Leonhard Binzenhöfer

Aim: Sports-related physical activity is associated with an increased risk of ventricular dysfunction and arrhythmias in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). However, there are currently no standardized strategies for activity assessment. Thresholds for harmful levels of physical activity suggested by previous studies vary substantially and neither lifetime activity burden nor continuous modelling approaches were considered. Methods and results: For this single-centre retrospective study, ARVC patients were interviewed to assess sports-related and non-sports-related physical activity between the age of 10 years and the last follow-up. Activity data were aggregated to the median metabolic equivalent of task—hours (METh) per week for each year. The association between cumulative physical activity burden and clinical study endpoints was investigated using Cox regression models. A total of 124 patients (median age: 39.5 years, 48% male) were included in the analysis, of whom 93 had been diagnosed with definite ARVC. Study participants reported a median overall activity of 202.3 METh/week, with 38.7 METh/week attributed to sports-related activity. In the continuous model, cumulative overall activity burden was associated with the occurrence of symptomatic heart failure [hazard ratio (HR) per 100 METh/week: 1.017, 95% CI (1.003, 1.032), P = 0.015], sustained ventricular tachycardia [HR: 1.021, 95% CI (1.006, 1.037), P = 0.007], and implantable cardioverter defibrillator interventions [HR: 1.017, 95%CI (1.000, 1.034), P = 0.048]. This finding was consistent when considering sports-related activity separately as a predictor variable, whereas the resulting hazard ratios did not show a significant association for non-sports-related physical activity. Conclusion: This study demonstrates for the first time that cumulative physical activity as a continuous predictor variable is associated with symptomatic heart failure and arrhythmic risk in ARVC patients. Collaborative research is required in larger cohorts to investigate the influence of potential confounders on event occurrence and to develop threshold recommendations for clinical practice.

Background and Aims: Fulminant myocarditis (FM) is a complex clinical syndrome characterized by acute myocardial inflammation and cardiogenic shock. Evidence on long-term outcomes, mortality risk factors, and targeted treatment options remains limited. Methods: This retrospective analysis included consecutive adult patients admitted for FM between January 2012 and November 2022 at 26 European tertiary centres. According to endomyocardial biopsy (EMB) findings, patients were categorized as lymphocytic (LM), eosinophilic (EM), necrotizing eosinophilic (NEM), and giant-cell myocarditis (GCM) for the main analyses. Patients with inconclusive histopathology and those who did not undergo EMB were analysed separately. Primary outcomes were in-hospital and 1-year mortality. Multivariable logistic regression models were employed as generalized linear models to analyse the association of prespecified risk factors with mortality. Estimated associations are reported as odds ratios, generalized marginal effects, and adjusted prediction plots. Results: A total of 271 patients [median age 43 years (interquartile range: 33–55 years), 58% male] were included in the analysis, of whom 146 fulfilled histopathologic criteria of LM (n = 99), EM (n = 18), NEM (n = 3), or GCM (n = 26). In the remaining 125 cases, EMB was inconclusive (n = 48) or not performed (n = 77). While there were no significant differences in cardiac arrest rate, admission Simplified Acute Physiology Score (SAPS) II, ventricular function, initial pH, and liver and kidney function parameters between histopathologic subgroups, the use of immunosuppressive medications and need for organ replacement varied. In the overall population, in-hospital and 1-year mortality were 31% and 34%, respectively. The highest 1-year mortality rate was observed among patients with GCM (LM: 25%, EM: 28%, NEM: 33%, GCM: 54%, P = .04). Patients who survived to discharge had an excellent functional outcome and long-term recovery of ventricular function. In total, 17 patients (6%) received a heart transplant during follow-up. Older age, lower pH, and histopathologic diagnosis of GCM were independently associated with in-hospital and 1-year mortality. Conclusions: In-hospital mortality among patients with FM remains high. Age, pH, and histopathological findings may serve as prognostic markers to identify high-risk patients and to guide treatment strategies. Long-term outcomes are excellent among those who survive to discharge.

Background: MRI (magnetic resonance imaging) represents the diagnostic image modality of choice in several conditions. With an increasing number of patients requiring MRI for diagnostic purposes, the issue of safety in patients with cardiac implantable electronic devices (CIED) undergoing this imaging modality will play an ever more important role. The purpose of this study was to assess the safety and device function following MRI in an unrestricted real-world cohort of patients with a wide array of cardiac devices. Methods: We conducted a retrospective single-center study including 1010 MRI studies conducted in adult patients (≥18 years) with an implanted CIED treated in the University Hospital of Munich (LMU) between July 2012 and March 2024. Patients with non-MR conditionally labeled leads, abandoned or epicardial leads, as well as lead fragments, were included for analysis. Results: Across a total of 1010 MRIs (920 total MR-conditional device generators) performed in patients with an implanted CIED, there were no deaths, reports of discomfort, palpitations, heating, or ventricular arrythmias in the 24 h following MRI. Only 2/1010 MRIs were followed by a reported atrial arrhythmia within 24 h, both in patients with an MR-conditional pacemaker (PM) device without an abandoned lead. No significant changes in device function following MRI from baseline were observed across all included CIEDs. Lastly, no instances of severe malfunction, such as generator failure, loss of capture, electrical reset, or inappropriate inhibition of pacing, were found in post-MRI interrogation reports across all MRI studies. Conclusions: Based on the analysis of 1010 MRIs undergone by patients with CIEDs, following standardized device interrogation, manufacturer-advised device programming, monitoring of vital function, and manufacturer-advised reprogramming, MRI can be performed safely and without adverse events or changes in device function.

Sports-related physical activity is associated with an increased risk of ventricular dysfunction and arrhythmias in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). However, there are currently no standardized strategies for activity assessment. Thresholds for harmful levels of physical activity suggested by previous studies vary substantially and neither lifetime activity burden nor continuous modelling approaches were considered. For this single-centre retrospective study, ARVC patients were interviewed to assess sports-related and non-sports-related physical activity between the age of 10 years and the last follow-up. Activity data were aggregated to the median metabolic equivalent of task—hours (METh) per week for each year. The association between cumulative physical activity burden and clinical study endpoints was investigated using Cox regression models. A total of 124 patients (median age: 39.5 years, 48% male) were included in the analysis, of whom 93 had been diagnosed with definite ARVC. Study participants reported a median overall activity of 202.3 METh/week, with 38.7 METh/week attributed to sports-related activity. In the continuous model, cumulative overall activity burden was associated with the occurrence of symptomatic heart failure [hazard ratio (HR) per 100 METh/week: 1.017, 95% CI (1.003, 1.032), P = 0.015], sustained ventricular tachycardia [HR: 1.021, 95% CI (1.006, 1.037), P = 0.007], and implantable cardioverter defibrillator interventions [HR: 1.017, 95%CI (1.000, 1.034), P = 0.048]. This finding was consistent when considering sports-related activity separately as a predictor variable, whereas the resulting hazard ratios did not show a significant association for non-sports-related physical activity. This study demonstrates for the first time that cumulative physical activity as a continuous predictor variable is associated with symptomatic heart failure and arrhythmic risk in ARVC patients. Collaborative research is required in larger cohorts to investigate the influence of potential confounders on event occurrence and to develop threshold recommendations for clinical practice. ARVC, arrhythmogenic right ventricular cardiomyopathy; CI; confidence interval; HR, hazard ratio; ICD, implantable cardioverter defibrillator; METh, metabolic equivalent of task—hours; SCD, sudden cardiac death; VT, ventricular tachycardia.

Discussion of the DanGer Shock trial. CI, confidence interval; HR, hazard ratio; ICU, intensive care unit; RR, relative risk.

OBJECTIVES: Cardiogenic shock (CS) is associated with high mortality. Patients treated for CS mostly require heparin therapy, which may be associated with complications such as heparin-induced thrombocytopenia (HIT). HIT represents a serious condition associated with platelet decline and increased hypercoagulability and remains a poorly researched field in intensive care medicine. Primary purpose of this study was to: 1) determine HIT prevalence in CS, 2) assess the performance of common diagnostic tests for the workup of HIT, and 3) compare outcomes in CS patients with excluded and confirmed HIT. DESIGN: Retrospective dual-center study including adult patients 18 years old or older with diagnosed CS and suspected HIT from January 2010 to November 2022. SETTING: Cardiac ICU at the Ludwig-Maximilians University hospital in Munich and the university hospital of Bonn. PATIENTS AND INTERVENTIONS: In this retrospective analysis, adult patients with diagnosed CS and suspected HIT were included. Differences in baseline characteristics, mortality, neurologic and safety outcomes between patients with excluded and confirmed HIT were evaluated. MEASUREMENTS AND MAIN RESULTS: In cases of suspected HIT, positive screening antibodies were detected in 159 of 2808 patients (5.7%). HIT was confirmed via positive functional assay in 57 of 2808 patients, corresponding to a prevalence rate of 2.0%. The positive predictive value for anti-platelet factor 4/heparin screening antibodies was 35.8%. Total in-hospital mortality (58.8% vs. 57.9%; p > 0.999), 1-month mortality (47.1% vs. 43.9%; p = 0.781), and 12-month mortality (58.8% vs. 59.6%; p > 0.999) were similar between patients with excluded and confirmed HIT, respectively. Furthermore, no significant difference in neurologic outcome among survivors was found between groups (Cerebral Performance Category [CPC] score 1: 8.8% vs. 8.8%; p > 0.999 and CPC 2: 7.8% vs. 12.3%; p = 0.485). CONCLUSIONS: HIT was a rare complication in CS patients treated with unfractionated heparin and was not associated with increased mortality. Also, HIT confirmation was not associated with worse neurologic outcome in survivors. Future studies should aim at developing more precise, standardized, and cost-effective strategies to diagnose HIT and prevent complications.

Background: Heparin-induced thrombocytopenia (HIT) is a serious, immune-mediated adverse drug reaction to unfractionated heparin (UFH) affecting also patients undergoing venoarterial extracorporeal membrane oxygenation (VA-ECMO). Although the association between VA-ECMO support and the development of thrombocytopenia has long been known and discussed, HIT as one underlying cause is still insufficiently understood. Therefore, the purpose of this study was to further investigate the epidemiology, mortality, diagnosis, and clinical management of HIT occurring in VA-ECMO patients treated with UFH. Methods: We conducted a retrospective single-center study including adult patients (≥18 years) with VA-ECMO support in the cardiac intensive care unit (ICU) of the University Hospital of Munich (LMU) between January 2013 and May 2022, excluding patients with a known history of HIT upon admission. Differences in baseline characteristics and clinical outcome between excluded HIT (positive anti-platelet factor 4 (PF4)/heparin antibody test but negative functional assay) and confirmed HIT (positive anti-PF4/heparin antibody test and positive functional assay) VA-ECMO patients as well as diagnosis and clinical management of HIT were analysed. Results: Among the 373 patients included, anti-PF4/heparin antibodies were detected in 53/373 (14.2%) patients. Functional HIT testing confirmed HIT in 13 cases (3.5%) and excluded HIT in 40 cases (10.7%), corresponding to a prevalence of confirmed HIT of 13/373 (3.5%) [1.6, 5.3] and a positive predictive value (PPV) of 24.5% for the antibody screening test. The platelet course including platelet recovery following argatroban initiation was similar between all groups. One-month mortality in patients with excluded HIT was 14/40 (35%) and 3-month mortality 17/40 (43%), compared to 5/13 (38%) (p > 0.999), and 6/13 (46%) (p > 0.999) in patients with confirmed HIT. Neurological outcome in both groups measured by the cerebral performance category of survivors on hospital discharge was similar, as well as adverse events during VA-ECMO therapy. Conclusions: With a prevalence of 3.5%, HIT is a non-frequent complication in patients on VA-ECMO and was not associated with a higher mortality rate. HIT was ultimately excluded by functional essay in 75% of VA-ECMO patients with clinical suspicion of HIT and positive anti-PF4/heparin antibody test. Argatroban seems to be an appropriate and safe therapeutic option for confirmed HIT-positive patients on VA-ECMO support.

(1) Herpes simplex virus (HSV) reactivation in critically ill patients can cause infection in the lower respiratory tract, prolonging mechanical ventilation. However, the association of HSV reactivation with cardiogenic shock (CS) is unclear. As CS is often accompanied by pulmonary congestion and reduced immune system activity, the aim of our study was to determine the incidence and outcome of HSV reactivation in these patients. (2) In this retrospective, single-center study, bronchial lavage (BL) was performed on 181 out of 837 CS patients with mechanical ventilation. (3) In 44 of those patients, HSV was detected with a median time interval of 11 days since intubation. The occurrence of HSV was associated with an increase in C-reactive protein and the fraction of inspired oxygen at the time of HSV detection. Arterial hypertension, bilirubin on ICU admission, the duration of mechanical ventilation and out-of-hospital cardiac arrest were associated with HSV reactivation. (4) HSV reactivation could be detected in 24.3% of patients with CS on whom BL was performed, and its occurrence should be considered in patients with prolonged mechanical ventilation. Due to the limited current evidence, the initiation of treatment for these patients remains an individual choice. Dedicated randomized studies are necessary to investigate the efficacy of antiviral therapy.

Antibodies are central effectors of the adaptive immune response, widespread used therapeutics, but also potentially disease-causing biomolecules. Antibody folding catalysts in the plasma cell are incompletely defined. Idiopathic pulmonary fibrosis (IPF) is a fatal chronic lung disease with increasingly recognized autoimmune features. We found elevated expression of FK506-binding protein 11 (FKBP11) in IPF lungs where FKBP11 specifically localized to antibody-producing plasma cells. Suggesting a general role in plasma cells, plasma cell-specific FKBP11 expression was equally observed in lymphatic tissues, and in vitro B cell to plasma cell differentiation was accompanied by induction of FKBP11 expression. Recombinant human FKBP11 was able to refold IgG antibody in vitro and inhibited by FK506, strongly supporting a function as antibody peptidyl-prolyl cis-trans isomerase. Induction of ER stress in cell lines demonstrated induction of FKBP11 in the context of the unfolded protein response in an X-box-binding protein 1 (XBP1)-dependent manner. While deficiency of FKBP11 increased susceptibility to ER stress-mediated cell death in an alveolar epithelial cell line, FKBP11 knockdown in an antibody-producing hybridoma cell line neither induced cell death nor decreased expression or secretion of IgG antibody. Similarly, antibody secretion by the same hybridoma cell line was not affected by knockdown of the established antibody peptidyl-prolyl isomerase cyclophilin B. The results are consistent with FKBP11 as a novel XBP1-regulated antibody peptidyl-prolyl cis-trans isomerase and indicate significant redundancy in the ER-resident folding machinery of antibody-producing hybridoma cells.