Effects of Early Empagliflozin Initiation on Diuresis and Kidney Function in Patients With Acute Decompensated Heart Failure (EMPAG-HF).

BACKGROUND: Effective diuretic regimens using loop diuretics in patients with acute decompensated heart failure are often limited by the development of worsening kidney function. Sodium-glucose cotransporter-2 inhibitors induce glucosuria and sodium excretion with nephroprotective effects in patients with stable heart failure but their role in acute decompensated heart failure is unclear. METHODS: In this single-center, prospective, double-blind, placebo-controlled, randomized study, we randomly assigned patients with acute decompensated heart failure to empagliflozin 25 mg daily or placebo in addition to standard decongestive treatments that included loop diuretics. The primary end point was cumulative urine output over 5 days. Secondary end points included diuretic efficiency, dynamics in markers of kidney function and injury, and NT-proBNP (N-terminal pro-B-type natriuretic peptide). RESULTS: Sixty patients were randomized within 12 hours of hospitalization for acute decompensated heart failure. Addition of empagliflozin daily to standard medical treatment of acute decompensated heart failure resulted in a 25% increase in cumulative urine output over 5 days (median 10.8 versus 8.7 L mL in placebo, group difference estimation 2.2 L [95% CI, 8.4 to 3.6]; P=0.003). Empagliflozin increased diuretic efficiency compared with placebo (14.1 mL urine per milligram furosemide equivalent [95% CI, 0.6-27.7]; P=0.041) without affecting markers of renal function (estimated glomerular filtration rate, 51±19 versus 54±17 mL/min per 1.73 m²; P=0.599) or injury (total urinary protein, 492±845 versus 503±847 mg/g creatinine; P=0.975; and urinary α1-microglobulin, 55.4±38.6 versus 31.3±33.6 mg/g creatinine; P=0.066) with more pronounced decrease in NT-proBNP in the empagliflozin group compared with placebo (-1861 versus -727.2 pg/mL after 5 days; quotient in slope, 0.89 [95% CI, 0.83-0.95]; P<0.001). There were no differences in the incidence of safety events between groups. CONCLUSIONS: Early addition of empagliflozin to standard diuretic therapy increases urine output without affecting renal function in patients with acute decompensated heart failure. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04049045.

[Acute heart failure and cardiogenic shock : An update]. / Akute Herzinsuffizienz und kardiogener Schock : Ein Update.

Acute heart failure is a clinical syndrome resulting from elevated intracardiac filling pressures and a systemic venous congestion. In general, patients can present acutely without a history of structural cardiac disease (de novo heart failure) or with acute worsening of a pre-existing dysfunction of the right or left ventricle. The patient population is overall very inhomogeneous and as a result there is also a distinct heterogeneity with respect to the underlying cardiac pathology that leads to the acute presentation. Ultimately, ventricular dysfunction leads to increased preload and afterload resulting in decreased perfusion and retrograde congestion. The forward failure (hypoperfusion) and backwards failure (systemic congestion) can lead to impaired end organ function or even organ failure resulting in cardiogenic shock, in which sufficient organ and tissue perfusion is no longer possible. Consequently, therapeutic strategies currently focus on rectification of the underlying cardiac dysfunction, reduction of volume overload (decongestion) and hemodynamic stabilization with drugs supporting the circulation in the case of a hypoperfusion syndrome. Despite numerous new therapeutic strategies within the last two decades, the empirical data based on randomized trials is considerably less solid than in chronic heart failure, which is expressed in the almost unchanged 1­year mortality of approximately 20-30%.

Prognostic Value of Galectin-3 after Left Atrial Appendage Occlusion for Predicting Peri-Device Leakage.

Echocardiographic detection of residual peri-device leakage (PDL) after percutaneous left atrial appendage occlusion (LAAO) is crucial for managing anticoagulation. Galectin-3, a protein involved in tissue-foreign body interactions, may hold significance in understanding PDL and cardiac tissue remodeling after LAAO. This study aimed to analyze galectin-3 serum levels in relation to PDL using a novel echo-morphological classification. LAAO eligible patients were included in the study. Galectin-3 serum levels were measured before LAAO, at 45 days (45D), and at 6 months (6M) after the procedure. Transesophageal echocardiography was used to assess LAAO success. A new echo-morphological classification categorized the degree of LAAO into three different types (A: homogenous echodensity, indicating completely thrombosed device; B: inhomogeneous echolucencies (<50% of device); and C: partially thrombosed device with echolucencies > 50%). Among 47 patients, complete LAAO was achieved in 60% after 45D and in 74% after 6M. We observed a significant increase and distribution of serum levels of galectin-3 [ng/mL] after 45D among the three types (baseline: 13.1 ± 5.8 ng/mL; 45D: 16.3 ± 7.2 ng/mL (Type A) vs. 19.2 ± 8.6 ng/mL (Type B) vs. 25.8 ± 9.4 ng/mL (Type C); p = 0.031), followed by a drop in galectin-3 for Types A and B after 6M toward and below the baseline levels (6M: 8.9 ± 3.1 ng/mL (Type A) vs. 12.4 ± 5.5 ng/mL (Type B)), whereas Type C persisted in showing elevated galectin-3 levels compared to all other types (6M: 17.5 ± 4.5 ng/mL (Type C); p < 0.01). Increased galectin-3 serum levels after LAAO likely reflect the transition from thrombus formation to fibrotic scar development in the LAA lumen. Successful occlusion is associated with a time-restricted decrease in galectin-3 levels after 6 months, while relevant PDL leads to persistently elevated levels, making galectin-3 a potential predictor of occlusion success.

Serum Biomarkers of Cardiovascular Remodelling Reflect Extra-Valvular Cardiac Damage in Patients with Severe Aortic Stenosis.

In patients with aortic stenosis (AS), a novel staging classification of extra-valvular left and right heart damage with prognostic relevance was introduced in 2017. The aim of the study was to evaluate the biomarkers of cardiovascular tissue remodelling in relation to this novel staging classification. Patients were categorized according to the novel staging classification into stages 0 to 4. The levels of matrix metalloproteinase 9 (MMP-9), tissue inhibitor of metalloproteinases 1 (TIMP-1), B and C domain containing tenascin-C (B+ Tn-C, C+ Tn-C), the ED-A and ED-B domain containing fibronectin (ED-A+ Fn, ED-B+ Fn), endothelin 1 (ET-1) and neutrophil gelatinase-associated lipocalin (NGAL) were determined in serum by ELISA. There were significantly decreased serum levels of MMP-9 and increased levels of B+ Tn-C and C+ Tn-C when comparing stages 0 and 1 with stage 2, with no further dynamics in stages 3 and 4. In contrast, for TIMP-1, C+ Tn-C, ED-A+ Fn, ET-1 and NGAL, significantly increased serum levels could be detected in stages 3 and 4 compared to both stages 0 and 1 and stage 2. ED-A+ Fn and ET-1 could be identified as independent predictors of the presence of stage 3 and/or 4. To the best of our knowledge, this is the first study identifying novel serum biomarkers differentially reflecting the patterns of left and right heart extra-valvular damage in patients suffering from AS. Our findings might indicate a more precise initial diagnosis and risk stratification.

The MOGE(S) classification for cardiomyopathies: current status and future outlook.

Cardiomyopathies are complex diseases of multifactorial pathogenesis and have a high morbidity and mortality. Over the past decades, several revisions of classifications and definitions of cardiomyopathies have been proposed, primarily focusing on the phenotypic characterization of cardiomyopathies. The MOGE(S) classification system published in 2013 encompasses the classification of rapidly growing knowledge on genetic mutations, acquired causes (i.e., intramyocardial inflammation, viral infections), and further conditions involved in the induction of cardiomyopathies (e.g., storage diseases, toxicity). It is based on five attributes, including morphofunctional characteristics (M), organ involvement (O), genetic or familial inheritance pattern (G), etiological annotation (E), and optional information about the heart failure functional status (S). This review summarizes the development, the cornerstones of the MOGE(S) classification, and the published data on the clinical relevance of the MOGE(S) classification. We furthermore discuss new issues which might be considered for future updates of the MOGE(S) classification of cardiomyopathies.

Generation of human induced pluripotent stem cell lines UKJi001-A and UKJi006-A from patients with heterozygous mutation in the PKP2 gene.

One of the main signs we do not know enough about arrhythmogenic right ventricular dysplasia 9/cardiomyopathy (ARVCD9, OMIM #609040, autosomal dominant) is the lack of early markers and therapeutic alternatives. To better study disease pathways in vitro, we generated human induced pluripotent stem cell (hiPSC) lines from the father (UKJi006-A) and son (UKJi001-A), who both shared the same heterozygous mutation in the PKP2 gene (OMIM *602861). While the father had a clinical diagnosis of ARVC, the son lacked the ARVC phenotype. To generate hiPSC lines, non-integrating Sendai virus (SeV) vectors expressing the reprogramming factors (OCT4, SOX2, KLF4, and c-MYC) were used for reprogramming patient peripheral blood mononuclear cells (PBMCs).

The Jena Method: Perfusionist Independent, Standby Wet-Primed Extracorporeal Membrane Oxygenation (ECMO) Circuit for Immediate Catheterization Laboratory and/or Hybrid Operating Room Deployment.

Background: The timely initiation of extracorporeal membrane oxygenation (ECMO) is crucial for providing life support. However, delays can occur when perfusionists are not readily available. The Jena Method aims to address this issue by offering a wet-primed ECMO system that can be rapidly established without the perfusionist's presence. Methods: The goal was to ensure prompt ECMO initiation while maintaining patient safety. The method focuses on meeting hygienic standards, safe primed storage of the circuit, staff training, and providing clear step-by-step instructions for the ECMO unit. Results: Since implementing the Jena Method in 2015, 306 patients received VA-ECMO treatment. Bacterial tests confirmed the sterility of the primed ECMO circuits during a 14-day period. The functionality of all the components of the primed ECMO circuit after 14 days, especially the pump and oxygenator, were thoroughly checked and no malfunction was found to this day. To train staff for independent ECMO initiation, a step-by-step system involves safely bringing the ECMO unit to the intervention site and establishing all connections. This includes powering up, managing recirculation, de-airing the system, and preparing it for cannula connection. A self-developed picture-based guide assists in this process. New staff members learn from colleagues and receive quarterly training sessions by perfusionists. After ECMO deployment, the perfusionist provides a new primed system for a potential next patient. Conclusions: Establishing a permanently wet-primed on-demand extracorporeal life support circuit without direct perfusionist support is feasible and safe. The Jena Method enables rapid ECMO deployment and has the potential to be adopted in emergency departments as well.

Metabolic Profiling Identifies 1-MetHis and 3-IPA as Potential Diagnostic Biomarkers for Patients With Acute and Chronic Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Metabolomics has become a valuable tool for identifying potential new biomarkers and metabolic profiles. It has the potential to improve the diagnosis and prognosis of different phenotypes of heart failure. To generate a distinctive metabolic profile, we assessed and compared the metabolic phenotypes of patients with acute decompensated heart failure (ADHF), patients with chronic heart failure (CHF), and healthy controls. METHODS: Plasma metabolites were analyzed by liquid-chromatography mass spectrometry/mass spectrometry and the MxP Quant 500 kit in 15 patients with ADHF, 50 patients with CHF (25 with dilated cardiomyopathy, 25 with ischemic cardiomyopathy), and 13 controls. RESULTS: Of all metabolites identified to be significantly altered, 3-indolepropionic acid and 1-methyl histidine showed the highest concentration differences in ADHF and CHF compared with control. Area under the curve-receiver operating characteristic analysis showed an area under the curve ≥0.8 for 3-indolepropionic acid and 1-methyl histidine, displaying good discrimination capabilities between control and patient cohorts. Additionally, symmetrical dimethylarginine (mean, 1.97±0.61 [SD]; P=0.01) was identified as a suitable biomarker candidate for ADHF and kynurenine (mean, 1.69±0.39 [SD]; P=0.009) for CHF when compared with control, both demonstrating an area under the curve ≥0.85. CONCLUSIONS: Our study provides novel insights into the metabolic differences between ADHF and CHF and healthy controls. We here identify new metabolites for potential diagnostic and prognostic purposes.

Prognostic relevance of mitral and tricuspid regurgitation after transcatheter aortic valve implantation: Impact of follow-up time point for decision-making.

Background: In patients with aortic stenosis treated by transcatheter aortic valve implantation (TAVI), mitral and tricuspid regurgitation (MR and TR) at baseline and after TAVI are likely to be of prognostic relevance, and questions such as whether and when treatment further improves prognosis in these patients arise. Aims: Against that background, the purpose of this study was to analyze a variety of clinical characteristics including MR and TR with respect to their potential value as predictors of 2-year mortality after TAVI. Methods: A cohort of 445 typical TAVI patients was available for the study and clinical characteristics were evaluated baseline, 6 to 8 weeks as well as 6 months after TAVI. Results: In 39% of the patients relevant (moderate or severe) MR and in 32% of the patients relevant (moderate or severe) TR could be detected at baseline. The rates were 27% for MR (p = 0.001, compared to baseline) and 35% for TR (p = n.s., compared to baseline) at the 6- to 8-week follow-up. After 6 months, relevant MR was observable in 28% (p = 0.036, compared to baseline) and relevant TR in 34% (p = n.s., compared to baseline) of the patients. As predictors of 2-year mortality, a multivariate analysis identified the following parameters for the different time points: sex, age, AS entity, atrial fibrillation, renal function, relevant TR, systolic pulmonary artery pressure (PAPsys), and 6-min walk distance at baseline; clinical frailty scale and PAPsys 6-8 weeks after TAVI and BNP and relevant MR 6 months after TAVI. There was a significantly worse 2-year survival in patients with relevant TR at baseline (68.4% vs. 82.6%, p < 0.001; whole population, n = 445) and in patients with relevant MR at 6 months (87.9% vs. 95.2%, p = 0.042; landmark analysis: n = 235). Conclusion: This real-life study demonstrated the prognostic relevance of repeated evaluation of MR and TR before and after TAVI. Choosing the right time point for treatment is a remaining clinical challenge, which should be further addressed in randomized trials.

Impact of a VA-ECMO in Combination with an Extracorporeal Cytokine Hemadsorption System in Critically Ill Patients with Cardiogenic Shock-Design and Rationale of the ECMOsorb Trial.

BACKGROUND: Cardiogenic shock and arrest present as critical, life-threatening emergencies characterized by severely compromised tissue perfusion and inadequate oxygen supply. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) serves as a mechanical support system for patients suffering shock refractory to conventional resuscitation. Despite the utilization of VA-ECMO, clinical deterioration due to systemic inflammatory response syndrome (SIRS) resulting from the underlying shock and exposure of blood cells to the artificial surfaces of the ECMO circuit may occur. To address this issue, cytokine adsorbers offer a valuable solution by eliminating blood proteins, thereby controlling SIRS and potentially improving hemodynamics. Consequently, a prospective, randomized, blinded clinical trial will be carried out with ECMOsorb. METHODS AND STUDY DESIGN: ECMOsorb is a single-center, controlled, randomized, triple-blinded trial that will compare the hemodynamic effects of treatment with a VA-ECMO in combination with a cytokine adsorber (CytoSorb®, intervention) to treatment with VA-ECMO only (control) in patients with cardiogenic shock (with or without prior cardiopulmonary resuscitation (CPR)) requiring extracorporeal, hemodynamic support. Fifty-four patients will be randomized in a 1:1 fashion to the intervention or control group over a 36-month period. The primary endpoint of ECMOsorb is the improvement of the Inotropic Score (IS) 72 h after the intervention. Prognostic indicators, including mortality rates, hemodynamic parameters, laboratory findings, echocardiographic assessments, quality of life measurements, and clinical parameters, will serve as secondary outcome measures. The safety evaluation encompasses endpoints such as air embolisms, allergic reactions, peripheral ischemic complications, vascular complications, bleeding incidents, and stroke occurrences. CONCLUSIONS: The ECMOsorb trial seeks to assess the efficacy of a cytokine adsorber (CytoSorb®; CytoSorbents Europe GmbH, Berlin, Germany) in reducing SIRS and improving hemodynamics in patients with cardiogenic shock who are receiving VA-ECMO. We hypothesize that a reduction in cytokine levels can lead to faster weaning from inotropic and mechanical circulatory support, and ultimately to improved recovery.

A case report of a 37-year-old woman with pulmonary arterial hypertension first presented during her 3rd pregnancy and favourable long-term vasoreactive response.

BACKGROUND: Pulmonary arterial hypertension is a rare disease associated with high rates of mortality and can significantly complicate pregnancy posing health risks for the mother and child alike. CASE SUMMARY: We present the case of a 37-year-old female patient with World Health Organisation functional Class IV symptoms during the 34th week of her 3rd pregnancy. Initial echocardiography showed a significantly elevated estimated systolic pulmonary artery pressure of 86 mmHg + central vein pressure as well as signs of chronic pulmonary hypertension. After a successful emergent caesarean section, pulmonary hypertension was confirmed via right heart catheterization. After exclusion of secondary aetiologies of pulmonary hypertension, the diagnosis of Class 1 pulmonary artery hypertension was made. We initially treated the patient with the phosphodiesterase-5 inhibitor sildenafil (20 mg oral bid trice daily) and later extended the medication with the dual endothelin receptor antagonist Macicentan (10 mg daily). Since the patient remained symptomatic vasodilator testing was performed and showed a significant response to intravenous Epoprostenol. We initiated a high-dose calcium channel blocker (CCB) therapy with amlodipine (20 mg daily) which led to symptomatic relief, increased exercise capacity as well as reduction in mean pulmonary artery pressure and pulmonary vascular resistance as confirmed by another right heart catheterization after therapy initiation. DISCUSSION: Since the presentation is usually non-specific, the diagnosis of pulmonary artery hypertension can be challenging and cause a delay in treatment initiation. Even though rare vasodilator testing and invasive haemodynamic measurements should be performed to identify patients with favourable long-term response to high-dose CCB.

A Novel Echocardiographic-Based Classification for the Prediction of Peri-Device Leakage following Left Atrial Appendage Occluder Implantation.

(1) Background: The assessment of residual peri-device leakages (PDL) after left atrial appendage occlusion (LAAO) remains crucial for post-procedural management. Our study aimed to verify a novel echocardiographic classification for the prediction of PDL. (2) Methods: Echocardiographic data of 72 patients who underwent percutaneous LAAO were evaluated. All echo images were analyzed by two independent investigators using standard analysis software (Image-Arena IA-4.6.4.44 by TomTec®, Munich, Germany). A total number of 127 studies was evaluated. Forty-four patients had baseline studies, at 45 days and at 6 months post-implantation. We propose a morphological classification of LAA devices based on the amount of echodensity inside the devices into three types: type A showing complete homogenous thrombosis, type B incompletely thrombosed device with inhomogeneous echo-free space <50% of device, and type C with partially thrombosed device in which the echo free space was >50% of device in various planes, which we called the "ice-cream cone" sign. Each type was matched to the degree of PDL and clinical outcome parameters. (3) Results: Patients with type C had the highest percentage of PDL at 45 days follow-up (type A: 24%, type B: 31%, type C 100% PDL, p < 0.001) and at 6 months follow-up (type A: 7%, type B: 33%, type C 100% PDL, p < 0.001). Notably, device size in patients with PDL was larger than that in patients without PDL at 6 months follow-up (25.6 ± 3.5 mm vs. 28.7 ± 3.4 mm, p = 0.004). Device size in patients with type C appearance was the largest of the three types (type A: 25.9 ± 3.6 mm, type B: 25.8 ± 3.4 mm, type C 29.8 ± 3.0 mm, type A vs. C; p = 0.019; type B vs. C, p = 0.007). (4) Conclusions: In conclusion, PDL are common post-LAAO, and their frequency is underestimated and under-recognized. PDL are much more common in patients with larger LAA ostial sizes and likely lower longitudinal compression. Type C appearance of the LAAO devices ("ice-cream cone sign") has a high positive predictive value for PDL. Further studies are needed for better delineation of the clinical importance of this proposed classification.

Rationale and Design of JenaMACS-Acute Hemodynamic Impact of Ventricular Unloading Using the Impella CP Assist Device in Patients with Cardiogenic Shock.

INTRODUCTION: Cardiogenic shock due to myocardial infarction or heart failure entails a reduction in end organ perfusion. Patients who cannot be stabilized with inotropes and who experience increasing circulatory failure are in need of an extracorporeal mechanical support system. Today, small, percutaneously implantable cardiac assist devices are available and might be a solution to reduce mortality and complications. A temporary, ventricular, continuous flow propeller pump using magnetic levitation (Impella®) has been approved for that purpose. METHODS AND STUDY DESIGN: JenaMACS (Jena Mechanical Assist Circulatory Support) is a monocenter, proof-of-concept study to determine whether treatment with an Impella CP® leads to improvement of hemodynamic parameters in patients with cardiogenic shock requiring extracorporeal, hemodynamic support. The primary outcomes of JenaMACS are changes in hemodynamic parameters measured by pulmonary artery catheterization and changes in echocardiographic parameters of left and right heart function before and after Impella® implantation at different support levels after 24 h of support. Secondary outcome measures are hemodynamic and echocardiographic changes over time as well as clinical endpoints such as mortality or time to hemodynamic stabilization. Further, laboratory and clinical safety endpoints including severe bleeding, stroke, neurological outcome, peripheral ischemic complications and occurrence of sepsis will be assessed. JenaMACS addresses essential questions of extracorporeal, mechanical, cardiac support with an Impella CP® device in patients with cardiogenic shock. Knowledge of the acute and subacute hemodynamic and echocardiographic effects may help to optimize therapy and improve the outcome in those patients. CONCLUSION: The JenaMACS study will address essential questions of extracorporeal, mechanical, cardiac support with an Impella CP® assist device in patients with cardiogenic shock. Knowledge of the acute and subacute hemodynamic and echocardiographic effects may help to optimize therapy and may improve outcome in those patients. ETHICS AND DISSEMINATION: The protocol was approved by the institutional review board and ethics committee of the University Hospital of Jena. Written informed consent will be obtained from all participants of the study. The results of this study will be published in a renowned international medical journal, irrespective of the outcomes of the study. Strengths and Limitations: JenaMACS is an innovative approach to characterize the effect of additional left ventricular mechanical unloading during cardiogenic shock via a minimally invasive cardiac assist system (Impella CP®) 24 h after onset and will provide valuable data for acute interventional strategies or future prospective trials. However, JenaMACS, due to its proof-of-concept design, is limited by its single center protocol, with a small sample size and without a comparison group.

Clonal haematopoiesis of indeterminate potential-related mutations and outcome in dilated and ischaemic cardiomyopathy.

AIMS: Clonal haematopoiesis of indeterminate potential (CHIP)-associated mutation is a risk factor for the development of ischaemic cardiomyopathy (ICM), but its association with non-ischaemic dilated cardiomyopathy (DCM) remains unclear. We aimed to determine the prevalence of CHIP in patients with DCM and define its risk for disease progression. METHODS AND RESULTS: Next-generation sequencing targeting 54 common CHIP-associated genes was performed in 48 ICM and 52 DCM patients. The patients were monitored for a median of 3.1 years, and a COX proportional hazards model was used to examine the association between CHIP and adverse clinical outcome with regard to all-cause death or all-cause hospitalization. Overall, the prevalence of CHIP mutations was 19% and 13% in DCM and ICM, respectively. Seventeen per cent of ICM patients over 75 years were CHIP carriers. In DCM cohort, mutation event had already been observed in the patients who were under the age of 45 (13%). Among 54 genes analysed, DNMT3A had the highest mutation frequency, followed by TET2 and CUX1. Kaplan-Meier curve over a median of 3.1 year tracking period showed a trend towards poor clinical outcome in the DCM patients who carried DNMT3A or TET2 mutation; however, such association was not statistically significant. CONCLUSIONS: The prevalence of CHIP is detected at a young age in DCM, and accumulation of mutational frequency in DCM patients is independent of age. However, a larger patient cohort is required to validate the association between CHIP and clinical progression in the DCM patients.

Acute myocarditis after COVID-19 vaccination with mRNA-1273 in a patient with former SARS-CoV-2 infection.

We describe a case of a 20-year-old healthy man developing chest pain and classical symptoms of vaccine reactogenicity 12 h after receiving the first dose of mRNA-1273 (Moderna). Cardiac troponin T was increased, and subepicardial inflammation and focal contractile dysfunction were detected by cardiac magnetic resonance imaging and echocardiography. We confirmed the diagnosis of acute myocarditis by endomyocardial biopsy demonstrating significant infiltration of monocytes and T lymphocytes. Although we detected IgG against nucleocapsid protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) indicating prior infection, the patient repeatedly tested negative for SARS-CoV-2 and had been asymptomatic for several months. Furthermore, viral genome analysis of endomyocardial biopsy samples was negative for SARS-CoV-2 and other potential cardiotropic viruses. These findings and the strong temporal relation between the vaccination and the symptom onset imply a potential side effect of mRNA-1273.

Relation of left atrial function with exercise capacity and muscle endurance in patients with heart failure.

AIMS: Both left atrial strain (LAS) and skeletal muscle endurance demonstrate a linear relationship to peak VO2 . Less is known about the relationship between central (cardiac) and peripheral (muscle endurance) limitations of exercise capacity in patients with heart failure (HF). We investigated this relationship using novel cardiac markers such as LAS and left atrial emptying fraction (LAEF). METHODS AND RESULTS: We analysed echocardiographic measurements, cardiopulmonary exercise testing (CPET), and isokinetic muscle function in 55 subjects with HF and controls [17 heart failure with preserved ejection fraction (HFpEF), 18 heart failure with reduced ejection fraction (HFrEF), and 20 healthy controls]. Patients with reduced LAEF showed reduced peak VO2 : 14.3 ± 3.5 vs. 18.5 ± 3.5 mL/min/kg, P = 0.003, and reduced muscle endurance (RME): 64.3 ± 23.9 vs. 88.5 ± 32.3 Nm/kg, P = 0.028. Patients with reduced LAS showed similar results. Neither left ventricular global longitudinal strain (LVGLS) nor left atrial volume index (LAVI) was associated with RME. The area under the curve of LAS and LAEF in patients with HF in association with RME were (0.76 vs. 0.80) with 95% confidence interval (CI) (0.59-0.96, P = 0.012 vs. 0.63-0.98, P = 0.006, respectively). In a multiple linear regression, LAEF and working load measured during CPET (watt) were independent factors for RME after adjusting for age, LVGLS, and 6 min walk test (6MWT) [LAEF (B: 0.09, 95% CI: 1.01; 1.18, P = 0.024), working load (B: 0.05, 95% CI: 1.01; 1.08, P = 0.006)]. Peak torque of the left leg was associated with E/LAS (E: early diastolic) in patients with HFpEF (r = -0.6, P = 0.020). Endurance of the left leg was associated with LAEF (r = 0.79, P = 0.001) in patients with HFrEF. CONCLUSIONS: LAS/LAEF are potential cardiac markers in demonstrating the link between cardiac and peripheral limitations of exercise capacity. Thus, integrating LAS/LAEF in the evaluation of exercise intolerance in patients with HF could be useful.

Depression and anxiety in elderly patients with severe symptomatic aortic stenosis persistently improves after transcatheter aortic valve replacement (TAVR).

INTRODUCTION: Data on the prevalence of depression and anxiety in elderly cardiovascular disease patients are limited and there are only few studies focussing on treatment effects. Thus, the current study aimed to analyse elderly patients suffering from aortic stenosis (AS) and undergoing transcatheter aortic valve replacement (TAVR) with respect to both, prevalence rates before TAVR and dynamics in the clinical course. METHODS: The study included 140 AS patients undergoing TAVR (77.8 ±â€¯7.7 years, 42.9% male, mean STS-Score 4.4 ±â€¯2.2). Detailed clinical, laboratory and functional analysis was performed. In addition, quality of life (EQ-5D, EQ VAS), clinical frailty (CFS) and anxiety/depression (HADS-D), was assessed at baseline, 6 weeks, 6 months and 12 months after TAVR. RESULTS: Before TAVR, HADS-D revealed ≥8 points for anxiety and/or depression in 54 patients (38.6%), depression in 33 patients (23.6%) and for anxiety in 40 patients (28.6%). In the group showing HADS-D ≥8 points for anxiety, there was an improvement already 6 weeks after TAVR for anxiety (p < 0.05) but not for depression. In the group showing HADS-D ≥8 points for depression, there was a significant improvement at the 6 weeks' follow-up for both, depression (p < 0.001) and anxiety (p = 0.012) remaining stable for depression but not for anxiety until 12 months after TAVR. CONCLUSIONS: TAVR leads to reductions of depression and anxiety in patients showing pathologic baseline values in HADS-D. There were no associations between pre-existing depression and anxiety with long-term mortality in our study.

Skeletal Muscle Function, Structure, and Metabolism in Patients With Heart Failure With Reduced Ejection Fraction and Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Reduced exercise capacity in patients with heart failure (HF) could be partially explained by skeletal muscle dysfunction. We compared skeletal muscle function, structure, and metabolism among clinically stable outpatients with HF with preserved ejection fraction, HF with reduced ejection fraction, and healthy controls (HC). Furthermore, the molecular, metabolic, and clinical profile of patients with reduced muscle endurance was described. METHODS: Fifty-five participants were recruited prospectively at the University Hospital Jena (17 HF with preserved ejection fraction, 18 HF with reduced ejection fraction, and 20 HC). All participants underwent echocardiography, cardiopulmonary exercise testing, 6-minute walking test, isokinetic muscle function, and skeletal muscle biopsies. Expression levels of fatty acid oxidation, glucose metabolism, atrophy genes, and proteins as well as inflammatory biomarkers were assessed. Mitochondria were evaluated using electron microscopy. RESULTS: Patients with HF with preserved ejection fraction showed compared with HF with reduced ejection fraction and HC reduced muscle strength (eccentric extension: 13.3±5.0 versus 18.0±5.9 versus 17.9±5.1 Nm/kg, P=0.04), elevated levels of MSTN-2 (myostatin-2), FBXO-32 (F-box only protein 32 [Atrogin1]) gene and protein, and smaller mitochondrial size (P<0.05). Mitochondrial function and fatty acid and glucose metabolism were impaired in HF-patients compared with HC (P<0.05). In a multiple regression analysis, GDF-15 (growth and differentiation factor 15), CPT1B (carnitine palmitoyltransferase IB)-protein and oral anticoagulation were independent factors for predicting reduced muscle endurance after adjusting for age (log10 GDF-15 [pg/mL] [B, -54.3 (95% CI, -106 to -2.00), P=0.043], log10 CPT1B per fold increase [B, 49.3 (95% CI, 1.90-96.77), P=0.042]; oral anticoagulation present [B, 44.8 (95% CI, 27.90-61.78), P<0.001]). CONCLUSIONS: Patients with HF with preserved ejection fraction have worse muscle function and predominant muscle atrophy compared with those with HF with reduced ejection fraction and HC. Inflammatory biomarkers, fatty acid oxidation, and oral anticoagulation were independent factors for predicting reduced muscle endurance.