Search

Pathological cardiac remodeling predisposes individuals to developing heart failure. Here, we investigated two co-regulated long non-coding RNAs (lncRNAs), termed Gadlor1 and Gadlor2, which are upregulated in failing hearts of patients and mice. Cardiac overexpression of Gadlor1 and Gadlor2 aggravated myocardial dysfunction and enhanced hypertrophic and fibrotic remodeling in mice exposed to pressure overload. Compound Gadlor1/2 knockout (KO) mice showed markedly reduced myocardial hypertrophy, fibrosis, and dysfunction, while exhibiting increased angiogenesis during short and prolonged periods of pressure overload. Paradoxically, Gadlor1/2 KO mice suffered from sudden death during prolonged overload, possibly due to cardiac arrhythmia. Gadlor1 and Gadlor2, which are mainly expressed in endothelial cells (ECs) in the heart, where they inhibit pro-angiogenic gene expression, are strongly secreted within extracellular vesicles (EVs). These EVs transfer Gadlor lncRNAs to cardiomyocytes, where they bind and activate calmodulin-dependent kinase II, and impact pro-hypertrophic gene expression and calcium homeostasis. Therefore, we reveal a crucial lncRNA-based mechanism of EC-cardiomyocyte crosstalk during heart failure, which could be specifically modified in the future for therapeutic purposes.

Background: The prevalence of vitamin D deficiency and secondary hyperparathyroidism (sHPT) in adult Fontan patients remains unstudied, and the role of vitamin D and parathyroid hormone (PTH) levels in assessing heart and circulatory failure in these patients is unclear. Methods: We compared vitamin D deficiency and sHPT prevalence in adult Fontan patients (n = 35; mean age 33 ± 7.5 years) to adults with mild congenital heart disease (ACHD, n = 14). We analyzed associations between laboratory measurements, patient characteristics, and clinical events. Findings: Vitamin D deficiency was highly prevalent in both Fontan patients and ACHD controls (76.5 % vs. 71.4 %, p = 0.726). sHPT was exclusively present in Fontan patients (31.4 %). PTH levels correlated with NYHA class (r = 0.412), O2 saturation (r = −0.39), systemic ventricular function (r = 0.465), and NT-proBNP levels (r = 0.742). 25-hydroxyvitamin D showed an inverse correlation with NYHA class and systemic ventricular function (both r ≤ −0.38). Fontan patients with sHPT had a higher incidence of prior hospitalization for worsening heart failure and atrial arrhythmias compared to Fontan patients without HPT or ACHD controls. (Hospitalization: Fontan with HPT vs. Fontan without HPT: OR 5.46 [95 % CI 1.25–23.86], p = 0.021; arrhythmia: Fontan with HPT vs. Fontan without HPT: OR 1.96 [95 % CI 1.13–3.4], p = 0.035; ACHD: OR 11.45 [95 % CI 1.7–77.28], p=

The mortality of patients with MI has significantly decreased in recent decades, mainly due to early reperfusion therapy with a probability of surviving of more than 90% if the patient reaches the hospital [...]

BackgroundHypertrophic cardiomyopathy (HCM), the most common genetic heart disease, is classified into hypertrophic non-obstructive and hypertrophic obstructive cardiomyopathy (HOCM). Patients with HOCM and coexisting heart failure or arterial hypertension are often prescribed afterload-reducing drugs. Although recommended in current guidelines, data on the direct effect of discontinuing afterload-reducing medication are scarce. This study aims to demonstrate the benefit of discontinuing afterload-reducing medication in HOCM patients.MethodsThis monocentric retrospective analysis included 24 patients with HOCM with afterload-reducing medication, including angiotensin-converting enzyme inhibitors, angiotensin-1 receptor blocker and dihydropyridine-calcium channel blocker, at their first outpatient visit. Effects of discontinuing this medication on LVOTO were examined compared to patients with persistent use despite medical advice.Results16 patients discontinued their afterload-reducing drugs, resulting in a significant decrease in median LVOT gradient from 86.5 [60.5–109.3] mmHg to 61.5 [28.3–97.50] mmHg (p = 0.0004). In 6 patients, beta-blocker therapy was initiated simultaneously, or the dose was increased. Regardless, LVOT gradient reduction was also significant in the remaining 10 patients (p = 0.001). The gradient was not changed significantly in the 8 patients continuing their afterload-reducing medication.ConclusionsDiscontinuation of afterload-reducing drugs significantly decreases LVOTO. Our study underscores the significance of abstaining from afterload-reducing drugs in HOCM patients, particularly in patients with concomitant hypertension or heart failure. According to recently published European guidelines, HOCM patients should preferably be treated with beta-blockers or non-dihydropyridine-calcium channel blockers.

AimsImproved long-term survival has widened the treatment goals for adults with congenital heart disease (ACHD) by addressing parameters that impact mental well-being and exercise capacity. Depression, a frequent co-morbidity in ACHD, is linked to both. Whether successful treatment of depression also affects cardiac parameters is a matter of debate.MethodsThis prospective, cross-sectional, longitudinal study included N = 150 ACHD (mean age 35.2 ± 11.3 years, 57% male) at baseline (t0) and N = 114 at follow-up (mean follow-up: 4.8 ± 0.6 years; t1). Patients were interviewed using a structured clinical interview, and severity of depression was assessed using the Montgomery-Asperg Depression Scale (MADRS). Additional testing was performed using self-rating questionnaires concerning depression, anxiety and quality of life (QoL). Exercise capacity (VO2max) was assessed by symptom limited exercise testing.ResultsOf N = 33 patients diagnosed with depression at t0, N = 18 patients remitted and N = 15 were non-remitters. Remitters displayed significantly decreased anxiety (P = 0.013), improved global QoL (P = 0.002), and preserved VO2max (P = 0.958) at t1 compared to t0. This was associated with favourable health behaviour at t1 and stable body-mass-index. Contrarily, non-remitters reported further increased anxiety (P = 0.021) and no significant improvement in QoL (P = 0.405). VO2max declined significantly (P = 0.006) and body-mass-index increased (P = 0.004). Never-depressed patients showed no significant changes in anxiety (P = 0.415) or QoL (P = 0.211). VO2max decreased significantly (P

Abstract Ventricular tachyarrhythmia (VTA) are frequent arrhythmias in patients with hypertrophic cardiomyopathy (HCM). Representing a major risk factor for sudden cardiac death, Holter ECG at first clinical presentation appears insufficient. This study aims to investigate the ability of routinely obtained parameters associated with myocardial remodeling in stratifying for VTA in HCM. In this monocentric analysis, patients with HCM underwent 12-channel electrocardiography and echocardiography, including tissue doppler imaging. The study’s primary endpoint was the documentation of non-sustained and sustained ventricular tachycardia—summarized as ventricular tachyarrhythmias (VTA) on Holter ECG or active devices. The occurrence of VTA was exploratory. Based on our collective, we developed a risk model regarding VTA. Of 140 HCM patients, 38 (27.1%) had an episode of VTA. Patients with VTA were likelier to have a history of atrial fibrillation (p

Abstract In an era focused on value-based healthcare, the quality of healthcare and resource allocation should be underpinned by empirical evidence. Pragmatic clinical trials (pRCTs) are essential in this endeavor, providing randomized controlled trial (RCT) insights that encapsulate real-world effects of interventions. The rising popularity of pRCTs can be attributed to their ability to mirror real-world practices, accommodate larger sample sizes, and provide cost advantages over traditional RCTs. By harmonizing efficacy with effectiveness, pRCTs assist decision-makers in prioritizing interventions that have a substantial public health impact and align with the tenets of value-based health care. An international network for pRCT provides several advantages, including larger and diverse patient populations, access to a broader range of healthcare settings, sharing knowledge and expertise, and overcoming ethical and regulatory barriers. The hypothesis and study design of pRCT answers the decision-maker’s questions. pRCT compares clinically relevant alternative interventions, recruits participants from diverse practice settings, and collects data on various health outcomes. They are scarce because the medical products industry typically does not fund pRCT. Prioritizing these studies by expanding the infrastructure to conduct clinical research within the healthcare delivery system and increasing public and private funding for these studies will be necessary to facilitate pRCTs. These changes require more clinical and health policy decision-makers in clinical research priority setting, infrastructure development, and funding. This paper presents a comprehensive overview of pRCTs, emphasizing their importance in evidence-based medicine and the advantages of an international collaborative network for their execution. It details the development of PRIME-9, an international initiative across nine countries to advance pRCTs, and explores various statistical approaches for these trials. The paper underscores the need to overcome current challenges, such as funding limitations and infrastructural constraints, to leverage the full potential of pRCTs in optimizing healthcare quality and resource utilization.

Background Alveolar hypoxia is protective in the context of cardiovascular and ischemic heart disease; however, the underlying mechanisms are incompletely understood. The present study sought to test the hypothesis that hypoxia is cardioprotective in left ventricular pressure overload (LVPO)–induced heart failure. We furthermore aimed to test that overlapping mechanisms promote cardiac recovery in heart failure patients following left ventricular assist device‐mediated mechanical unloading and circulatory support. Methods and Results We established a novel murine model of combined chronic alveolar hypoxia and LVPO following transverse aortic constriction (HxTAC). The HxTAC model is resistant to cardiac hypertrophy and the development of heart failure. The cardioprotective mechanisms identified in our HxTAC model include increased activation of HIF (hypoxia‐inducible factor)‐1α–mediated angiogenesis, attenuated induction of genes associated with pathological remodeling, and preserved metabolic gene expression as identified by RNA sequencing. Furthermore, LVPO decreased Tbx5 and increased Hsd11b1 mRNA expression under normoxic conditions, which was attenuated under hypoxic conditions and may induce additional hypoxia‐mediated cardioprotective effects. Analysis of samples from patients with advanced heart failure that demonstrated left ventricular assist device–mediated myocardial recovery revealed a similar expression pattern for TBX5 and HSD11B1 as observed in HxTAC hearts. Conclusions Hypoxia attenuates LVPO‐induced heart failure. Cardioprotective pathways identified in the HxTAC model might also contribute to cardiac recovery following left ventricular assist device support. These data highlight the potential of our novel HxTAC model to identify hypoxia‐mediated cardioprotective mechanisms and therapeutic targets that attenuate LVPO‐induced heart failure and mediate cardiac recovery following mechanical circulatory support.

BackgroundThe echocardiographic parameters total atrial conduction time (PA-TDI duration), left atrial (LA) volume index (LAVI), and LA strain reflect adverse atrial remodeling and predict atrial fibrillation (AF).ObjectivesThe aim of this study was to investigate echocardiographic parameters indicating reverse LA remodeling and potential associations with AF recurrence after pulmonary vein isolation (PVI).MethodsThis prospective observational study consecutively enrolled patients scheduled for PVI for symptomatic AF. Electrocardiogram (ECG) test and transthoracic echocardiography were performed the day before and after PVI and again 3 months later. AF recurrence was determined by Holter ECG at 3 months, and telephone follow-up at 12 months, after PVI. The parameters of LA remodeling [PA-TDI, LAVI, and LA strain analysis: reservoir strain (LASr), conduit strain (LAScd), contraction strain (LASct)] were determined by transthoracic echocardiography.ResultsA total of 48 patients were included in the study (mean age: 61.4 ± 12.2 years). PA-TDI significantly decreased the day after PVI compared with the baseline (septal PA-TDI 103 ± 13 vs. 82 ± 14.9 ms, p ≤ 0.001; lateral PA-TDI 122.4 ± 14.8 vs. 106.9 ± 14.4 ms, p ≤ 0.001) and at the 3-month follow-up (septal PA-TDI: 77.8 ± 14.5, p ≤ 0.001; lateral PA-TDI 105.2 ± 16.1, p ≤ 0.001). LAVI showed a significant reduction at the 3-month follow-up compared with the baseline (47.7 ± 14.4 vs. 40.5 ± 9.7, p

Abstract Over the last 15–20 years, remarkable developments of heart failure (HF) pharmacotherapies have been achieved. However, HF remains a global healthcare challenge with more than 64 million patients worldwide. Optimization of guideline‐directed chronic HF medical therapy is highly recommended with every patient visit to improve outcomes in patients with HF with reduced ejection fraction. However, the majority of patients in real‐world settings are treated with doses that are lower than those with proven efficacy in clinical trials, which might be due to concerns of adverse effects and inertia of physicians. Likewise, a significant proportion of patients still do not receive all drug classes that could improve their prognosis. The recent European Society of Cardiology guidelines do not provide detailed recommendations on how these drug classes should be implemented in the treatment of inpatients to allow for both safety and a high likelihood of efficacy. We therefore propose a practical approach algorithm to support physicians to treat HF patients in their daily practice.

Abstract Aims Peripartum cardiomyopathy (PPCM) is a rare heart disease, occurring in previously heart‐healthy women during the last month of pregnancy or the first months after delivery due to left ventricular (LV) systolic dysfunction. A common pathomechanistic pathway of PPCM includes increased oxidative stress and the subsequent generation of a cleaved prolactin fragment (16 kDa PRL), which promotes the onset of heart failure (HF) in a microRNA (miR)‐146a‐dependent manner. Inhibition of prolactin secretion with the dopamine D2 receptor (D2R) agonist bromocriptine combined with standard HF therapy supports cardiac recovery. This study examined whether treatment with the more selective D2R agonist cabergoline prevents HF development in an experimental PPCM mouse model and might be used as an alternative treatment regime for PPCM. Methods and results Postpartum (PP) female PPCM‐prone mice with a cardiomyocyte restricted STAT3‐deficiency (αMHC‐Cretg/+; Stat3fl/fl; CKO) were treated over two consecutive nursing periods with cabergoline (CKO Cab, 0.5 mg/kg/day) and were compared with bromocriptine treated CKO (CKO Br) and postpartum‐matched WT and CKO mice. Cabergoline treatment in CKO PP mice preserved cardiac function [fractional shortening (FS): CKO Cab: 34.5 ± 9.4% vs. CKO: 22.1 ± 9%, P

Worsening heart failure (WHF) is a distinct under-diagnosed and under-treated condition, independent of location of care. Heart failure (HF) progression is punctuated by repeated WHF events, each resulting in reduced cardiac function. One-third of the patients with HF with reduced ejection fraction experience a decompensation event. These decompensation events often result in the emergency department visits and HF hospitalization. Despite its inclusion in recent guidelines, there is no precise definition of WHF or its various forms. It is worth noting that WHF signals a need for treatment optimization as per guideline-directed medical therapy and the addition of novel drugs like a stimulator of soluble guanylate cyclase that benefit this high-risk patient population. This practical document is based on the expert opinion of cardiologists, cardiothoracic surgeons, and physicians that discussed the definition, assessment, pharmacological management, and monitoring of WHF patients in a hospitalized setting. In addition, there is also a need for an expert opinion for the management of WHF in an outpatient setting.

Abstract Heart failure (HF) treatment has changed substantially over the last 30 years, leading to significant reductions in mortality and hospital admissions in patients with HF with reduced ejection fraction (HFrEF). Currently, the optimization of guideline‐directed chronic HF therapy remains the mainstay to further improve quality of life, mortality, and HF hospitalizations for patients with HFrEF. The angiotensin receptor‐neprilysin inhibitor sacubitril/valsartan (S/V) has an important role in the treatment of patients with HFrEF. The PARADIGM‐HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) randomized controlled trial has established solid evidence for the treatment of HFrEF in various subgroups. Apart from HFrEF, several studies have been conducted using S/V in various indications: patients hospitalized with acute decompensated HF, HF with preserved ejection fraction, acute myocardial infarction with reduced ejection fraction, uncontrolled and resistant hypertension, and chronic kidney disease. Data from the German Institute for Drug Use Evaluation reveal that implementation of S/V has increased steadily over time and, by the end of 2021, an estimated 266 000 patients were treated with S/V in Germany. The estimated cumulative real‐world patient exposure is >5.5 million patient‐treatment years worldwide. The number of patients treated with S/V largely exceeds the number of patients treated in clinical trials, and the current indication for S/V is larger than the strict inclusion/exclusion criteria of the randomized trials. Especially elderly patients, women, and patients with more and more severe comorbidities are underrepresented in the clinical trials. We therefore aimed to summarize the importance of S/V in HF in terms of efficacy and safety in clinical trials and daily clinical practice.

Abstract Major depressive disorder (MDD) is frequently associated with poor response to treatment. Common antidepressants target neurotransmission and neuronal plasticity, which require adequate energy supply. As imaging studies indicate disturbances in central energy metabolism, and caloric restriction improves neuroplasticity and impacts mood and cognition, correction of energy status might increase the effectiveness of antidepressant treatments and reduce the psychopathological symptoms of depression. Metabolic parameters, stress hormones, and brain-derived neurotrophic factor (BDNF) levels were assessed in serum of depressed inpatients (MDD, N = 21) and healthy volunteers (Ctrl, N = 28) before and after a 72 h fasting period during which only water was consumed. Depression severity was assessed by Beck’s Depression Inventory (BDI)-2 sum-score and cognitive-affective and somatic sub-scores. Fasting similarly impacted metabolic parameters and stress systems in both groups. Fasting elevated BDI-2 sum-scores and somatic sub-scores in Ctrl. In MDD, fasting increased somatic-, but decreased cognitive-affective symptoms. Sub-group analyses based on BDI-2 sum-scores pre-fasting showed that cognitive-affective symptoms decreased in patients with moderate/severe but not in those with mild symptoms. This was associated with differential changes in BDNF levels. In conclusion, fasting improved cognitive-affective sub-scores in MDD patients with moderate/severe symptoms that had not responded to prior therapy. Interventions that modulate energy metabolism might directly improve cognitive-affective symptoms and/or augment therapeutic efficacy in moderate-to-severely depressed patients.

Cachexia is associated with poor prognosis in heart failure. Here the authors show that mice and patients with cardiac cachexia display reduced skeletal muscle expression and circulating levels of Musclin. Musclin ablation in skeletal muscle worsens, while its muscle-specific overexpression ameliorates heart failure in mice.

BackgroundPerturbed mitochondrial energetics and vitamin A (VitA) metabolism are associated with the pathogenesis of diet-induced obesity (DIO) and type 2 diabetes (T2D).MethodsTo test the hypothesis that VitA regulates tissue-specific mitochondrial energetics and adverse organ remodeling in DIO, we utilized a murine model of impaired VitA availability and high fat diet (HFD) feeding. Mitochondrial respiratory capacity and organ remodeling were assessed in liver, skeletal muscle, and kidney tissue, which are organs affected by T2D-associated complications and are critical for the pathogenesis of T2D.ResultsIn liver, VitA had no impact on maximal ADP-stimulated mitochondrial respiratory capacity (VADP) following HFD feeding with palmitoyl-carnitine and pyruvate each combined with malate as substrates. Interestingly, histopathological and gene expression analyses revealed that VitA mediates steatosis and adverse remodeling in DIO. In skeletal muscle, VitA did not affect VADP following HFD feeding. No morphological differences were detected between groups. In kidney, VADP was not different between groups with both combinations of substrates and VitA transduced the pro-fibrotic transcriptional response following HFD feeding.ConclusionThe present study identifies an unexpected and tissue-specific role for VitA in DIO that regulates the pro-fibrotic transcriptional response and that results in organ damage independent of changes in mitochondrial energetics.

Abstract Aim The wearable cardioverter‐defibrillator (WCD) is used for temporary protection from sudden cardiac death (SCD) in patients with newly diagnosed heart failure with reduced ejection fraction before considering an implantable cardioverter‐defibrillator (ICD). However, the prognostic significance of the WCD remains controversial due to conflicting evidence. The aim of the present study was to evaluate prognosis of patients receiving life‐saving WCD shocks. Methods and results All patients receiving a WCD at Hannover Medical School for heart failure with reduced ejection fraction between 2012 and 2017 were included. Data were acquired at baseline, at 3 months and at last available follow‐up (FU). Three hundred and fifty‐three patients were included (69% male; age 56 ± 15 years; left ventricular ejection fraction 25 ± 8%). FU after the WCD was 2.8 ± 1.5 years with a maximum of 6.8 years. Daily WCD wear time was 22 ± 4 h. Fourteen patients (4%) received appropriate WCD shocks. Two patients (0.6%) died during the WCD period. Thirty patients (9%) died during extended FU. Mean estimated survival after the WCD was similar between patients with and without WCD shocks. Patients without an ICD recommendation after WCD prescription did not experience SCD during FU. Conclusions Patients with WCD shocks showed a favourable survival. Patients without an ICD recommendation after WCD prescription had no SCD during FU. These findings support the practice of careful risk stratification before considering an ICD and the use of the WCD for temporary protection from SCD.

BackgroundFibroblast activation protein α (FAP), a membrane glycoprotein with dipeptidyl-peptidase and collagenase properties, is expressed in atherosclerotic plaques and remodeling of the extracellular matrix based on fibrosis. Fibrosis is a main contributor of atrial cardiomyopathies. In acute MI, circulating FAP is associated with outcome. Here, we investigated the correlation of circulating FAP to echocardiographic parameters of atrial remodeling and neurological impairment in acute ischemic stroke.MethodsCirculating FAP plasma concentrations were determined by ELISA in 47 patients with acute stroke and 22 control patients without stroke. Echocardiography was performed in all participants. Laboratory analysis, National Institutes of Health Stroke Scale (NIHSS) scoring and prolonged Holter-ECG-monitoring were performed in all stroke patients.ResultsPatients with acute stroke had lower circulating FAP concentrations than the control cohort (92 ± 24 vs. 106 ± 22 ng/mL, P < 0.001). There was no difference between the circulating FAP concentration comparing stroke due to atrial fibrillation, embolic stroke of undetermined source (ESUS) or atherosclerotic origin. Septal atrial conduction time (sPA-TDI) and left atrial (LA) volume index to tissue Doppler velocity (LAVI/a‘) representing echocardiographic parameters of LA remodeling did not correlate with FAP concentrations (sPA-TDI: r = 0.123, p = 0.31; LAVI/a‘: r = 0.183, p = 0.132). Stroke severity as assessed by NIHSS inversely correlated with circulating FAP (r = −0.318, p = 0.04). FAP concentration had a fair accuracy for identifying stroke in the receiver operating characteristic (ROC) analysis (AUC = 0.710, 95% CI: 0.577–0.843). A FAP concentration of 101 ng/mL discriminated between presence and absence of stroke with a sensitivity of 72% and a specificity of 77%. Lower circulating FAP concentration was associated with cardio-cerebro-vascular events within 12 months after admission.ConclusionsOur study is the first to associate FAP with echocardiographic parameters of LA-remodeling and function. FAP did not correlate with sPA-TDI and LAVI/a‘. However, FAP was associated with stroke, neurological impairment, and cardio-cerebral events within 12 months. Therefore, FAP might enable individualized risk stratification in ischemic stroke.

Background: Adults with congenital heart disease (ACHD) display changes in adaptive immunity related to early open-heart surgery and subsequent incidental thymectomy. In acquired heart failure (HF) systemic inflammation, innate and adaptive immune cells play an important role. However, cellular immune alterations of monocyte, T lymphocyte and natural killer (NK) cell subsets have not been related to HF in ACHD. Methods and results: This cross-sectional study included 209 ACHD outpatients (mean age: 35.3 ± 11.0 years; NYHA class I/II/III-IV 64.1%/21.5%/14.4%; 59.8% male) and 21 healthy controls (29.8 ± 12.6 years; 47.6% male). Patients with clinical signs of infection, inflammatory diseases or malignancies were excluded. Flow cytometry of fresh whole blood revealed significantly elevated levels of CD14++CD16+ (Mon2) and CD14+CD16++ (Mon3) monocytes that increased in advanced NYHA class. Immature CD14+HLA-DRneg/low monocytes were significantly higher in ACHD, but did not relate to NT-proBNP or NYHA class. Frequencies of Mon2, CD14+HLA-DRneg/low and neutrophils related to plasma S100A8/A9 levels. Furthermore, ACHD had decreased T helper and cytotoxic T cell counts, however NKT and CD3bright T cells remained unchanged compared to control. The cytokine-producing CD56bright NK subset related to NT-proBNP and expanded in advanced HF stages. Patients with elevated Mon2 and CD14+HLA-DRneg/low monocytes exhibited a worse outcome regarding all-cause mortality/cardiac decompensations after a mean follow-up of 5.5 years. High Mon2, low total lymphocyte and low T helper cell counts were independent prognostic markers for the onset of adverse cardiac events. Conclusions: Altered immune cell compositions related to heart failure and exhibited prognostic relevance. This suggests an important link between immunity, inflammation and HF in ACHD bearing potential for refined clinical risk stratification.

Background and aimAdverse childhood experiences (ACEs) are a major risk factor for unfavorable behavioral, mental and health outcomes later in life. However, the precise pathway via which ACEs convey these risks, in particular regarding health outcomes such as cardiovascular disease, remains unknown. Here, we combined psychiatric and cardiac methods to investigate the pathway via which childhood adversities may lead to adult adverse cardiovascular health, with a focus on epicardial adipose tissue (EAT) as a risk marker.Methods210 adult congenital heart disease outpatients (mean age 35.5 y, 43% female) completed a thorough cardiac and psychiatric evaluation. Psychiatric measurements included an expert interview, the childhood trauma questionnaire (CTQ), Beck's depression inventory II (BDI-II), quality of life and the global scale of functioning, amongst others. All patients completed a full cardiac workup including EAT assessment using echocardiography. We then computed bootstrapping mediation models using ACEs as a predictor, depression and physical activity as mediators and EAT as dependent variable in PROCESS.ResultsCTQ scores had a significant indirect effect on EAT via a serial mediation of BDI and physical activity [a*b2*d = 0.0260, 95% BCa CI [0.0047, 0.0619]].ConclusionUsing mediation analyses, we show that adverse childhood events are linked to increased depressive symptoms, which are linked to decreased physical activity, which in turn are linked to a higher amount of epicardial adipose tissue. While other pathways most certainly exist and replication is needed, this suggests a meaningful pathway via which ACEs lead to adverse cardiovascular health, with several potential targets for health interventions across time.

ObjectiveVeno-venous (V-V) extracorporeal membrane oxygenation (ECMO) is increasingly used to support patients with severe acute respiratory distress syndrome (ARDS). In case of additional cardio-circulatory failure, some experienced centers upgrade the V-V ECMO with an additional arterial return cannula (termed V-VA ECMO). Here we analyzed short- and long-term outcome together with potential predictors of mortality.DesignMulticenter, retrospective analysis between January 2008 and September 2021.SettingThree tertiary care ECMO centers in Germany (Hannover, Bonn) and Switzerland (Zurich).PatientsSeventy-three V-V ECMO patients with ARDS and additional acute cardio-circulatory deterioration required an upgrade to V-VA ECMO were included in this study.Measurements and main resultsFifty-three patients required an upgrade from V-V to V-VA and 20 patients were directly triple cannulated. Median (Interquartile Range) age was 49 (28–57) years and SOFA score was 14 (12–17) at V-VA ECMO upgrade. Vasoactive-inotropic score decreased from 53 (12–123) at V-VA ECMO upgrade to 9 (3–37) after 24 h of V-VA ECMO support. Weaning from V-VA and V-V ECMO was successful in 47 (64%) and 40 (55%) patients, respectively. Duration of ECMO support was 12 (6–22) days and ICU length of stay was 32 (16–46) days. Overall ICU mortality was 48% and hospital mortality 51%. Two additional patients died after hospital discharge while the remaining patients survived up to two years (with six patients being lost to follow-up). The vast majority of patients was free from higher degree persistent organ dysfunction at follow-up. A SOFA score > 14 and higher lactate concentrations at the day of V-VA upgrade were independent predictors of mortality in the multivariate regression analysis.ConclusionIn this analysis, the use of V-VA ECMO in patients with ARDS and concomitant cardiocirculatory failure was associated with a hospital survival of about 50%, and most of these patients survived up to 2 years. A SOFA score > 14 and elevated lactate levels at the day of V-VA upgrade predict unfavorable outcome.

BackgroundMechanical heart valves (MHVs) are preferred prosthesis types in many, especially younger patients who need surgical valve replacement. Although echocardiography is most frequently performed for prosthesis assessment during follow-up, ultrasound artifacts usually preclude a precise investigation of prosthesis function. Cinefluoroscopy (CF) is a simple and effective method to analyze and quantify opening and closing of prosthesis leaflets but requires careful visualization of the valve using optimal viewing angles. Here, we investigated the quality of CF studies in clinical routine and their suitability for quantitative analysis of prosthesis function.Methods and resultsWe retrospectively identified 94 patients with 118 cinefluoroscopies performed by 31 different investigators in one tertiary center from 2012 to 2021. Of 150 MHVs (98% bi-leaflet prostheses), 87 (58%) were aortic, 53 (34%) mitral, 7 (5%) tricuspid, and 5 (3%) pulmonary valve prostheses, respectively. CF studies were categorized by their suitability to quantitatively assess opening and closing angles. Visualization of valve function was “sufficient” in 23%, “suboptimal” in 46%, and “unsuitable” in 31% of the cases.ConclusionIn clinical routine, only one-fourth of CF studies allow for a complete assessment of leaflet motion of MHVs. Although this may be in part due to the varying experience of operators, the high number of unsuitable studies suggests that optimal viewing angles may not be achievable in all patients. Further research is required to investigate standard viewing angles and anatomy after MHV implantation to improve the quality of CF studies and reduce radiation exposure of patients and operators.

Abstract Aims Heart failure (HF) is the most common primary inpatient diagnosis in Germany. We examined temporal trends of HF hospitalization within Germany focusing on regional differences. Methods and results We analysed aggregated data of more than 320 million hospitalizations in Germany from 2000 to 2017. Temporal trends of HF‐related parameters were analysed, focusing on regional differences between the federal states. The absolute number of HF‐related hospitalizations throughout Germany increased continuously and almost doubled (from 239 694 to 464 724 cases, +94%) with the relative increase being higher in East Germany compared with West Germany (119% vs. 88%). These regional differences persisted after age standardization with 609 and 490 cases per 100 000 population, respectively. The length of stay decreased continuously across Germany (from 14.3 to 10.2 days; −29%), while the total number of HF‐related hospital days increased by 51% in East Germany and 35% in West Germany. In 2017, HF remained the leading cause of in‐hospital death (8.9% of all cases), with a markedly higher rate in East vs. West Germany (65 vs. 43 deaths per 100 000 population). Conclusions Heart failure remains the most common cause of hospitalization and in‐hospital death throughout Germany. The increase in HF‐related morbidity and mortality was much higher in East Germany compared with West Germany during the observation period. A more detailed understanding of these striking disparities 30 years after the German reunification requires further investigations. There is an urgent need for action with regard to stronger control of risk factors and improvement of both chronic HF management and healthcare structures.

Abstract Aims Peripartum cardiomyopathy (PPCM) is a pregnancy‐associated cardiomyopathy that occurs in previously heart‐healthy women towards the end of pregnancy or in the first months after delivery and is characterized by heart failure due to systolic dysfunction. The clinical course of PPCM differs between mild symptoms and severe forms with acute heart failure complicated by cardiogenic shock (CS). Treatment of CS complicating PPCM is challenging, as β‐adrenergic receptor (β‐AR) stimulation seems to be associated with progression of heart failure and adverse outcome. This experimental study aims to examine whether postpartum treatment with the glucose uptake‐promoting drug perhexiline alone or as co‐treatment with β‐AR stimulation prevents heart failure in the experimental PPCM mouse model. Methods and results Postpartum (PP) female PPCM‐prone mice with a cardiomyocyte‐restricted STAT3‐deficiency (αMHC‐Cretg/+;Stat3fl/fl; CKO) were treated with perhexiline over two to three pregnancies and nursing periods (2/3PP) or were co‐treated with perhexiline after one pregnancy (1PP) under chronic β‐AR stimulation using isoproterenol (Iso) infusion. Perhexiline was not able to prevent onset of PPCM in CKO mice (FS: CKO Pexsig‐2/3PP: 25 ± 12% vs. CKO Ctrl‐2/3PP: 24 ± 9%, n.s.) but attenuated worsening of left ventricular function in response to treatment with the β‐AR agonist Iso (FS: CKO Pexsig‐Iso‐1PP: 19 ± 4% vs. CKO Ctrl‐Iso‐1PP: 11 ± 5%, P

Abstract Aims Acute pulmonary disorders are known physical triggers of takotsubo syndrome (TTS). This study aimed to investigate prevalence of acute pulmonary triggers in patients with TTS and their impact on outcomes. Methods and results Patients with TTS were enrolled from the International Takotsubo Registry and screened for triggering factors and comorbidities. Patients were categorized into three groups (acute pulmonary trigger, chronic lung disease, and no lung disease) to compare clinical characteristics and outcomes. Of the 1670 included patients with TTS, 123 (7%) were identified with an acute pulmonary trigger, and 194 (12%) had a known history of chronic lung disease. The incidence of cardiogenic shock was highest in patients with an acute pulmonary trigger compared with those with chronic lung disease or without lung disease (17% vs. 10% vs. 9%, P = 0.017). In‐hospital mortality was also higher in patients with an acute pulmonary trigger than in the other two groups, although not significantly (5.7% vs. 1.5% vs. 4.2%, P = 0.13). Survival analysis demonstrated that patients with an acute pulmonary trigger had the worst long‐term outcome (P = 0.002). The presence of an acute pulmonary trigger was independently associated with worse long‐term mortality (hazard ratio 2.12, 95% confidence interval 1.33–3.38; P = 0.002). Conclusions The present study demonstrates that TTS is related to acute pulmonary triggers in 7% of all TTS patients, which accounts for 21% of patients with physical triggers. The presence of acute pulmonary trigger is associated with a severe in‐hospital course and a worse long‐term outcome.

BackgroundEmpagliflozin, an inhibitor of the sodium glucose co-transporter 2 (SGLT2) and developed as an anti-diabetic agent exerts additional beneficial effects on heart failure outcomes. However, the effect of empagliflozin on vascular cell function and vascular remodeling processes remains largely elusive.Methods/ResultsImmunocytochemistry and immunoblotting revealed SGLT2 to be expressed in human smooth muscle (SMC) and endothelial cells (EC) as well as in murine femoral arteries. In vitro, empagliflozin reduced serum-induced proliferation and migration of human diabetic and non-diabetic SMCs in a dose-dependent manner. In contrast, empagliflozin significantly increased the cell count and migration capacity of human diabetic ECs, but not of human non-diabetic ECs. In vivo, application of empagliflozin resulted in a reduced number of proliferating neointimal cells in response to femoral artery wire-injury in C57BL/6J mice and prevented neointima formation. Comparable effects were observed in a streptozocin-induced diabetic model of apolipoprotein E–/– mice. Conclusive to the in vitro-results, re-endothelialization was not significantly affected in C57BL/6 mice, but improved in diabetic mice after treatment with empagliflozin assessed by Evan’s Blue staining 3 days after electric denudation of the carotid artery. Ribonucleic acid (RNA) sequencing (RNA-seq) of human SMCs identified the vasoactive peptide apelin to be decisively regulated in response to empagliflozin treatment. Recombinant apelin mimicked the in vitro-effects of empagliflozin in ECs and SMCs.ConclusionEmpagliflozin significantly reduces serum-induced proliferation and migration of SMCs in vitro and prevents neointima formation in vivo, while augmenting EC proliferation in vitro and re-endothelialization in vivo after vascular injury. These data document the functional impact of empagliflozin on vascular human SMCs and ECs and vascular remodeling in mice for the first time.

BackgroundHeart failure (HF) is associated with development of depressive symptoms and reduced quality of life (QoL). Patients with HF and an implantable cardioverter-defibrillator (ICD) were evaluated regarding depressive symptoms and QoL.MethodsThe present study included 446 patients with HF and an ICD. Depressive symptoms were assessed using the Patient Health Questionnaire 9 (PHQ-9), QoL was evaluated using the Minnesota Living with Heart Failure Questionnaire (MLHFQ). Functional ability and exercise tolerance were assessed at inclusion and after 6 months with help of the 6-min walking test (6MWT).ResultsPatients included in the study had a mean age of 65.8 years and were predominantly male (83.6%), with mostly ischemic (n = 277; 62.1%) or dilated (n = 150; 33.6%) cardiomyopathy. One hundred ninety-three (43.2%) patients had depressive symptoms, of whom 75 patients (16.8%) were classified as moderate to severe depression according to the PHQ-9 at baseline. Depressive symptoms were associated with low QoL independent of NYHA functional class. High NYHA functional class, high PHQ-9 score, age and body mass index (BMI) were associated with a lower 6MWT at enrollment, while depressive symptoms (expressed as higher PHQ-9 score) and age were associated with a lower 6MWT after 6 months. Patients with history of smoking and a higher BMI showed higher PHQ-9 scores after 6 months. Patients under antidepressant medication showed improved PHQ-9 score after 6 months, indicating controlled/treated depression. However, patients with low QoL at inclusion remained with low QoL after 6 months.ConclusionDepressive symptoms correlate with low QoL and lower long-term functional status in patients with HF and an ICD. Depressive symptoms are associated with smoking and obesity, which themselves are risk factors for a poor prognosis in HF. Only a small fraction of patients with HF and ICD showing depressive symptoms receives appropriate treatment. Assessing depressive symptoms and lifestyle factors should be part of a multimodal treatment plan in patients with HF and an ICD.

Abstract Aims In peripartum cardiomyopathy (PPCM), electrocardiography (ECG) and its relationship to echocardiography have not yet been investigated in large multi‐centre and multi‐ethnic studies. We aimed to identify ECG abnormalities associated with PPCM, including regional and ethnic differences, and their correlation with echocardiographic features. Methods and results We studied 411 patients from the EURObservational PPCM registry. Baseline demographic, clinical, and echocardiographic data were collected. ECGs were analysed for rate, rhythm, QRS width and morphology, and QTc interval. The median age was 31 [interquartile range (IQR) 26–35] years. The ECG was abnormal in > 95% of PPCM patients. Sinus tachycardia (heart rate > 100 b.p.m.) was common (51%), but atrial fibrillation was rare (2.27%). Median QRS width was 82 ms [IQR 80–97]. Left bundle branch block (LBBB) was reported in 9.30%. Left ventricular (LV) hypertrophy (LVH), as per ECG criteria, was more prevalent amongst Africans (59.62%) and Asians (23.17%) than Caucasians (7.63%, P 55 mm included a QRS complex > 120 ms (OR 11.32 [95% CI 1.52–84.84], P = 0.018), LBBB (OR 4.35 [95% CI 1.30–14.53], P = 0.017), and LVH (OR 2.03 [95% CI 1.13–3.64], P = 0.017). Conclusions PPCM patients often have ECG abnormalities. Sinus tachycardia predicted poor systolic function, whereas wide QRS, LBBB, and LVH were associated with LV dilatation.

Immune checkpoint inhibitors (ICIs) have revolutionized oncology and transformed the treatment of various malignancies. By unleashing the natural immunological brake of the immune system, ICIs were initially considered an effective, gentle therapy with few side effects. However, accumulated clinical knowledge reveals that ICIs are associated with inflammation and tissue damage in multiple organs, leading to immune-related adverse effects (irAEs). Most irAEs involve the skin and gastrointestinal tract; however, cardiovascular involvement is associated with very high mortality rates, and its underlying pathomechanisms are poorly understood. Ranging from acute myocarditis to chronic cardiomyopathies, ICI-induced cardiotoxicity can present in various forms and entities. Revealing the inciting factors, understanding the pathogenesis, and identifying effective treatment strategies are needed to improve the care of tumor patients and our understanding of the immune and cardiovascular systems.

Abstract Background Extracorporeal membrane oxygenation (ECMO) support in acute respiratory failure may be lifesaving, but bleeding and thromboembolic complications are common. The optimal anticoagulation strategy balancing these factors remains to be determined. This retrospective study compared two institutional anticoagulation management strategies focussing on oxygenator changes and both bleeding and thromboembolic events. Methods We conducted a retrospective observational cohort study between 04/2015 and 02/2020 in two ECMO referral centres in Germany in patients receiving veno-venous (VV)-ECMO support for acute respiratory failure for > 24 h. One centre routinely applied low-dose heparinization aiming for a partial thromboplastin time (PTT) of 35–40 s and the other routinely used a high-dose therapeutic heparinization strategy aiming for an activated clotting time (ACT) of 140–180 s. We assessed number of and time to ECMO oxygenator changes, 15-day freedom from oxygenator change, major bleeding events, thromboembolic events, 30-day ICU mortality, activated clotting time and partial thromboplastin time and administration of blood products. Primary outcome was the occurrence of oxygenator changes depending on heparinization strategy; main secondary outcomes were the occurrence of severe bleeding events and occurrence of thromboembolic events. The transfusion strategy was more liberal in the low-dose centre. Results Of 375 screened patients receiving VV-ECMO support, 218 were included in the analysis (117 high-dose group; 101 low-dose group). Disease severity measured by SAPS II score was 46 (IQR 36–57) versus 47 (IQR 37–55) and ECMO runtime was 8 (IQR 5–12) versus 11 (IQR 7–17) days (P = 0.003). There were 14 oxygenator changes in the high-dose group versus 48 in the low-dose group. Freedom from oxygenator change at 15 days was 73% versus 55% (adjusted HR 3.34 [95% confidence interval 1.2–9.4]; P = 0.023). Severe bleeding events occurred in 23 (19.7%) versus 14 (13.9%) patients (P = 0.256) and thromboembolic events occurred in 8 (6.8%) versus 19 (19%) patients (P = 0.007). Mortality at 30 days was 33.3% versus 30.7% (P = 0.11). Conclusions In this retrospective study, ECMO management with high-dose heparinization was associated with lower rates of oxygenator changes and thromboembolic events when compared to a low-dose heparinization strategy. Prospective, randomized trials are needed to determine the optimal anticoagulation strategy in patients receiving ECMO support.

Abstract Hypertrophic cardiomyopathy (HCM) is one of the most common hereditary heart diseases and can be classified into an obstructive (HOCM) and non-obstructive (HNCM) form. Major characteristics for HCM are the hypertrophy of cardiomyocytes and development of cardiac fibrosis. Patients with HCM have a higher risk for sudden cardiac death compared to a healthy population. In the present study, we investigated the abundancy of selected proteins as potential biomarkers in patients with HCM. We included 60 patients with HCM and 28 healthy controls and quantitatively measured the rate of a set of 92 proteins already known to be associated with cardiometabolic processes via protein screening using the proximity extension assay technology in a subgroup of these patients (20 HCM and 10 healthy controls). After validation of four hits in the whole cohort of patients consisting of 88 individuals (60 HCM patients, 28 healthy controls) we found only one candidate, c-KIT, which was regulated significantly different between HCM patients and healthy controls and thus was chosen for further analyses. c-KIT is a tyrosine-protein kinase acting as receptor for the stem cell factor and activating several pathways essential for cell proliferation and survival, hematopoiesis, gametogenesis and melanogenesis. Serum protein levels of c-KIT were significantly lower in patients with HCM than in healthy controls, even after adjusting for confounding factors age and sex. In addition, c-KIT levels in human cardiac tissue of patients with HOCM were significant higher compared to controls indicating high levels of c-KIT in fibrotic myocardium. Furthermore, c-KIT concentration in serum significantly correlated with left ventricular end-diastolic diameter in HOCM, but not HCM patients. The present data suggest c-KIT as a novel biomarker differentiating between patients with HCM and healthy population and might provide further functional insights into fibrosis-related processes of HOCM.

Abstract Aims Peripartum cardiomyopathy (PPCM) is a heart disease affecting women during the last month of pregnancy or in the first months after delivery. The impact of the disease on mental health is largely unknown. Methods and results Major mental disorders were assessed by a structured clinical interview in 40 patients with a confirmed PPCM diagnosis, and the data were compared with published prevalence in postpartum women. Circulating biomarkers associated with mental health, such as kynurenine, serotonin, and microRNA (miR)‐30e, were evaluated in PPCM and compared with matched healthy pregnancy‐matched postpartum controls (PP‐Ctrl). Major mental disorders were diagnosed in 65% (26/40) of the PPCM cohort. The prevalence for major depressive disorders was 4‐fold, for post‐traumatic stress disorder 14‐fold, and for panic disorder 6‐fold higher in PPCM patients compared with postpartum women without a PPCM diagnosis. Compared with PP‐Ctrl, PPCM patients displayed elevated levels of serum kynurenine (P

BackgroundCardiogenic shock (CS) alters whole body metabolism and circulating biomarkers serve as prognostic markers in CS patients. Percutaneous ventricular assist devices (pVADs) unload the left ventricle by actively ejecting blood into the aorta. The goal of the present study was to identify alterations in circulating metabolites and transcripts in a large animal model that might serve as potential prognostic biomarkers in acute CS and additional left ventricular unloading by Impella ® pVAD support.MethodsCS was induced in a preclinical large animal model by injecting microspheres into the left coronary artery system in six pigs. After the induction of CS, mechanical pVAD support was implemented for 30 min total. Serum samples were collected under basal conditions, after the onset of CS, and following additional pVAD unloading. Circulating metabolites were determined by metabolomic analysis, circulating RNA entities by RNA sequencing.ResultsCS and additional pVAD support alter the abundance of circulating metabolites involved in Aminoacyl-tRNA biosynthesis and amino acid metabolism. RNA sequencing revealed decreased abundance of the hypoxia sensitive miRNA-200b following the induction of CS, which was reversed following pVAD support.ConclusionThe hypoxamir miRNA-200b is a potential circulating marker that is repressed in CS and is restored following pVAD support. The early transcriptional response with increased miRNA-200b expression following only 30 min of pVAD support suggests that mechanical unloading alters whole body metabolism. Future studies are required to delineate the impact of serum miRNA-200b levels as a prognostic marker in patients with acute CS and pVAD unloading.

BackgroundPatients after out-of-hospital cardiac arrest (OHCA) are at increased risk for mortality and poor neurological outcome. We assessed the additive impact of interleukin 6 (IL-6) at admission to neuron-specific enolase (NSE) at day 3 for prognosis of 30-day mortality and long-term neurological outcome in OHCA patients.MethodsA total of 217 patients from the HAnnover COoling REgistry with return of spontaneous circulation (ROSC) after OHCA and IL-6 measurement immediately after admission during 2017–2020 were included to investigate the prognostic value and importance of IL-6 in addition to NSE obtained on day 3. Poor neurological outcome was defined by cerebral performance category (CPC) ≥ 3 after 6 months.ResultsPatients with poor outcome showed higher IL-6 values (30-day mortality: 2,224 ± 524 ng/l vs 186 ± 15 ng/l, p < 0.001; CPC ≥ 3 at 6 months: 1,440 ± 331 ng/l vs 180 ± 24 ng/l, p < 0.001). IL-6 was an independent predictor of mortality (HR = 1.013/ng/l; 95% CI 1.007–1.019; p < 0.001) and poor neurological outcome (HR = 1.004/ng/l; 95% CI 1.001–1.007; p = 0.036). In ROC-analysis, AUC for IL-6 was 0.98 (95% CI 0.96–0.99) for mortality, but only 0.76 (95% CI 0.68–0.84) for poor neurological outcome. The determined cut-off value for IL-6 was 431 ng/l for mortality (NPV 89.2%). In patients with IL-6 > 431 ng/l, the combination with NSE < 46 μg/l optimally identified those individuals with potential for good neurological outcome (CPC ≤ 2).ConclusionElevated IL-6 levels at admission after ROSC were closely associated with 30-day mortality. The combination of IL-6 and NSE provided clinically important additive information for predict poor neurological outcome at 6 months.

Introduction: The risk of thromboembolism increases with duration of Fontan circulation. Preventive drug strategies are still discussed controversially. We aimed to characterize clinical relevant thromboembolism in long-standing Fontan circulation and to analyse the protective effect of Acetylsalicylic acid (ASA) and Vitamin K Antagonists (VKA). Method: 78 patients (age ≥16 years) were included (mean age 20.7 ± 5.7 years; 51 male). Last medication and duration of therapy were documented. Perioperative events were excluded. Mean time of Fontan circulation was 21.1 ± 6.3 years, mean observation time 8.1 ± 5.6 years. Results: 44 patients were on VKA, 15 on ASA, 19 without treatment. Fifteen (19.2%) patients experienced thromboembolism. Nine patients had deep venous thromboses, among these five experienced pulmonary embolism. Four patients presented with supraventricular tachycardia (SVT), two with cerebral embolism and thrombus within the Fontan tunnel respectively. Two patients had an isolated thrombus in the Fontan tunnel. Time of Fontan circulation was significantly longer in thromboembolism (25.6 ± 8.3 years vs. 20.0 ± 5.2 years, p

BackgroundEchocardiographic parameters representing impaired left atrial (LA) function and remodeling are of high value to predict atrial fibrillation (AF). This study aimed to develop a prediction model for AF easily to apply in clinical routine containing echocardiographic parameters associated with LA remodeling and—function.Methods and ResultsThis monocentric, semi-blinded, controlled analysis included 235 patients to derive a prediction model. This prediction model was tested in a validation cohort encompassing 290 cardiovascular inpatients. The derivation and validation cohort included 54 (23%) and 66 (23%) patients with AF, respectively. Transthoracic echocardiography, comprising parameters indicating left atrial remodeling [septal/lateral total atrial conduction time (s/l PA-TDI)] and left atrial volume indexed to a' (LAVI/a') was performed in each patient. Based on multivariable regressions analysis, four variables were enclosed into the EAHsy (Echocardiography, Age, Hypertension)-AF risk score for AF prediction: Hypertension, Age, LAVI/a‘ and septal PA-TDI. In the validation cohort discrimination was strong (C-statistic 0.987, 95%CI 0.974–0.991) with an adequately performed calibration. The EAHsy-AF risk score was associated with a more precise prediction of AF in comparison to commonly used AF-scores (CHADS2-, ATLAS-, ARIC-, CHARGE-AF score).ConclusionThe EAHsy-AF-Score containing age, hypertension and echocardiographic parameters of atrial dysfunction and remodeling precisely predicts the incidence of AF in a general population of patients with cardiovascular disease. The EAHsy-AF risk score may enable more selective rhythm monitoring in specific patients at high risk for AF.

Summary: To identify cellular mechanisms responsible for pressure overload triggered heart failure, we isolated cardiomyocytes, endothelial cells, and fibroblasts as most abundant cell types from mouse hearts in the subacute and chronic stages after transverse aortic constriction (TAC) and performed RNA-sequencing. We detected highly cell-type specific transcriptional responses with characteristic time courses and active intercellular communication. Cardiomyocytes after TAC exerted an early and sustained upregulation of inflammatory and matrix genes and a concomitant suppression of metabolic and ion channel genes. Fibroblasts, in contrast, showed transient early upregulation of inflammatory and matrix genes and downregulation of angiogenesis genes, but sustained induction of cell cycle and ion channel genes during TAC. Endothelial cells transiently induced cell cycle and extracellular matrix genes early after TAC, but exerted a long-lasting upregulation of inflammatory genes. As we found that matrix production by multiple cell types triggers pathological cellular responses, it might serve as a future therapeutic target.

BackgroundPercutaneous mitral valve edge-to-edge procedure (PMVR) using the MitraClip® system (Abbot Vascular, CA) is an established therapy for severe mitral regurgitation (MR) in patients judged inoperable or at high surgical risk. Besides determining exercise capacity, right ventricular (RV) function has prognostic value in heart failure and after cardiac surgery. We therefore investigated the impact of PMVR on RV function in patients with severe MR.Methods and ResultsSixty-three patients undergoing PMVR at our department were prospectively enrolled. Transthoracic echocardiography was performed before, early (2–12d) after PMVR and after 3 months, including advanced echocardiographic analyses such as 3D imaging and strain analyses. At baseline, all patients presented with advanced heart failure symptoms. Etiology of MR was more often secondary and, if present, left ventricular (LV) dysfunction was predominantly caused by ischemic cardiomyopathy. PMVR substantially reduced MR to a grade ≤ 2 in most patients. Echocardiographic assessment revealed a largely unchanged LV systolic function early after PMVR, while in contrast RV function substantially improved after PMVR [3D RV EF (%): pre 33.7% [27.4; 39.6], post 40.0% [34.5; 46.0] (p < 0.01 vs. pre), 3 months 42.8% [38.3; 48.1] (p < 0.01 vs. pre); 2D RV GLS (%): pre −12.9% [−14.5; −10.5], post −16.0% [−17.9; −12.6] (p < 0.01 vs. pre), 3 months −17.2% [−21.7; −14.9] (p < 0.01 vs. pre)]. Factors that attenuated RV improvement were larger ventricular volumes, lower LV function, secondary MR, and a higher STS score (all p < 0.05).ConclusionBy using advanced echocardiographic parameters, we discovered an early improvement of RV function after PMVR that is preserved for months, independent from changes in LV function. Improvement of RV function was less pronounced in patients presenting with an advanced stage of heart failure and a higher burden of comorbidities reflected by the STS score.

IntroductionIn March 2020, the World Health organization declared COVID-19 a global pandemic. One year later, the direct and indirect burden of the COVID-19 pandemic become more visible. In this context, there is concern about the allocation of medical resources and medical treatment of other diseases than COVID-19. Particularly, patients with chronic diseases need constant medical and pharmacological treatment. Therefore, we evaluated a large cohort of patients with adult congenital heart disease (ACHD) regarding postponed medical appointments and their possibilities to receive medical treatment during the COVID-19 pandemic.MethodsThis cross-sectional study included 559 patients with ACHD (mean age 37.32 ± 11.98; 47% female). Clinical characteristics, answers to questionnaires concerning lifestyle, psychological well-being, addictive behavior and adherence were related to postponed medical appointments and limited access to medical care.ResultsOne hundred and nine patients (19.5%) reported problems getting necessary medical treatment or visiting a physician. Higher anxiety levels (p = 0.004) emerged as the main factor associated with medical undertreatment. The main risk factors for postponement of least one medical appointment (n = 91) were higher depression (p = 0.013) and anxiety (p = 0.05) symptoms as well as female sex (p ≤ 0.0001) and documented arrhythmias (p = 0.007) indicating a particular risk group of cardiovascular complications. In contrast, frequent physical activity identified patients at lower risk.ConclusionIn ACHD anxiety and depressive symptoms handicap patients to receive medical care. Postponement of medical appointments additionally relates to female sex and documented arrhythmias. The latter indicates that patients at high risk of adverse cardiac outcome avoid routine medical care. Our data may lead policy makers to develop strategies for the provision of medical services to particular vulnerable patient groups, and to optimize management of both future pandemics and daily routine.

Abstract Background To test the effects of guided endurance training on work ability in middle-aged female hospital workers of various occupations. Methods We randomized 265 healthy, sedentary, middle-aged women (45–65 years) to an endurance training group (EG 210 min/week) or a wait-list control group (CG). At baseline and at 6-month follow-up, we assessed work ability (Work Ability Index [WAI]), physical activity (Freiburger activity questionnaire) and peak oxygen uptake (VO2peak) by cardiopulmonary exercise testing. To examine the influence of baseline work ability, participants were divided into poor-moderate (WAI 1, 7–36 points, n = 83), good (WAI 2, 37–43 points, n = 136) and excellent (WAI 3, 44–49 points, n = 46) WAI subgroups. Results Cardiorespiratory fitness improved significantly after 6 months in the EG but not in the CG. The WAI total score increased significantly in the EG (38.3 ± 5.0 to 39.8 ± 4.9 points) but not in the CG (39.4 ± 4.7 to 39.3 ± 4.9 points), with a significant difference between groups (p

Abstract Aims This study aims to compare the clinical course of peripartum cardiomyopathy (PPCM) cohorts from Germany (G‐PPCM) and South Africa (SA‐PPCM) with fibrosis‐related markers to get insights into novel pathomechanisms of PPCM. Methods and results G‐PPCM (n = 79) and SA‐PPCM (n = 72) patients and healthy pregnancy‐matched women from Germany (n = 56) and South Africa (n = 40) were enrolled. Circulating levels of procollagen type‐I (PINP) and type‐III (PIIINP) N‐terminal propeptides, soluble ST2, galectin‐3, and full‐length and cleaved osteopontin (OPN) were measured at diagnosis (baseline) and 6 months of follow‐up. Both cohorts received standard heart failure therapy while anticoagulation therapy was applied in 100% of G‐PPCM but only in 7% of SA‐PPCM patients. In G‐PPCM patients, baseline left ventricular ejection fraction (LVEF) was lower, and outcome was better (baseline LVEF, 24 ± 8%, full recovery: 52%, mortality: 0%) compared with SA‐PPCM patients (baseline LVEF: 30 ± 9%, full recovery: 32%, mortality: 11%; P < 0.05). At baseline, PINP/PIIINP ratio was lower in SA‐PPCM and higher in G‐PPCM compared with respective controls, whereas total OPN was elevated in both collectives. Cleaved OPN, which increases PIIINP levels, is generated by thrombin and was reduced in patients receiving anticoagulation therapy. High baseline galectin‐3, soluble ST2, and OPN levels were associated with poor outcome in all PPCM patients. Conclusions SA‐PPCM patients displayed a more profibrotic biomarker profile, which was associated with a less favourable outcome despite better cardiac function at baseline, compared with G‐PPCM patients. Use of bromocriptine and anticoagulation therapy in G‐PPCM may counteract fibrosis and may in part be responsible for their better outcome.

BackgroundMortality after out-of-hospital cardiac arrest (OHCA) with return of spontaneous circulation (ROSC) remains high despite numerous efforts to improve outcome. For patients with suspected coronary cause of arrest, coronary angiography is crucial. However, there are other causes and potentially life-threatening injuries related to cardiopulmonary resuscitation (CPR), which can be detected by routine computed tomography (CT).Materials and MethodsAt Hannover Medical School, rapid coronary angiography and CT are performed in successfully resuscitated OHCA patients as a standard of care prior to admission to intensive care. We analyzed all patients who received CT following OHCA with ROSC over a three-year period.ResultsThere were 225 consecutive patients with return of spontaneous circulation following out-of-hospital cardiac arrest. Mean age was 64 ± 13 years, 75% were male. Of them, 174 (77%) had witnessed arrest, 145 (64%) received bystander CPR, and 123 (55%) had a primary shockable rhythm. Mean time to ROSC was 24 ± 20 min. There were no significant differences in CT pathologies in patients with or without ST-segment elevations in the initial ECG. Critical CT findings qualifying as a potential cause for cardiac arrest were intracranial bleeding (N = 6), aortic dissection (N = 5), pulmonary embolism (N = 17), pericardial tamponade (N = 3), and tension pneumothorax (N = 11). Other pathologies were regarded as consequences of CPR and relevant for further treatment: aspiration (N = 62), rib fractures (N = 161), sternal fractures (N = 50), spinal fractures (N = 11), hepatic bleeding (N = 12), and intra-abdominal air (N = 3).ConclusionEarly CT fallowing OHCA uncovers a high number of causes and consequences of OHCA and CPR. Those are relevant for post-arrest care and are frequently life-threatening, suggesting that CT can contribute to improving prognosis following OHCA.

Cardiac resynchronization therapy (CRT) is an essential pillar in the therapy of heart failure patients with reduced ejection fraction (HFrEF) presenting with broad left bundle branch block (LBBB) or pacemaker dependency. To achieve beneficial effects, CRT requires high bi-ventricular (BiV) pacing rates. Therefore, device-manufacturers designed pacing algorithms which maintain high BiV pacing rates by a left ventricular (LV) pacing stimulus immediately following a right ventricular sensed beat. However, data on clinical impact of these algorithms are sparse. We studied 17 patients implanted with a CRT device providing triggered left ventricular pacing (tLVp) in case of atrioventricular nodal conduction. Assessment of LV dyssynchrony was performed using echocardiographic and electrocardiographic examination while CRT-devices were set to three different settings: 1. Optimized bi-ventricular-stimulation (BiV); 2. Physiological AV nodal conduction (tLVp-off); 3. Physiological AV nodal conduction and tLVp-algorithm turned on (tLVp-on). QRS duration increased when the CRT-device was set to tLVp-off compared to BiV-Stim, while QRS duration was comparable to BiV-Stim with the tLVp-on setting. Echocardiographic analysis revealed higher dyssynchrony during tLVp-off compared to BiV-Stim. TLVp-on did not improve LV dyssynchrony compared to tLVp-off. QRS duration significantly decreased using tLVp-algorithms compared to physiological AV nodal conduction. However, echocardiographic examination could not show functional benefit from tLVp-algorithms, suggesting that these algorithms are inferior to regular biventricular pacing regarding cardiac resynchronization. Therefore, medical treatment and ablation procedures should be preferred, when biventricular pacing rates have to be increased. TLVp-algorithms can be used in addition to these treatment options.

(1) Background: Diabetic cardiomyopathy is a major health problem worldwide. CTRP9, a secreted glycoprotein, is mainly expressed in cardiac endothelial cells and becomes downregulated in mouse models of diabetes mellitus; (2) Methods: In this study, we investigated the impact of CTRP9 on early stages of diabetic cardiomyopathy induced by 12 weeks of high-fat diet; (3) Results: While the lack of CTRP9 in knock-out mice aggravated insulin resistance and triggered diastolic left ventricular dysfunction, AAV9-mediated cardiac CTRP9 overexpression ameliorated cardiomyopathy under these conditions. At this early disease state upon high-fat diet, no fibrosis, no oxidative damage and no lipid deposition were identified in the myocardium of any of the experimental groups. Mechanistically, we found that CTRP9 is required for insulin-dependent signaling, cardiac glucose uptake in vivo and oxidative energy production in cardiomyocytes. Extensive RNA sequencing from myocardial tissue of CTRP9-overexpressing and knock-out as well as respective control mice revealed that CTRP9 acts as an anti-inflammatory mediator in the myocardium. Hence, CTRP9 knock-out exerted more, while CTRP9-overexpressing mice showed less leukocytes accumulation in the heart during high-fat diet; (4) Conclusions: In summary, endothelial-derived CTRP9 plays a prominent paracrine role to protect against diabetic cardiomyopathy and might constitute a therapeutic target.

Objectives: This study was designed to analyze the prevalence and potential genetic basis of cancer and heart failure in peripartum cardiomyopathy (PPCM). Background: PPCM manifests as heart failure late in pregnancy or postpartum in women without previous heart disease. Methods: Clinical history and cancer prevalence were evaluated in a cohort of 236 PPCM patients from Germany and Sweden. Exome sequencing assessed variants in 133 genes associated with cancer predisposition syndromes (CPS) and in 115 genes associated with dilated/hypertrophic cardiomyopathy (DCM/HCM) in 14 PPCM patients with a history of cancer, and in 6 PPCM patients without a history of cancer. Results: The prevalence of cancer was 16-fold higher (8.9%, 21 of 236 patients) in PPCM patients compared to age-matched women (German cancer registry, Robert-Koch-Institute: 0.59%; p < 0.001). Cancer before PPCM occurred in 12 of 21 patients of whom 11 obtained cardiotoxic cancer therapies. Of those, 17% fully recovered cardiac function by 7 ± 2 months of follow-up compared to 55% of PPCM patients without cancer (p = 0.015). Cancer occurred after PPCM in 10 of 21 patients; 80% had left ventricular ejection fraction of ≥50% after cancer therapy. Whole-exome sequencing in 14 PPCM patients with cancer revealed that 43% (6 of 14 patients) carried likely pathogenic (Class IV) or pathogenic (Class V) gene variants associated with DCM/HCM in CPT2, DSP, MYH7, TTN, and/or with CPS in ATM, ERCC5, NBN, RECQL4, and SLX4. All CPS variants affected DNA damage response genes. Conclusions: Cardiotoxic cancer therapy before PPCM is associated with delayed full recovery. The high cancer prevalence in PPCM is linked to likely pathogenic/pathogenic gene variants associated with DCM/HCM and/or CPS/DNA damage response–related cancer risk. This may warrant genetic testing and screening for heart failure in pregnant women with a cancer history and screening for cancer in PPCM patients.

Background: Specific microRNAs (miRs) have been implicated in the pathophysiology of atherosclerosis and may represent interesting diagnostic and therapeutic targets in carotid stenosis. We hypothesized that the levels of specific circulating miRs are altered in patients with symptomatic carotid stenosis (sCS) in comparison to those in patients with asymptomatic carotid stenosis (aCS) planned to undergo carotid endarterectomy (CEA). We also studied whether miR levels are associated with plaque vulnerability and stability over time after CEA.Methods: Circulating levels of vascular-enriched miR-92a, miR-126, miR-143, miR-145, miR-155, miR-210, miR-221, miR-222, and miR-342-3p were determined in 21 patients with sCS and 23 patients with aCS before CEA and at a 90-day follow-up. Transcranial Doppler ultrasound for detection of microembolic signals (MES) in the ipsilateral middle cerebral artery was performed prior to CEA. Carotid plaques were histologically analyzed.Results: Mean levels of miRs were not considerably different between groups and were only marginally higher in sCS than aCS concerning miR-92a, miR-210, miR-145, and miR-143 with the best evidence concerning miR-92a. After adjustment for vascular risk factors and statin pre-treatment, the effect sizes remained essentially unchanged. At follow-up, however, these modest differences remained uncorroborated. There were no relevant associations between miR-levels and MES or histological plaque vulnerability features.Conclusions: This study does not provide evidence for strong associations between specific circulating miRs and symptomatic state in a collective of comprehensively characterized patients with carotid stenosis. Further work is needed to elucidate the role of circulating miRs as targets in advanced carotid atherosclerosis.

Objective: Innovative operative and interventional procedures have improved survival in congenital heart disease (CHD), and today more than 90% of these children reach adulthood. Consequently, adherence and psychosocial issues are becoming increasingly important because non-adherence to treatment recommendations worsens morbidity and mortality. This study aimed to identify factors modifying adherence to medication in adult congenital heart disease (ACHD).Methods: This cross-sectional study included 451 outpatients (female 47.9%, average age ± SD: 37.9 ± 12 years) from the ACHD department, who completed a questionnaire assessing medication non-adherence and individual barriers to treatment. Further assessments included psychological well-being (Hospital Anxiety and Depression scale; HADS), childhood traumatization, sociodemographic, and clinical data. Binary logistic regression analysis calculated the impact of these factors on drug adherence.Results: Of the 451 patients 162 participants (35.9%) reported to be non-adherent. In univariate analysis non-adherence to treatment was associated with smoking (P = < 0.001) and internet addiction (P = 0.005). Further factors negatively influencing adherence were the presence of depressive symptoms (P = 0.002), anxiety (P = 0.004), and childhood traumatization (p = 0.002). Factors positively associated with adherence were older age (P = 0.003) and more advanced heart disease as indicated by NYHA class (P = 0.01), elevated NT-proBNP (P = 0.02), device therapy (P = 0.002) and intermittent arrhythmias (P = 0.01). In multivariate analysis especially psychopathological factors such as depression (P = 0.009), anxiety (P = 0.032) and childhood traumatization (P = 0.006) predicted non-adherence.Conclusion: Adherence is a critical issue in the long-term management of ACHD. Identifying modifiable factors that worsen adherence offers the opportunity for targeted interventions. Depressive symptoms, anxiety, and adverse childhood experiences are amenable to psychosocial interventions, as well as cigarette smoking. Our study suggests that a multimodal and interdisciplinary treatment concept for the long-term management of adults with congenital heart disease could be beneficial. Whether it will further improve morbidity and mortality, should be assessed in prospective interventions.

Capillary endothelial cells modulate myocardial growth and function during pathological stress, but it is unknown how and whether this contributes to the development of heart failure. We found that the endothelial cell transcription factor GATA2 is downregulated in human failing myocardium. Endothelial GATA2 knock-out (G2-EC-KO) mice develop heart failure and defective myocardial signal transduction during pressure overload, indicating that the GATA2 downregulation is maladaptive. Heart failure and perturbed signaling in G2-EC-KO mice could be induced by strong upregulation of two unknown, endothelial cell-derived long non-coding (lnc) RNAs (AK037972, AK038629, termed here GADLOR1 and 2). Mechanistically, the GADLOR1/2 lncRNAs transfer from endothelial cells to cardiomyocytes, where they block stress-induced signalling. Thereby, lncRNAs can contribute to disease as paracrine effectors of signal transduction and therefore might serve as therapeutic targets in the future.

Aims: Unclear neurological outcome often precludes severely compromised patients after out-of-hospital cardiac arrest (OHCA) from mechanical circulatory support (MCS), while it may be considered as rescue therapy for patients with refractory cardiogenic shock (rCS) in the absence of OHCA. This analysis sought to investigate the role of left ventricular (LV) unloading in patients with rCS related to acute myocardial infarction (AMI) after OHCA.Methods: Of 273 consecutive patients receiving microaxial pumps in the Hannover Cardiac Unloading Registry between January 2013 and August 2018, 47 presented with AMI–rCS following successful resuscitation. Subsequently, the patients were compared by propensity score matching to patients with OHCA AMI–rCS without MCS. The patient data for OHCA without LV unloading was available from 280 patients of the Hannover Cooling Registry for the same time period. Furthermore, the patients with OHCA without rCS were compared to the patients with OHCA AMI–rCS and LV unloading.Results: In total, 15 OHCA AMI–rCS patients without MCS were matched to patients with AMI–rCS and Impella. Patients without LV support had a higher proportion of a cardiac cause of death (n = 7 vs. n = 3; p = 0.024). LV unloading with Impella counteract rCS status and was associated with a preferable 30-day survival (66.7 vs. 20%, p = 0.01) and a favorable neurological outcome after 30 days (Cerebral Performance Category ≤2, 47 vs. 27%). Impella support is associated with a higher 30-day survival (odds ratio, 2.67; 95% confidence interval, 1.02–13.66).Conclusion: In patients after OHCA with AMI–rCS, Impella support incorporated in a strict standardized treatment algorithm results in a preferable 30-day survival and counteracts severe rCS status.

Background Atrial fibrillation (AF) is a major risk factor for mortality. The prevalence, clinical correlates, and prognostic impact of AF in Takotsubo syndrome (TTS) have not yet been investigated in a large patient cohort. This study aimed to investigate the prevalence, clinical correlates, and prognostic impact of AF in patients with TTS. Methods and Results Patients with TTS were enrolled from the International Takotsubo Registry, which is a multinational network with 26 participating centers in Europe and the United States. Patients were dichotomized according to the presence or absence of AF at the time of admission. Of 1584 patients with TTS, 112 (7.1%) had AF. The mean age was higher (P