Anti-coagulation for COVID-19 treatment: both anti-thrombotic and anti-inflammatory?

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has been linked to a higher risk of mortality compared to influenza, which is mainly due to severe secondary diseases, such as acute respiratory distress syndrome (ARDS). In turn, ARDS is characterized by an acute inflammation and an excessive activity of the coagulation cascade, rising the vulnerability for venous thromboembolic events. In order to investigate the relation of inflammation and the influence of coagulation factors on their release, human peripheral mononuclear blood cells (PBMCs) were treated with autologous serum, heparinized plasma and different doses of fibrin. Thereafter, the concentration of pro-inflammatory cytokines and chemokines in the secretome of PBMCs was measured by enzyme-linked immunosorbent assay. Our analyses revealed autologous serum to significantly increase the secretion of cytokines and chemokines after 24 h of incubation time. Furthermore, the addition of fibrin markedly increased the secretion of cytokines and chemokines by PBMCs in a dose-dependent manner. Consequently, in accordance with previous studies, our study outlines that anti-coagulation may constitute a promising tool for the treatment of SARS-CoV-2, reducing both, the cytokine storm, as well as the risk for thrombotic complications.

Tumor necrosis factor alpha-an underestimated risk predictor in patients undergoing transcatheter aortic valve replacement (TAVR)?

BACKGROUND: Systemic inflammation has been identified as a major cardiovascular risk factor in patients undergoing transcatheter aortic valve replacement (TAVR), yet currently, it is not adequately portrayed in scores for pre-interventional risk assessment. The aim of this study was to investigate the predictive ability of TNF-α in TAVR. METHODS: A total of 431 patients undergoing transfemoral TAVR were enrolled in this study. Blood samples were drawn prior to intervention, 24 h post-intervention, 4, 5, and 7 days post-intervention, and 1, 3, and 6 months post-TAVR. RESULTS: In a univariate Cox proportional hazard analysis, plasma concentrations of TNF-α after 24 h and after 5 days were associated with mortality after 12 months (after 24 h: HR 1.002 (1.000-1.004), p = 0.028; after 5d: HR 1.003 (1.001-1.005), p = 0.013). This association remained significant even after correction for confounders in a multivariate Cox regression analysis. Additionally, cut-offs were calculated. Patients above the cut-off for TNF-α after 5d had a significantly worse 12-month mortality than patients below the cut-off (18.8% vs. 2.8%, p = 0.046). CONCLUSION: Plasma levels of TNF-α after 24 h and 5 days were independently associated with 12-month mortality in patients undergoing TAVR. Thus, TNF-α could represent a novel biomarker for enhanced risk stratification in these patients.

Blood markers of cardiac stress after generalized convulsive seizures.

OBJECTIVE: Generalized convulsive seizures (GCS) are associated with high demands on the cardiovascular system, thereby facilitating cardiac complications. To investigate occurrence, influencing factors, and extent of cardiac stress or injury, the alterations and time course of the latest generation of cardiac blood markers were investigated after documented GCS. METHODS: Adult patients with refractory epilepsy who underwent video-electroencephalography (EEG) monitoring along with simultaneous one-lead electrocardiography (ECG) recordings were included. Cardiac biomarkers (cardiac troponin I [cTNI]; high-sensitive troponin T [hsTNT]; N-terminal prohormone of brain natriuretic peptide [NT-proBNP]; copeptin; suppression of tumorigenicity-2 [SST-2]; growth differentiation factor 15, [GDF-15]; soluble urokinase plasminogen activator receptor [suPAR]; and heart-type fatty acid binding protein [HFABP]) and catecholamines were measured at inclusion and at different time points after GCS. Periictal cardiac properties were assessed by analyzing heart rate (HR), HR variability (HRV), and corrected QT intervals(QTc). RESULTS: Thirty-six GCS (6 generalized-onset tonic-clonic seizures and 30 focal to bilateral tonic-clonic seizures) were recorded in 30 patients without a history of cardiac or renal disease. Postictal catecholamine levels were elevated more than twofold. A concomitant increase in HR and QTc, as well as a decrease in HRV, was observed. Elevations of cTNI and hsTNT were found in 3 of 30 patients (10%) and 6 of 23 patients (26%), respectively, which were associated with higher dopamine levels. Copeptin was increased considerably after most GCS, whereas SST-2, HFABP, and GDF-15 displayed only subtle variations, and suPAR was unaltered in the postictal period. Cardiac symptoms did not occur in any patient. SIGNIFICANCE: The use of more sensitive biomarkers such as hsTNT suggests that signs of cardiac stress occur in about 25% of the patients with GCS without apparent clinical symptoms. SuPAR may indicate clinically relevant troponin elevations. Copeptin could help to diagnose GCS, but specificity needs to be tested.

Potential mechanisms of endothelialisation in individuals implanted with a leadless pacemaker systems: An experimental in vitro study.

BACKGROUND: Leadless pacemaker technology is a promising upcoming field in clinical rhythmology. Today, the most commonly used system in the clinical setting is the Micra™ leadless pacemaker system (Medtronic). In autopsies of patients who witnessed non-pacemaker associated death, unexpected ingrowth/encapsulation within the wall of the right ventricle was reported. The occurrence of a complete encapsulation was not expected and the process of endothelialisation remains unclear. We hypothesized, that a local inflammatory response might be the cause of these findings. The aim of our experimental in-vitro study was to investigate the effect of the Micra™ system and its single components on inflammatory processes. METHODS: For this purpose, whole Micra™ pacemakers were incubated in heparin plasma from 25 healthy volunteers for 48 h at 37 °C. Furthermore, 1 g gold, steel, titanium, tungsten and nitinol wires were incubated in heparin plasma for 48 h at 37 °C as well (n = 10). To detect eventual inflammatory processes, interleukin- (IL) 1ß, IL-6, and tumor necrosis factor alpha (TNF-α), the chemokine IL-8 were measured using enzyme-linked immunosorbent assay (ELISA). Additionally, the level of transforming growth factor beta 1 (TGF-ß1) and vascular endothelial growth factor (VEGF) were analysed. RESULTS: ELISA analyses showed that the whole Micra system leads to a significant increase in the inflammatory cytokine IL-6 which correlates with the data gained by the incubation of whole blood with the different wires. In particular, 0.5 g of tungsten showed a significant rise of IL-6 which could also be found for IL-1ß and IL-8. CONCLUSIONS: The in vitro study of the Micra system showed that the material composition led to an onset of inflammatory processes in whole blood. Consequently, one may speculate that the composition of Micra pacemaker may have a local inflammatory, though subclinical, effects in patients implanted with a Micra™ pacemakers.

Pathophysiology of Calcium Mediated Ventricular Arrhythmias and Novel Therapeutic Options with Focus on Gene Therapy.

Cardiac arrhythmias constitute a major health problem with a huge impact on mortality rates and health care costs. Despite ongoing research efforts, the understanding of the molecular mechanisms and processes responsible for arrhythmogenesis remains incomplete. Given the crucial role of Ca2+-handling in action potential generation and cardiac contraction, Ca2+ channels and Ca2+ handling proteins represent promising targets for suppression of ventricular arrhythmias. Accordingly, we report the different roles of Ca2+-handling in the development of congenital as well as acquired ventricular arrhythmia syndromes. We highlight the therapeutic potential of gene therapy as a novel and innovative approach for future arrhythmia therapy. Furthermore, we discuss various promising cellular and mitochondrial targets for therapeutic gene transfer currently under investigation.

Postoperative ergometry-guided programming does not prevent T-wave oversensing and inappropriate shocks in S-ICD patients.

BACKGROUND: T-wave oversensing (TWOS) is a feared complication after subcutaneous implantable cardioverter-defibrillator (S-ICD) implantation, potentially leading to inappropriate shocks (IS) with tremendous impact on quality of life. HYPOTHESIS: Postoperative ergometry facilitates primary and secondary prevention of TWOS or other potential causes of IS and optimizes S-ICD programming. METHODS: We analyze the impact of ergometry guided-programming (EMGP) on primary and secondary prevention of TWOS/IS in S-ICD patients, we screened 146 patients implanted in our center (2010-2016) for the incidence of TWOS/IS during postoperative ergometry. Furthermore, to evaluate the outcome in 123 eligible patients complete follow-up (FU) of at least 6 months up to 2 years was retrospectively analyzed. RESULTS: (1) Primary prevention: TWOS could only be provoked postoperatively in 3.7% of patients (n = 3/82). FU analyses did not reveal significant differences compared to our control group (Ctrl: n = 6/61, 9.8% vs EMGP: n = 5/62, 8.1%; P = 0.731). Further subgroup analyses of patients with postoperative ergometry in the close postoperative period (< 7 days; n = 3/45, 6.7%; P = 0.563) did not yield any significant difference. (2) Secondary prevention: We found various causes of TWOS/IS. In patients who underwent reprogramming due to previous TWOS/IS events we observed a 66.7% (n = 6/9) reduction of TWOS/IS using EMGP. CONCLUSION: TWOS/IS has various causes while not all cases are exercise-associated. Postoperative ergometry does not seem to be useful for primary prevention. Further trials need to investigate the potential benefit of EMGP for secondary prevention of TWOS/IS.

Through modulation of cardiac Ca2+ handling, UCP2 affects cardiac electrophysiology and influences the susceptibility for Ca2+ -mediated arrhythmias.

NEW FINDINGS: What is the central question of this study? Knockdown of UCP2 reduces mitochondrial Ca2+ uptake. This suggests that Ucp2 knockout mice need to have additional effects on cytosolic Ca2+ handling to prevent Ca2+ overload. However, the specific mechanisms and their impact on cardiac electrophysiology remain speculative. What is the main finding and its importance? In Ucp2 knockout mice, decreased mitochondrial Ca2+ uptake is compensated for by functional inhibition of L-type Ca2+ channels and resultant shortening of action potential duration. UCP2-dependent modulations have a major impact on cardiac electrophysiology, resulting in alterations of ECG characteristics and a higher susceptibility to Ca2+ -mediated ventricular arrhythmias. Uncoupling protein 2 (mitochondrial, proton carrier) (UCP2) belongs to a superfamily of mitochondrial ion transporters. Owing to its beneficial influence on production of reactive oxygen species, it is suggested to reduce cardiac ischaemia-reperfusion injury. Recent studies have uncovered its ability to regulate mitochondrial Ca2+ uptake and therefore to influence cardiac cytosolic Ca2+ handling, indicating compensatory pathways to avoid toxic Ca2+ overload in Ucp2 knockout (Ucp2-/- ) mice. However, the specific mechanisms and their impact on cardiac electrophysiology remain speculative. Molecular analyses, whole-cell patch clamp in cardiomyocytes and ECG studies were performed in Ucp2-/- and wild-type (WT) control mice. Furthermore, to explore the impact on cardiac arrhythmogenicity, ECG monitoring was performed in basal conditions and during Ca2+ -mediated stress using Bay K 8644. Although cardiac ryanodine receptor 2, NCX1, L-type Ca2+ channel (LTCC) and SERCA2a expression were not altered, Ucp2-/- mice revealed major variations in cardiac electrophysiology. The LTCC current and APD90 were decreased in Ucp2-/- mice, indicating compensatory mechanisms. Furthermore, in Ucp2-/- mice, an increased slope factor of action potential upstrokes and more hyperpolarized resting membrane potential were measured, suggesting variations in cardiac excitability. In agreement with alterations of cellular physiology in Ucp2-/- mice, reductions in PR and QRS as well as shortening of the QTc interval were noted in ECG recordings. Importantly, an increased incidence of cellular after-depolarizations and more pronounced susceptibility to Ca2+ -mediated arrhythmias were observed. Furthermore, although expression of UCP3 was not different, levels of PRMT1 were significantly higher in Ucp2-/- mice. Our observations indicate compensatory mechanisms by which Ucp2-/- mice prevent toxic cytosolic Ca2+ overload. UCP2-dependent modulations have a major impact on cardiac electrophysiology and influence susceptibility to Ca2+ -mediated ventricular arrhythmias.

UCP3 Regulates Single-Channel Activity of the Cardiac mCa1.

Mitochondrial Ca(2+) uptake (mCa(2+) uptake) is thought to be mediated by the mitochondrial Ca(2+) uniporter (MCU). UCP2 and UCP3 belong to a superfamily of mitochondrial ion transporters. Both proteins are expressed in the inner mitochondrial membrane of the heart. Recently, UCP2 was reported to modulate the function of the cardiac MCU related channel mCa1. However, the possible role of UCP3 in modulating cardiac mCa(2+) uptake via the MCU remains inconclusive. To understand the role of UCP3, we analyzed cardiac mCa1 single-channel activity in mitoplast-attached single-channel recordings from isolated murine cardiac mitoplasts, from adult wild-type controls (WT), and from UCP3 knockout mice (UCP3(-/-)). Single-channel registrations in UCP3(-/-) confirmed a murine voltage-gated Ca(2+) channel, i.e., mCa1, which was inhibited by Ru360. Compared to WT, mCa1 in UCP3(-/-) revealed similar single-channel characteristics. However, in UCP3(-/-) the channel exhibited decreased single-channel activity, which was insensitive to adenosine triphosphate (ATP) inhibition. Our results suggest that beyond UCP2, UCP3 also exhibits regulatory effects on cardiac mCa1/MCU function. Furthermore, we speculate that UCP3 might modulate previously described inhibitory effects of ATP on mCa1/MCU activity as well.

Glycogen synthase kinase 3ß transfers cytoprotective signaling through connexin 43 onto mitochondrial ATP-sensitive K+ channels.

Despite compelling evidence supporting key roles for glycogen synthase kinase 3ß (GSK3ß), mitochondrial adenosine triphosphate-sensitive K(+) (mitoK(ATP)) channels, and mitochondrial connexin 43 (Cx43) in cytoprotection, it is not clear how these signaling modules are linked mechanistically. By patch-clamping the inner membrane of murine cardiac mitochondria, we found that inhibition of GSK3ß activated mitoK(ATP). PKC activation and protein phosphatase 2a inhibition increased the open probability of mitoK(ATP) channels through GSK3ß, and this GSK3ß signal was mediated via mitochondrial Cx43. Moreover, (i) PKC-induced phosphorylation of mitochondrial Cx43 was reduced in GSK3ß-S9A mice; (ii) Cx43 and GSK3ß proteins associated in mitochondria; and (iii) SB216763-mediated reduction of infarct size was abolished in Cx43 KO mice in vivo, consistent with the notion that GSK3ß inhibition results in mitoK(ATP) opening via mitochondrial Cx43. We therefore directly targeted mitochondrial Cx43 by the Cx43 C-terminal binding peptide RRNYRRNY for cardioprotection, circumventing further upstream pathways. RRNYRRNY activated mitoK(ATP) channels via Cx43. We directly recorded mitochondrial Cx43 channels that were activated by RRNYRRNY and blocked by the Cx43 mimetic peptide (43)GAP27. RRNYRRNY rendered isolated cardiomyocytes in vitro and the heart in vivo resistant to ischemia/reperfusion injury, indicating that mitochondrial Cx43- and/or mitoK(ATP)-mediated reduction of infarct size was not undermined by RRNYRRNY-related opening of sarcolemmal Cx43 channels. Our results demonstrate that GSK3ß transfers cytoprotective signaling through mitochondrial Cx43 onto mitoK(ATP) channels and that Cx43 functions as a channel in mitochondria, being an attractive target for drug treatment against cardiomyocyte injury.

Long-Term Outcomes of COVID-19 in Hospitalized Type 2 Diabetes Mellitus Patients.

With the onset of the coronavirus pandemic, it has become clear that patients with diabetes are at risk for more severe and fatal COVID-19. Type 2 diabetes mellitus (T2D) is a major risk factor for adverse COVID-19 outcomes. The goal of study was to assess the characteristics and outcomes of hospitalized patients with COVID-19 with or without T2D in the hospital and at 10-month follow-up (FU). METHODS: A total of 2486 hospitalized patients in the first wave of COVID-19 were analyzed according to the absence/presence of T2D, with 2082 (84.1%) patients in the control COVID-19 group and 381 (15.5%) in the T2D group. Twenty-three patients had other types of diabetes and were therefore excluded from the study. In-hospital mortality and cardiovascular endpoints (myocardial infarction, stroke, cardiovascular deaths and hospitalizations and composite endpoints) at the 10-month follow-up were analyzed. To remove bias in patients' characteristics disproportion, Propensity Score Matching (PSM) was used for hospital and follow-up endpoints. RESULTS: Hospital mortality was considerably greater in T2D than in the control COVID-19 group (13.89% vs. 4.89%, p < 0.0001), and the difference remained after PSM (p < 0.0001). Higher glucose-level T2D patients had a higher mortality rate (p = 0.018). The most significant predictors of hospital death in T2D patients were a high CRP, glucose, neutrophils count, and Charlson Comorbidity Index. The follow-up of patients over 10 months showed a non-significant increase for all endpoints in the T2D group (p > 0.05), and significant increase in stroke (p < 0.042). After the PSM, the difference decreased in stroke (p = 0.090), but became significant in cardiovascular hospitalizations (p = 0.023). CONCLUSION: In T2D patients with COVID-19, an increase in hospital mortality, stroke and cardiovascular hospitalizations rates in the follow-up was observed.

Implementation of risk-based lipid-lowering therapies in older (age ≥ 65 years) and very-old adults (age ≥ 75 years) with ischemic heart disease in the greater Salzburg region.

Introduction: European guidelines recommend the implementation of lipid-lowering therapies (LLTs) in adults (≥ 65 years) with established atherosclerotic cardiovascular disease (ASCVD) and for risk-based primary prevention in older adults (≤ 75 years), yet their use in very-old adults (> 75 years) is controversial, discretionary, and oriented on the presence of risk factors. The aim of this retrospective study is to assess guideline-directed LLT implementation and low-density lipoprotein cholesterol (LDL-C) target achievement in high-/very-high-risk older/very-old adults (65-74 and ≥ 75 years) at presentation for ST-segment elevation myocardial infarction (STEMI) and also to assess evidence-based care delivery to older adults in our region. Methods: All STEMI patients with available LDL-C and total cholesterol presenting for treatment at a large tertiary center in Salzburg, Austria, 2018-2020, were screened (n = 910). High-risk/very-high-risk patients (n = 369) were classified according to European guidelines criteria and divided into cohorts by age: < 65 years (n = 152), 65-74 years (n = 104), and ≥ 75 years (n = 113). Results: Despite being at high-/very-high-risk, prior LLT use was < 40% in the total cohort, with no significant difference by age. Statin monotherapy predominated; 20%-23% of older/very-old adults in the entire cohort were using low-/moderate-intensity stains, 11%-13% were using high-intensity statins, 4% were on ezetimibe therapy, and none were taking proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. In the secondary prevention cohort, 53% of older/very-old patients used prior LLTs. Significantly higher percentages of older/oldest ASCVD patients (43% and 49%) met LDL-C targets < 70 mg/dL compared to patients < 65 years (29%; p = 0.033), although just 22% and 30% of these older groups attained stricter LDL-C targets of < 55 mg/dL. Low LLT uptake (16%) among older adults aged 64-74 years for primary prevention resulted in 17% and 10% attainment of risk-based LDL-C targets < 70 mg/dL and < 55 mg/dL, respectively. Oldest adults (≥ 75 years) in both primary and secondary prevention groups more often met risk-based targets than older and younger adults, despite predominantly receiving low-/moderate-intensity statin monotherapy. Conclusion: Secondary prevention was sub-optimal in our region. Less than half of older/very-old adults with established ASCVD met LDL-C targets at the time of STEMI, suggesting severe care-delivery deficits in LLT implementation. Shortcomings in initiation of risk-based LLTs were also observed among high-/very-high-risk primary prevention patients < 75 years, with the achievement of risk-based LDL-C targets in 10%-48% of these patients.

Harmonizing Heartbeats: The Mosaic of Cardiac Resynchronization Therapy Responders-A Comprehensive Exploration of Diverse Criteria and Predictors.

Background: Heart failure (HF) remains a challenging healthcare issue necessitating innovative therapies like cardiac resynchronization-defibrillation therapy (CRT-D). However, the definition of a CRT-D response lacks uniformity, impeding effective clinical evaluation. This study explores diverse CRT-D responder definitions encompassing functional, echocardiographic and laboratory criteria. Materials & Methods: A single-center study involving 132 CRT-D patients scrutinized responder criteria including NYHA stage, LVEF increase and proBNP decrease. Statistical analyses such as Kaplan-Meier curves and Cox hazard regression were employed to evaluate responder characteristics and survival outcomes. Results: Responder rates varied across criteria, revealing nuanced patient profiles. CRT-D responders defined by NYHA decrease, LVEF increase or proBNP decrease exhibit improved survival rates after 2 and 3 years (p < 0.050). Young age, absence of recent myocardial infarction and normal right ventricular echocardiographic parameters emerge as predictors for positive response. In part, drug-based HF therapy correlates with increased responder rates. Cox regression identified LVEF ≥ 5% and proBNP decrease ≥ 25% as independent predictors of extended survival. Conclusions: CRT-D responder definitions exhibit considerable variability, emphasizing the need for a nuanced patient-centered approach. Factors like right ventricular function, drug therapy, atrial fibrillation and renal function influence responses. This study enriches our understanding of CRT-D response and contributes to the foundation for personalized HF management.

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

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

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

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

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

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

Hypertrophic cardiomyopathy is characterized by alterations of the mitochondrial calcium uniporter complex proteins: insights from patients with aortic valve stenosis versus hypertrophic obstructive cardiomyopathy.

Introduction: Hypertrophies of the cardiac septum are caused either by aortic valve stenosis (AVS) or by congenital hypertrophic obstructive cardiomyopathy (HOCM). As they induce cardiac remodeling, these cardiac pathologies may promote an arrhythmogenic substrate with associated malignant ventricular arrhythmias and may lead to heart failure. While altered calcium (Ca2+) handling seems to be a key player in the pathogenesis, the role of mitochondrial calcium handling was not investigated in these patients to date. Methods: To investigate this issue, cardiac septal samples were collected from patients undergoing myectomy during cardiac surgery for excessive septal hypertrophy and/or aortic valve replacement, caused by AVS and HOCM. Septal specimens were matched with cardiac tissue obtained from post-mortem controls without cardiac diseases (Ctrl). Results and discussion: Patient characteristics and most of the echocardiographic parameters did not differ between AVS and HOCM. Most notably, the interventricular septum thickness, diastolic (IVSd), was the greatest in HOCM patients. Histological and molecular analyses showed a trend towards higher fibrotic burden in both pathologies, when compared to Ctrl. Most notably, the mitochondrial Ca2+ uniporter (MCU) complex associated proteins were altered in both pathologies of left ventricular hypertrophy (LVH). On the one hand, the expression pattern of the MCU complex subunits MCU and MICU1 were shown to be markedly increased, especially in AVS. On the other hand, PRMT-1, UCP-2, and UCP-3 declined with hypertrophy. These conditions were associated with an increase in the expression patterns of the Ca2+ uptaking ion channel SERCA2a in AVS (p = 0.0013), though not in HOCM, compared to healthy tissue. Our data obtained from human specimen from AVS or HOCM indicates major alterations in the expression of the mitochondrial calcium uniporter complex and associated proteins. Thus, in cardiac septal hypertrophies, besides modifications of cytosolic calcium handling, impaired mitochondrial uptake might be a key player in disease progression.

Case report: Short-long-short mechanism triggering sustained ventricular tachycardia in a patient with a single-chamber ICD but inhibiting antitachycardia therapy.

Introduction: Short-long-short (SLS) sequences are an important cause of ICD pro-arrhythmia and can initiate both polymorphic and monomorphic ventricular tachycardias (VT). Depending on the programming of a single-chamber ICD, the interplay between SLS sequences and combined VT detection criteria can be responsible for withholding adequate anti-tachycardia pacing (ATP) or shock therapy. Methods: A 78-year-old patient with ICD was admitted to our emergency department after external cardioversion of a long-lasting VT with hemodynamic compromise. The interrogation of the ICD revealed an SLS sequence initiating a monomorphic VT at a rate of 171 bpm (350 ms). The VT discrimination of the implanted single-chamber ICD was based on the onset and stability criteria as the patient had a history of paroxysmal atrial fibrillation. The ICD was programmed that both criteria had to be met for VT detection and initiation of anti-tachycardia therapy. Results: Due to the SLS sequence in combination with the programmed VT detection interval, the onset threshold was not fulfilled and inhibited adequate therapy. Some relatively slow VT beats following the SLS sequence resulted finally in a considerable delay in the declaration of the episode onset. As a first step, the threshold for VT detection was programmed to 150 instead of 160 bpm. To avoid SLS sequences and pause-dependent ventricular tachyarrhythmias, VVI backup stimulation was increased from 35 to 55 ppm. Besides, a device-specific algorithm called rate smoothing was activated as a potential preventive feature. On the 3-month follow-up, all sustained VT episodes were detected adequately by the reprogrammed device, resulting in appropriate anti-tachycardia pacing. After further refinement and less aggressive programming of rate smoothing, the patient remained free of symptoms and arrhythmias over a follow-up of more than 2.5 years, particularly since progression to permanent atrial fibrillation and pacing at a lower rate of 60 ppm. Conclusions: SLS sequences may initiate or trigger VT episodes. Misclassification of the true onset may occur in some ICD devices due to specific programming of VT detection criteria. If both criteria "Onset and Stability" have to be fulfilled, ICD therapy is not delivered despite ongoing VT. Anti-bradycardia backup pacing at a very low stimulation rate may facilitate SLS sequences in patients with ICD resembling a potential pro-arrhythmic mechanism. In case of gradual VT onset with some intervals slower than the programmed VT threshold, the detection rate has to be adjusted down to guarantee appropriate identification of the onset.

Differential Diagnosis between Takotsubo Syndrome and Acute Coronary Syndrome-A Prospective Analysis of Novel Cardiovascular Biomarkers for a More Selective Triage.

INTRODUCTION: Takotsubo syndrome (TTS) is clinically indistinguishable from an ACS. Despite the implementation of clinical scoring systems and novel biomarkers, coronary angiography currently remains necessary for differential diagnosis. METHODS: 93 patients with chest pain and the suspicion of TTS were enrolled in two study centers. Fetuin-A, IGFBP-2, Galectin-3, and TNF α were determined in serum samples, collected within 24 h after the onset of symptoms. Serum levels of biomarkers were analyzed for the differential diagnostic value between TTS and ACS. RESULTS: Compared to TTS, patients with ACS had significantly lower serum levels of Fetuin-A and IGFBP-2. The cut-off value of Fetuin-A for the identification of TTS compared to ACS was 55.74 µg/mL (sensitivity: 100.0%, specificity: 82.6%, PPV: 63.2%, NPV: 100.0%). An optimal cut-off value for IGFBP-2 for the differential diagnosis between TTS and ACS was determined as 171.77 ng/mL (sensitivity: 76.0%, specificity: 82.6%, PPV: 76.4%, NPV 72.7%). CONCLUSION: Fetuin-A and IGFBP-2 might facilitate the triage between TTS and ACS and could be therefore of great benefit for the guidance of treatment.

Pretreatment with Betablockers, a Potential Predictor of Adverse Cardiovascular Events in Takotsubo Syndrome.

Introduction: Treatment with betablockers is controversial in Takotsubo syndrome (TTS); however, many physicians intuitively initiate or continue betablocker therapy in these patients. The effect of preadmission betablocker use on adverse cardiovascular events has not been studied in the literature. Methods: To investigate this issue, we evaluated clinical complications, defined by the endpoint of occurrence of hemodynamically relevant arrythmia, cardiac decompensation, and all-cause adverse cardiac events, during hospitalization, in 56 patients hospitalized for TTS between April 2017 and July 2021. We compared the risk of adverse cardiovascular events between patients with preadmission betablocker therapy and those without preadmission betablocker therapy. Pretreatment betablocker therapy was defined as daily betablocker intake for more than a week including day of admission. Results: TTS patients taking preadmission betablockers had a significantly increased risk of all-cause complications relative to patients without betablockers in preadmission medication ((52.0% vs. 19.4%, p = 0.010; OR 4.5 (95% Cl 1.38-14.80)). Furthermore, TTS patients already taking betablockers on admission showed a statistically significant increased risk of cardiac decompensation when compared to patients without pretreatment with betablockers (p = 0.013). There were no significant differences in patient characteristics in patients who were taking beta blockers as an adjunct therapy prior to admission for TTS relative to those who were not. There is however an increase in comorbidities, hypertension, and atrial fibrillation, in past medical history in patients taking a preadmission betablocker. The difference is related to therapeutic applications for beta blockers and was not significant based on endpoints of our study. Conclusions: Preadmission betablocker treatment was associated with a 4.5 times higher risk of adverse cardiac events. This increased risk of all-cause complications and of cardiac decompensation within the acute phase of TTS is presumably due to the negative inotropic effects of betablockers and upregulation of ß-adrenergic receptors in patients with chronic betablocker therapy.

How spaceflight challenges human cardiovascular health.

The harsh environmental conditions in space, particularly weightlessness and radiation exposure, can negatively affect cardiovascular function and structure. In the future, preventive cardiology will be crucial in enabling safe space travel. Indeed, future space missions destined to the Moon and from there to Mars will create new challenges to cardiovascular health while limiting medical management. Moreover, commercial spaceflight evolves rapidly such that older persons with cardiovascular risk factors will be exposed to space conditions. This review provides an overview on studies conducted in space and terrestrial models, particularly head-down bedrest studies. These studies showed that weightlessness elicits a fluid shift towards the head, which likely predisposes to the spaceflight-associated neuro-ocular syndrome, neck vein thrombosis, and orthostatic intolerance after return to Earth. Moreover, cardiovascular unloading produces cardiopulmonary deconditioning, which may be associated with cardiac atrophy. In addition to limiting physical performance, the mechanism further worsens orthostatic tolerance after return to Earth. Finally, space conditions may directly affect vascular health; however, the clinical relevance of these findings in terms of morbidity and mortality is unknown. Targeted preventive measures, which are referred to as countermeasures in aerospace medicine, and technologies to identify vascular risks early on will be required to maintain cardiovascular performance and health during future space missions.