypertension, diabetes mellitus, and multivessel coronary disease. Regarding long-term mortality, no sex-specific differences were observed (Kaplan–Meier survival estimates: 69% in women vs. 69% in men, plog-rank = 0.7). Survival rates decreased from 89% for patients without CKD at enrollment to 72% for patients with CKD stages 1–2 at enrollment and 49% for patients with CKD stages 3–5 at enrollment (plog-rank Conclusions Sex differences in CAD patients mainly exist in the cardiovascular risk profile and the extent of CAD. Long-term mortality was not depended on sex or multivessel disease. More attention should be given to treatment of comorbidities such as CKD and peripheral artery disease being independent predictors of death. Clinical Trail Registration ClinicalTrials.gov Identifier: NCT00679419 Graphic abstract

Aims The aim of this pooled sub-analysis of the Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) and Culprit Lesion Only PCI versus Multivessel PCI in Cardiogenic Shock (CULPRIT-SHOCK) trial was to compare the clinical outcome of patients with acute myocardial infarction complicated by cardiogenic shock treated either with clopidogrel or the newer, more potent ADP-receptor antagonists prasugrel or ticagrelor. Methods and results For the current analysis the primary endpoint was 1-year mortality and the secondary safety endpoint was moderate or severe bleedings until hospital discharge with respect to three different ADP-receptor antagonists. 856 patients were eligible for analysis. Of these, 507 patients (59.2%) received clopidogrel, 178 patients (20.8%) prasugrel and 171 patients (20.0%) ticagrelor as acute antiplatelet therapy. The adjusted rate of mortality after 1-year did not differ significantly between prasugrel and clopidogrel (hazard ratio [HR]: 0.81, 95% confidence interval [CI] 0.60–1.09, padj = 0.17) or between ticagrelor and clopidogrel treated patients (HR: 0.86, 95% CI 0.65–1.15, padj = 0.31). In-hospital bleeding events were significantly less frequent in patients treated with ticagrelor vs. clopidogrel (HR: 0.37, 95% CI 0.20 -0.69, padj = 0.002) and not significantly different in patients treated with prasugrel vs. clopidogrel (HR: 0.73, 95% CI 0.43 -1.24, padj = 0.24). Conclusion This pooled sub-analysis is the largest analysis on safety and efficacy of three oral ADP-receptor antagonists and shows that acute therapy with either clopidogrel, prasugrel or ticagrelor is no independent predictor of 1-year mortality. Treatment with ticagrelor seems independently associated with less in-hospital moderate and severe bleeding events compared to clopidogrel. This finding might be due to selection bias and should be interpreted with caution. Graphic abstract

Background Patients with cardiogenic shock or cardiac arrest undergoing venoarterial extracorporeal membrane oxygenation (V-A ECMO) frequently present with blood glucose levels out of normal range. The clinical relevance of such findings in the context of V-A ECMO is unknown. We therefore investigated the prognostic relevance of blood glucose at time of cannulation for V-A ECMO. Methods We conducted a single-center retrospective registry study. All patients receiving V-A ECMO from October 2010 to January 2020 were included if blood glucose level at time of cannulation were documented. Patients were divided in five groups according to the initial blood glucose level ranging from hypoglycemic ( 400 mg/dl) hyperglycemia, respectively. Clinical presentation, arterial blood gas analysis, and survival were compared between the groups. Results 392 patients met inclusion criteria. Median age was 62 years (51.5–70.0), SAPS II at admission was 54 (43.5–63.0), and 108/392 (27.6%) were female. 131/392 were discharged alive (hospital survival 33.4%). At time of cannulation, survivors had higher pH, hemoglobin, calcium, bicarbonate but lower potassium and lactate levels compared to non-survivors (all p 400 mg/dl) and low (p = 0.02). Glucose was independently associated with poor outcome after adjustment for other predictors of survival and persisted in all investigated subgroups. Conclusion Arterial blood glucose at time of V-A ECMO cannulation predicts in-hospital survival of patients with cardiac shock or after ECPR. Whether dysglycemia represents a potential therapeutic target requires further evaluation in prospective studies. Graphical Abstract

Introduction Supraventricular tachycardias (SVT) are often difficult to document due to their intermittent, short-lasting nature. Smartphone-based one-lead ECG monitors (sECG) were initially developed for the diagnosis of atrial fibrillation. No data have been published regarding their potential role in differentiating inappropiate sinus tachycardia (IST) from regular SVT. If cardiologists could distinguish IST from SVT in sECG, economic health care burden might be significantly reduced. Methods We prospectively recruited 75 consecutive patients with known SVT undergoing an EP study. In all patients, four ECG were recorded: a sECG during SVT and during sinus tachycardia and respective 12-lead ECG. Two experienced electrophysiologists were blinded to the diagnoses and separately evaluated all ECG. Results Three hundred individual ECG were recorded in 75 patients (47 female, age 50 ± 18 years, BMI 26 ± 5 kg/m2, 60 AVNRT, 15 AVRT). The electrophysiologists’ blinded interpretation of sECG recordings showed a sensitivity of 89% and a specificity of 91% for the detection of SVT (interobserver agreement κ = 0.76). In high-quality sECG recordings (68%), sensitivity rose to 95% with a specificity of 92% (interobserver agreement of κ = 0.91). Specificity increased to 96% when both electrophysiologists agreed on the diagnosis. Respective 12-lead ECG had a sensitivity of 100% and specificity of 98% for the detection of SVT. Conclusion A smartphone-based one-lead ECG monitor allows for differentiation of SVT from IST in about 90% of cases. These results should encourage cardiologists to integrate wearables into clinical practice, possibly reducing time to definitive diagnosis of an arrhythmia and unnecessary EP procedures. Graphical abstract A smartphone-based one lead ECG device (panel A) can be used reliably to differentiate supraventricular tachycardia (panel B) from inappropriate sinus tachycardia when compared to a simultaneously conducted gold-standard electrophysiology study (panels C, D).

Background Relevant atrial cardiomyopathy (ACM), defined as a left atrial (LA) low-voltage area ≥ 2 cm2 at 0.5 mV threshold on endocardial contact mapping, is associated with new-onset atrial fibrillation (AF), higher arrhythmia recurrence rates after pulmonary vein isolation (PVI), and an increased risk of stroke. The current study aimed to assess two non-invasive echocardiographic parameters, LA emptying fraction (EF) and LA longitudinal strain (LAS, during reservoir (LASr), conduit (LAScd) and contraction phase (LASct)) for the diagnosis of ACM and prediction of arrhythmia outcome after PVI. Methods We prospectively enrolled 60 consecutive, ablation-naive patients (age 66 ± 9 years, 80% males) with persistent AF. In 30 patients (derivation cohort), LA-EF and LAS cut-off values for the presence of relevant ACM (high-density endocardial contact mapping in sinus rhythm prior to PVI at 3000 ± 1249 sites) were established in sinus rhythm and tested in a validation cohort (n = 30). Arrhythmia recurrence within 12 months was documented using 72-h Holter electrocardiograms. Results An LA-EF of Conclusion The echocardiographic parameters LA-EF and LAS allow accurate, non-invasive diagnosis of ACM and prediction of arrhythmia recurrence after PVI. Graphic abstract

Objectives Barlow´s disease represents a wide spectrum of mitral valve pathologies associated with regurgitation (MR), excess leaflet tissue, and prolapse. Repair strategies range from complex repairs with annuloplasty plus neochords through resection to annuloplasty-only. The latter requires symmetric prolapse patterns and central regurgitant jets. We aimed to assess repair success and durability, survival, and intraoperative outcomes with symmetric and asymmetric Barlow’s disease. Methods Between 09/10 and 03/20, 103 patients (of 1939 with mitral valve surgery) presented with Barlow´s disease. All received surgery through mini-thoracotomy with annuloplasty plus neochords (n = 71) or annuloplasty-only (n = 31). One valve was replaced for endocarditis (repair rate: 99%). Results Annuloplasty-only patients were older (64 ± 16 vs. 55 ± 11 years, p = 0.008) and presented with higher risk (EuroSCORE II: 4.2 ± 4.9 vs. 1.6 ± 1.7, p = 0.007). Annuloplasty-only patients had shorter cross-clamp times (53 ± 18 min vs. 76 ± 23 min, p p p = 0.455). In three patients, annuloplasty-only caused intraoperative systolic anterior motion (SAM), which was fully resolved by neochords to the posterior leaflet. There were no conversions to sternotomy or deaths at 30-days. Three patients required reoperation for recurrent MR (at 25 days, 2.8 and 7.8 years). At the latest follow-up, there was no MR in 81.4%, mild in 14.7%, and moderate in 2.9%. Three patients died due to non-cardiac reasons. Surviving patients report the absence of relevant symptoms. Conclusions Minimally-invasive Barlow’s repair is safe with good durability. Annuloplasty-only may be a simple solution for complex but symmetric pathologies. However, it may carry an increased risk of intraoperative SAM.

Background The PASCAL system is a novel device for edge-to-edge treatment of mitral regurgitation (MR). The aim of this study was to compare the safety and efficacy of the PASCAL to the MitraClip system in a highly selected group of patients with complex primary mitral regurgitation (PMR) defined as effective regurgitant orifice area (MR-EROA) ≥ 0.40 cm2, large flail gap (≥ 5 mm) or width (≥ 7 mm) or Barlow’s disease. Methods 38 patients with complex PMR undergoing mitral intervention using PASCAL (n = 22) or MitraClip (n = 16) were enrolled. Primary efficacy endpoints were procedural success and degree of residual MR at discharge. The rate of major adverse events (MAE) according to the Mitral Valve Academic Consortium (MVARC) criteria was chosen as the primary safety endpoint. Results Patient collectives did not differ relevantly regarding pertinent baseline parameters. Patients` median age was 83.0 [77.5–85.3] years (PASCAL) and 82.5 [76.5–86.5] years (MitraClip). MR-EROA at baseline was 0.70 [0.68–0.83] cm2 (PASCAL) and 0.70 [0.50–0.90] cm2 (MitraClip), respectively. 3D-echocardiographic morphometry of the mitral valve apparatus revealed no relevant differences between groups. Procedural success was achieved in 95.5% (PASCAL) and 87.5% (MitraClip), respectively. In 86.4% of the patients a residual MR grade ≤ 1 + was achieved with PASCAL whereas reduction to MR grade ≤ 1 + with MitraClip was achieved in 62.5%. Neither procedure time number of implanted devices, nor transmitral gradient differed significantly. No periprocedural MAE according to MVARC occured. Conclusion In this highly selected patient group with complex PMR both systems exhibited equal procedural safety. MitraClip and PASCAL reduced qualitative and semi-quantitative parameters of MR to an at least comparable extent. Graphic abstract

Background Hemodynamic response after successful extracorporeal cardiopulmonary resuscitation (eCPR) is very heterogeneous. Pulse pressure (PP) as an easy to access surrogate parameter and correlate for myocardial damage or recovery from it, might be a valuable tool to estimate the outcome of these patients. Purpose To investigate the predictive value of the surrogate parameter PP in eCPR patients. Methods We report retrospective data of a single-centre registry of eCPR patients, treated at our Interdisciplinary Medical Intensive Care Unit between 01/2017 and 01/2020. The association between PP of the first 10 days after eCPR and hospital survival was investigated. Moreover, patients were divided into three groups according to their PP (low (0–9 mmHg), mid (10–29 mmHg) and high (≥30 mmHg)) at each time point. Results 143 patients (age 63 years, 74.1% male, 40% OHCA, average low flow time 49 min) were analysed. Overall hospital survival rate was 28%. A low PP both early after eCPR (after 1, 3, 6 and 12 hours) and in the further course after day 1 to day 8 was associated with reduced hospital survival. At each time point (1 hour to day 5) the classification of patients into a low, mid and high PP group was able to categorize the patients for a low (5–20%), moderate (20–40%) and high (50–70%) survival rate. A multivariable analysis showed that the mean PP of the first 24 hours was an independent predictor for survival (p=0.008, figure 1). Conclusion In this analysis, PP occurred to be a valuable parameter to estimate survival and maybe support clinical decision making in the further course of patients after eCPR. Funding Acknowledgement Type of funding sources: None. Figure 1. Survival of eCPR patients by mean 24hPP

Aims CMR feature tracking strain (CMR-FT) provides prognostic information. However, there is a paucity of data in hypertrophic cardiomyopathy (HCM). We sought to analyze global CMR-FT parameters in all four cardiac chambers and to assess associations with NT-proBNP and cardiac troponin T (hsTnT) in patients with HCM. Methods This retrospective study included 144 HCM patients and 16 healthy controls with CMR at 1.5 T. Analyses were performed on standard steady-state free precession cine (SSFP) CMR data using a commercially available software. Global left ventricular (LV) strain was assessed as longitudinal (LVLAX-GLS), circumferential (LVLAX-GCS) and radial strain (LVLAX-GRS) on long -axis (LAX) and as LVSAX-GCS and LVSAX-GRS on short- axis (SAX). Right ventricular (RV-GLS), left atrial (LA-GLS) and right atrial (RA-GLS) strain were assessed on LAX. Results We found LVLAX-GLS [− 18.9 (− 22.0, − 16.0), − 23.5 (− 25.5, − 22.0) %, p = 0.0001), LVSAX-GRS [86.8 (65.9–115.5), 119.6 (91.3–143.7) %, p = 0.001] and LALAX-GLS [LA2CH-GLS 29.2 (19.1–37.7), LA2CH-GLS 38.2 (34.3–47.1) %, p = 0.0036; LA4CH-GLS 22.4 (14.6–30.7) vs. LA4CH-GLS 33.4 (28.4–37.3) %, p = 0.0033] to be impaired in HCM compared to healthy controls despite normal LVEF. Furthermore, LV and LA strain parameters were impaired in HCM with elevated NT-proBNP and/or hsTnT, despite preserved LVEF compared to HCM with normal biomarker levels. There was a moderate correlation of LV and LA CMR-FT with levels of NT-proBNP and hsTnT. Conclusion CMR-FT reveals LV and LA dysfunction in HCM despite normal LVEF. The association between impaired LV strain and elevated NT-proBNP and hsTnT indicates a link between unapparent functional abnormalities and disease severity in HCM. Graphic abstract Typical CMR-FT findings in patients with hypertrophic cardiomyopathy

BackgroundThe recent AFFIRM-AHF trial assessing the effect of intravenous (IV) iron on outcomes in patients hospitalised with worsening heart failure who had iron deficiency (ID) narrowly missed its primary efficacy endpoint of recurrent hospitalisations for heart failure (HHF) or cardiovascular (CV) death. We conducted a meta-analysis to determine whether these results were consistent with previous trials.MethodsWe searched for randomised trials of patients with heart failure investigating the effect of IV iron vs placebo/control groups that reported HHF and CV mortality from 1st January 2000 to 5th December 2020. Seven trials were identified and included in this analysis. A fixed effect model was applied to assess the effects of IV iron on the composite of first HHF or CV mortality and individual components of these.ResultsAltogether, 2,166 patients were included (n = 1168 assigned to IV iron;n = 998 assigned to control). IV iron reduced the composite of HHF or CV mortality substantially [OR 0.73; (95% confidence interval 0.59–0.90);p = 0.003]. Outcomes were consistent for the pooled trials prior to AFFIRM-AHF. Whereas first HHF were reduced substantially [OR 0.67; (0.54–0.85);p = 0.0007], the effect on CV mortality was uncertain but appeared smaller [OR 0.89; (0.66–1.21);p = 0.47].ConclusionAdministration of IV iron to patients with heart failure and ID reduces the risk of the composite outcome of first heart failure hospitalisation or cardiovascular mortality, but this outcome may be driven predominantly by an effect on HHF. At least three more substantial trials of intravenous iron are underway.Graphic abstract

Background Since 1901, at least 15 scholars who contributed to cardiovascular research have received a Nobel prize in physiology or medicine. Methods Using the Nobel nomination database (nobelprize.org), which contains 5950 nominations in the accessible period from 1901 to 1953 in physiology or medicine, we listed all international nominees who contributed to cardiovascular research. We subsequently collected nomination letters and jury reports of the prime candidates from the archive of the Nobel Committee in Sweden to identify shortlisted candidates. Results The five most frequently nominated researchers with cardiovascular connections from 1901 to 1953 were, in descending order, the surgeon René Leriche (1879–1955) (FR) with a total of 79 nominations, the physiologist and 1924 Nobel laureate Willem Einthoven (1860–1927) (NL) (31 nominations), the surgeon Alfred Blalock (1899–1964) (US) (29 nominations), the pharmacologist and 1936 Nobel laureate Otto Loewi (1873–1961) (DE, AT, US) (27 nominations) and the paediatric cardiologist Helen Taussig (1898–1986) (US) (24 nominations). The research of these scholars merely hints at the width of topics brought up by nominators ranging from the physiological and pathological basics to the diagnosis and (surgical) interventions of diseases such as heart malformation or hypertension. Conclusion We argue that an analysis of Nobel Prize nominations can reconstruct important scientific trends within cardiovascular research during the first half of the twentieth century.

Objectives To assess the value of effective regurgitant orifice (ERO) in predicting outcome after edge-to-edge transcatheter mitral valve repair (TMVR) for secondary mitral regurgitation (SMR) and identify the optimal cut-off for patients’ selection. Methods Using the EuroSMR (European Registry of Transcatheter Repair for Secondary Mitral Regurgitation) registry, that included patients undergoing edge-to-edge TMVR for SMR between November 2008 and January 2019 in 8 experienced European centres, we assessed the optimal ERO threshold associated with mortality in SMR patients undergoing TMVR, and compared characteristics and outcomes of patients according to baseline ERO. Results Among 1062 patients with severe SMR and ERO quantification by proximal isovelocity surface area method in the registry, ERO was 2 in 575 patients (54.1%), who were more symptomatic at baseline (NYHA class ≥ III: 91.4% vs. 86.9%, for ERO 2; P = 0.004). There was no difference in all-cause mortality at 2-year follow-up according to baseline ERO (28.3% vs. 30.0% for ERO 2, P = 0.585). Both patient groups demonstrated significant improvement of at least one NYHA class (61.7% and 73.8%, P = 0.002), resulting in a prevalence of NYHA class ≤ II at 1-year follow-up of 60.0% and 67.4% for ERO 2, respectively (P = 0.05). Conclusion All-cause mortality at 2 years after TMVR does not differ if baseline ERO is 2, and both groups exhibit relevant clinical improvements. Accordingly, TMVR should not be withheld from patients with ERO 2 who remain symptomatic despite optimal medical treatment, if TMVR appropriateness was determined by experienced teams in dedicated valve centres.

Background Cardiovascular and metabolic regulation is governed by neurohumoral signalling in relevant organs such as kidney, liver, pancreas, duodenum, adipose tissue, and skeletal muscle. Combined targeting of relevant neural outflows may provide a unique therapeutic opportunity for cardiometabolic disease. Objectives We aimed to investigate the feasibility, safety, and performance of a novel device-based approach for multi-organ denervation in a swine model over 30 and 90 days of follow-up. Methods Five Yorkshire cross pigs underwent combined percutaneous denervation in the renal arteries and the common hepatic artery (CHA) with the iRF Denervation System. Control animals (n = 3) were also studied. Specific energy doses were administered in the renal arteries and CHA. Blood was collected at 30 and 90 days. All animals had a pre-terminal procedure angiography. Tissue samples were collected for norepinephrine (NEPI) bioanalysis. Histopathological evaluation of collateral structures and tissues near the treatment sites was performed to assess treatment safety. Results All animals entered and exited the study in good health. No stenosis or vessel abnormalities were present. No significant changes in serum chemistry occurred. NEPI concentrations were significantly reduced in the liver (− 88%, p = 0.005), kidneys (− 78%, p p = 0.018) and duodenum (− 95%, p = 0.028) following multi-organ denervation treatment compared to control animals. Histologic findings were consistent with favourable tissue responses at 90 days follow-up. Conclusions Significant and sustained denervation of the treated organs was achieved at 90 days without major safety events. Our findings demonstrate the feasibility of multi-organ denervation using a novel iRF Denervation System in a single procedure.

Aims Atrial fibrillation (AF) is associated with increased mortality after transcatheter aortic valve replacement (TAVR). Cerebrovascular complications and bleeding events associated with anticoagulation therapy are discussed to be possible causes for this increased mortality. The present study sought to assess whether AF is associated with impaired left ventricular (LV) reverse remodeling representing another possible mechanism for poor outcome. Methods All patients who underwent TAVR in our institution and had 1-year echocardiography follow-up were included. LV mass index (LVMI) at baseline and follow-up as well as LVMI change at 1 year were assessed with respect to the presence of AF (either at baseline or during hospitalization after TAVR) and sinus rhythm (SR). Results A total of 213 patients (n = 95 in AF; n = 118 in SR) were enrolled in the present study. Patients with AF had higher LVMI at 1 year compared to those with SR (173 ± 61 g/m2 vs. 154 ± 55 g/m2; p = 0.02) and they showed lower relative LVMI change at 1 year (− 2 ± 28% vs. − 9 ± 29%; p = 0.04). In linear regression analysis, AF was independently associated with relative LVMI change (regression coefficient ß 0.076 [95% CI 0.001–0.150]; p = 0.04). With respect to clinical outcome depending on AF and LVMI regression, the Kaplan–Meier estimated event-free of death or cardiac rehospitalization at 3 years was lowest among patients with AF and no LVMI regression. Conclusions The present study identified a significant association of AF with changes in LVMI after TAVR, which was also shown to be associated with clinical outcome.

Background Transcatheter tricuspid valve intervention became an option for pacemaker lead-associated tricuspid regurgitation. This study investigated the progression of tricuspid regurgitation (TR) in patients with or without pre-existing right ventricular dilatation (RVD) undergoing pacemaker implantation. Methods Patients were included if they had implantation of transtricuspid pacemaker lead and completed echocardiography before and after implantation. The cohort was divided in patients with and without RVD (cut-off basal RV diameter ≥ 42 mm). TR was graded in none/mild, moderate, and severe. Worsening of one grade was defined as progression. Survival analyses were plotted for 10 years. Results In total, 990 patients were analyzed (24.5% with RVD). Progression of TR occurred in 46.1% of patients with RVD and in 25.6% of patients without RVD (P P = 0.003), pre-existing TR (OR 4.30; 95% CI 2.51–7.38; P P = 0.006), single RV lead (OR 1.67; 95% CI 1.09–2.56; P = 0.018), mitral regurgitation (OR 2.08; 95% CI 1.42–3.05; P P = 0.03). Survival-predictors were pacemaker lead-associated TR (HR 1.38; 95% CI 1.04–1.84; P = 0.028), mitral regurgitation (HR 1.34; 95% CI 1.02–1.77; P = 0.034), heart failure (HR 1.75; 95% CI 1.31–2.33; P P P Conclusions Patients with RVD receiving pacemaker suffered from increased TR progression, leading to decreased survival. Graphic abstract

Objectives Direct toxic effects of transthyretin amyloid in patient plasma upon cardiomyocytes are discussed. However, no data regarding the relevance of this putative effect for clinical outcome are available. In this monocentric prospective study, we analyzed cellular hypertrophy after phenylephrine stimulation in vitro in the presence of patient plasma and correlated the cellular growth response with phenotype and prognosis. Methods and results Progress in automated microscopy and image analysis allows high-throughput analysis of cell morphology. Using the InCell microscopy system, changes in cardiomyocyte’s size after treatment with patient plasma from 89 patients suffering from transthyretin amyloidosis and 16 controls were quantified. For this purpose, we propose a novel metric that we named Hypertrophic Index, defined as difference in cell size after phenylephrine stimulation normalized to the unstimulated cell size. Its prognostic value was assessed for multiple endpoints (HTX: death/heart transplantation; DMP: cardiac decompensation; MACE: combined) using Cox proportional hazard models. Cells treated with plasma from healthy controls and hereditary transthyretin amyloidosis with polyneuropathy showed an increase in Hypertrophic Index after phenylephrine stimulation, whereas stimulation after treatment with hereditary cardiac amyloidosis or wild-type transthyretin patient plasma showed a significantly attenuated response. Hypertrophic Index was associated in univariate analyses with HTX (hazard ratio (HR) high vs low: 0.12 [0.02–0.58], p = 0.004), DMP: (HR 0.26 [0.11–0.62], p = 0.003) and MACE (HR 0.24 [0.11–0.55], p Conclusions Attenuated cardiomyocyte growth response after stimulation with patient plasma in vitro is an independent risk factor for adverse cardiac events in ATTR patients

Objectives The aim of this study was to investigate the impact of concomitant long-term medication—with a focus on ACE inhibitors and oral anticoagulation—on clinical outcomes in patients hospitalized with coronavirus disease 2019. Methods This is a retrospective cohort study using claims data of the biggest German health insurance company AOK, covering 26.9 million people all over Germany. In particular, patient-related characteristics and co-medication were evaluated. A multivariable logistic regression model was adopted to identify independent predictors for the primary outcome measure of all-cause mortality or need for invasive or non-invasive ventilation or extracorporeal membrane oxygenation. Results 6637 patients in 853 German hospitals were included. The primary outcome occurred in 1826 patients (27.5%). 1372 patients (20.7%) died, 886 patients (13.3%) needed respiratory support, and 53 patients (0.8%) received extracorporeal membrane oxygenation. 34 of these patients survived (64.2%). The multivariable model demonstrated that pre-existing oral anticoagulation therapy with either vitamin-K antagonists OR 0.57 (95% CI 0.40–0.83, p = 0.003) or direct oral anticoagulants OR 0.71 (95% CI 0.56–0.91, p = 0.007)—but not with antiplatelet therapy alone OR 1.10 (95% CI 0.88–1.23, p = 0.66)—was associated with a lower event rate. This finding was confirmed in a propensity match analysis. Conclusions In a multivariable analysis, a therapy with both direct oral anticoagulants or vitamin-K antagonists—but not with antiplatelet therapy—was associated with improved clinical outcomes. ACE inhibitors did not impact outcomes. Prospective randomized trials are needed to verify this hypothesis. Graphic abstract Supplementary Information The online version contains supplementary material available at 10.1007/s00392-020-01783-x.

Background Concomitant tricuspid regurgitation (TR) is a common finding in mitral regurgitation (MR). Transcatheter repair (TMVR) is a favorable treatment option in patients at elevated surgical risk. To date, evidence on long-term prognosis and the prognostic impact of TR after TMVR is limited. Methods Long-term survival data of patients undergoing isolated edge-to-edge repair from June 2010 to March 2018 (combinations with other forms of TMVR or tricuspid valve therapy excluded) were analyzed in a retrospective monocentric study. TR severity was categorized and the impact of TR on survival was analysed. Results Overall, 606 patients [46.5% female, 56.4% functional MR (FMR)] were enrolled in this study. TR at baseline was categorized severe/medium/mild/no or trace in 23.2/34.3/36.3/6.3% of the cases. At 30-day follow-up, improvement of at least one TR-grade was documented in 34.9%. Severe TR at baseline was identified as predictor of 1-year survival [65.2% vs. 77.0%, p = 0.030; HR for death 1.68 (95% CI 1.12–2.54), p = 0.013] and in FMR-patients also regarding long-term prognosis [adjusted HR for long-term mortality 1.57 (95% CI 1.00–2.45), p = 0.049]. Missing post-interventional reduction of TR severity was predictive for poor prognosis, especially in the FMR-subgroup [1-year survival: 92.9% vs. 78.3%, p = 0.025; HR for death at 1-year follow-up 3.31 (95% CI 1.15–9.58), p = 0.027]. While BNP levels decreased in both subgroups, TR reduction was associated with improved symptomatic benefit (NYHA-class-reduction 78.6 vs. 65.9%, p = 0.021). Conclusion In this large study, both, severe TR at baseline as well as missing secondary reduction were predictive for impaired long-term prognosis, especially in patients with FMR etiology. TR reduction was associated with increased symptomatic benefit. Graphic abstract

Background Frailty is common in patients with chronic heart failure (CHF) and is associated with poor outcomes. The natural history of frail patients with CHF is unknown. Methods Frailty was assessed using the clinical frailty scale (CFS) in 467 consecutive patients with CHF (67% male, median age 76 years, median NT-proBNP 1156 ng/L) attending a routine follow-up visit. Those with CFS > 4 were classified as frail. We investigated the relation between frailty and treatments, hospitalisation and death in patients with CHF. Results 206 patients (44%) were frail. Of 291 patients with HF with reduced ejection fraction (HeFREF), those who were frail (N = 117; 40%) were less likely to receive optimal treatment, with many not receiving a renin–angiotensin–aldosterone system inhibitor (frail: 25% vs. non-frail: 4%), a beta-blocker (16% vs. 8%) or a mineralocorticoid receptor antagonist (50% vs 41%). By 1 year, there were 56 deaths and 322 hospitalisations, of which 25 (45%) and 198 (61%), respectively, were due to non-cardiovascular (non-CV) causes. Most deaths (N = 46, 82%) and hospitalisations (N = 215, 67%) occurred in frail patients. Amongst frail patients, 43% of deaths and 64% of hospitalisations were for non-CV causes; 58% of cardiovascular (CV) deaths were due to advancing HF. Among non-frail patients, 50% of deaths and 57% of hospitalisations were for non-CV causes; all CV deaths were due to advancing HF. Conclusion Frailty in patients with HeFREF is associated with sub-optimal medical treatment. Frail patients are more likely to die or be admitted to hospital, but whether frail or not, many events are non-CV. Graphical abstract

Background The benefits of de novo cardiac resynchronization therapy (CRT) in patients with QRS-prolongation and impaired left-ventricular function (LVEF) are well established. Current guidelines also recommend CRT-upgrade in patients requiring permanent or frequent right ventricular pacing (RVP) with symptomatic heart failure and reduced LVEF. Whereas several predictors of response to de novo CRT-implantation such as female gender, QRS-duration, non-ischemic cardiomyopathy (NICM) are known due to large prospective trials, similar factors regarding CRT-upgrade are currently lacking. Methods and results We examine 114 patients 3–6 months after CRT-upgrade due to frequent RVP (> 50%) and symptomatic heart failure. Response to CRT was evaluated by improvement in NYHA class referring to the Minnesota Living With Heart Failure Questionnaire. Only cardiomyopathy type and use of Angiotensin-converting-enzyme (ACE) inhibitor had an impact on response to CRT-upgrade in a linear regression model. Patients with NICM presented a greater responder rate than patients with ischemic cardiomyopathy (ICM) (80.4 vs. 60.3%, p Conclusion Only underlying heart disease (NICM vs. ICM) and the use of ACE inhibitor were significant predictors of response to CRT-upgrade. In contrast to de novo CRT-recipients, where pre-implant QRS-duration is a key predictor, QRS-duration during RV-pacing has no significant impact on CRT-response in this cohort. Graphic abstract

Background Transcatheter tricuspid valve repair (TTVR) is a promising technique for the treatment of tricuspid regurgitation (TR). Data comparing the performance of novel edge-to-edge devices (PASCAL and MitraClip-XTR) are scarce. Methods We identified 80 consecutive patients who underwent TTVR using either the PASCAL or MitraClip-XTR system to treat symptomatic TR from July 2018 to June 2020. To adjust for baseline imbalances, we performed a propensity score (PS) 1:1 matching. The primary endpoint was a reduction in TR severity by at least one grade at 30 days. Results The PS-matched cohort (n = 44) was at high-surgical risk (EuroSCORE II: 7.5% [interquartile range (IQR) 4.8–12.1%]) with a mean TR grade of 4.3 ± 0.8 and median coaptation gap of 6.2 mm [IQR 3.2–9.1 mm]. The primary endpoint was similarly observed in both groups (PASCAL: 91% vs. MitraClip-XTR: 96%). Multiple device implantation was the most common form (59% vs. 82%, p = 0.19), and the occurrence of SLDA was comparable between the PASCAL and MitraClip-XTR system (5.7% [2 of 35 implanted devices] vs. 4.4% [2 of 45 implanted devices], p = 0.99). No periprocedural death or conversions to surgery occurred, and 30-day mortality (5.0% vs. 5.0%, log-rank p = 0.99) and 3-month mortality (10.0% vs. 5.0%, log-rank p = 0.56) were similar between both groups. During follow-up, functional NYHA class, 6-min walking distance, and health status improved in both groups. Conclusions Both TTVR devices, PASCAL and MitraClip-XTR, appeared feasible and comparable for an effective TR reduction. Randomized head-to-head comparisons will help to further define the appropriate scope of application of each system.

Background Sudden death (SD) and pump failure death (PFD) are leading modes of death in heart failure and preserved ejection fraction (HFpEF). Risk stratification for mode-specific death may aid in patient enrichment for new device trials in HFpEF. Methods Models were derived in 4116 patients in the Irbesartan in Heart Failure with Preserved Ejection Fraction trial (I-Preserve), using competing risks regression analysis. A series of models were built in a stepwise manner, and were validated in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Preserved and Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trials. Results The clinical model for SD included older age, men, lower LVEF, higher heart rate, history of diabetes or myocardial infarction, and HF hospitalization within previous 6 months, all of which were associated with a higher SD risk. The clinical model predicting PFD included older age, men, lower LVEF or diastolic blood pressure, higher heart rate, and history of diabetes or atrial fibrillation, all for a higher PFD risk, and dyslipidaemia for a lower risk of PFD. In each model, the observed and predicted incidences were similar in each risk subgroup, suggesting good calibration. Model discrimination was good for SD and excellent for PFD with Harrell’s C of 0.71 (95% CI 0.68–0.75) and 0.78 (95% CI 0.75–0.82), respectively. Both models were robust in external validation. Adding ECG and biochemical parameters, model performance improved little in the derivation cohort but decreased in validation. Including NT-proBNP substantially increased discrimination of the SD model, and simplified the PFD model with marginal increase in discrimination. Conclusions The clinical models can predict risks for SD and PFD separately with good discrimination and calibration in HFpEF and are robust in external validation. Adding NT-proBNP further improved model performance. These models may help to identify high-risk individuals for device intervention in future trials. Clinical trial registration I-Preserve: ClinicalTrials.gov NCT00095238; TOPCAT: ClinicalTrials.gov NCT00094302; CHARM-Preserved: ClinicalTrials.gov NCT00634712. Graphic abstract

Background Frailty is a common characteristic of patients undergoing transcatheter mitral valve repair (TMVR). It is unclear whether the physical vulnerability of frail patients translates into increased procedural health care utilization. Methods and results Frailty was assessed using the Fried criteria in 229 patients undergoing TMVR using the MitraClip system at our institution and associations with total costs and costs by cost centers within the hospital incurred during periprocedural hospitalization were examined. Frail patients (n = 107, 47%) compared to non-frail patients showed significantly higher total costs [median/interquartile range, excluding implant costs: 7,337 € (5,911–9,814) vs 6,238 € (5,584–7,499), p = 0.001], with a difference in means of 2,317 €. Frailty was the only clinical baseline characteristic with significant association with total costs. Higher total costs in frail patients were attributable primarily to longer stay on intermediate/intensive care unit (3.8 ± 5.7 days in frail vs 2.1 ± 1.7 days in non-frail, p = 0.003), but also to costs of clinical chemistry and physiotherapy. The prolonged stay on intermediate/intensive care unit in frail patients was attributable to postprocedural complications such as bleeding, kidney injury, infections and cardiovascular instability. Conclusion Frailty is associated with a mean 32% increase of hospital costs in patients undergoing TMVR, which is primarily the result of a prolonged recovery and increased vulnerability to complications. These findings are valuable for a hospital’s total cost calculation and resource allocation planning. Since frailty is regarded a potentially reversible health state, preventive interventions may help reduce costs in frail patients. Graphic abstract

Aims Stroke is a major complication after transcatheter aortic valve implantation (TAVI). Although multifactorial, it remains unknown whether the valve deployment system itself has an impact on the incidence of early stroke. We performed a meta- and network analysis to investigate the 30-day stroke incidence of self-expandable (SEV) and balloon-expandable (BEV) valves after transfemoral TAVI. Methods and results Overall, 2723 articles were searched directly comparing the performance of SEV and BEV after transfemoral TAVI, from which 9 were included (3086 patients). Random effects models were used for meta- and network meta-analysis based on a frequentist framework. Thirty-day incidence of stroke was 1.8% in SEV and 3.1% in BEV (risk ratio of 0.62, 95% confidence interval (CI) 0.49–0.80, p = 0.004). Treatment ranking based on network analysis (P-score) revealed CoreValve with the best performance for 30-day stroke incidence (75.2%), whereas SAPIEN had the worst (19.0%). However, network analysis showed no inferiority of SAPIEN compared with CoreValve (odds ratio 2.24, 95% CI 0.70–7.2). Conclusion Our analysis indicates higher 30-day stroke incidence after transfemoral TAVI with BEV compared to SEV. We could not find evidence for superiority of a specific valve system. More randomized controlled trials with head-to-head comparison of SEV and BEV are needed to address this open question. Graphic abstract

Aims During the COVID-19 pandemic, hospital admissions for cardiac care have declined. However, effects on mortality are unclear. Thus, we sought to evaluate the impact of the lockdown period in central Germany on overall and cardiovascular deaths. Simultaneously we looked at catheterization activities in the same region. Methods and results Data from 22 of 24 public health-authorities in central Germany were aggregated during the pandemic related lockdown period and compared to the same time period in 2019. Information on the total number of deaths and causes of death, including cardiovascular mortality, were collected. Additionally, we compared rates of hospitalization (n = 5178) for chronic coronary syndrome (CCS), acute coronary syndrome (ACS), and out of hospital cardiac arrest (OHCA) in 26 hospitals in this area. Data on 5,984 deaths occurring between March 23, 2020 and April 26, 2020 were evaluated. In comparison to the reference non-pandemic period in 2019 (deaths: n = 5832), there was a non-significant increase in all-cause mortality of 2.6% [incidence rate ratio (IRR) 1.03, 95% confidence interval (CI) 0.99–1.06; p = 0.16]. Cardiovascular and cardiac mortality increased significantly by 7.6% (IRR 1.08, 95%-CI 1.01–1.14; p = 0.02) and by 11.8% (IRR 1.12, 95%-CI 1.05–1.19; p Conclusion During the COVID-19-related lockdown a significant increase in cardiovascular mortality was observed in central Germany, whereas catherization activities were reduced. The mechanisms underlying both of these observations should be investigated further in order to better understand the effects of a pandemic-related lockdown and social-distancing restrictions on cardiovascular care and mortality. Graphic abstract