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Background: Several blood biomarkers have been identified as predictors for poor outcome after ischemic stroke. However, recent studies mainly focused on single or experimental biomarkers and considered rather short follow-up intervals limiting their value for daily clinical practice. We, therefore, aimed to compare various clinical routine blood biomarkers for their predictive value on post-stroke mortality over a 5-year follow-up period. Patients and methods: This data analysis of a prospective single-center study included all consecutive ischemic stroke patients admitted to the stroke unit of our university hospital over a 1-year period. Various blood biomarkers of inflammation, heart failure, metabolic disorders, and coagulation were analyzed from standardized routine blood samples collected within 24 h of hospital admission. All patients underwent a thorough diagnostic workup and were followed for 5 years post-stroke. Results: Of 405 patients (mean age: 70.3 years), 72 deceased (17.8%) during the follow-up period. While various routine blood biomarkers were associated with post-stroke mortality in univariable analyses, only NT-proBNP remained an independent predictor (adjusted odds ratio 5.1; 95% CI 2.0–13.1; p Conclusion: NT-proBNP represents the most relevant routine blood-based biomarker for the prediction of long-term mortality after ischemic stroke. Increased NT-proBNP levels indicate a vulnerable subgroup of stroke patients in which early and thorough cardiovascular assessment and consistent follow-ups could improve outcome after stroke.

Background: In the past years, several studies investigated how distinct immune cell subsets affects post–myocardial infarction repair. However, whether and how the tissue environment controls these local immune responses has remained poorly understood. We sought to investigate how antigen-specific T-helper cells differentiate under myocardial milieu’s influence. Methods: We used a transgenic T cell receptor (TCR-M) model and major histocompatibility complex-II tetramers, both myosin-specific, combined with single-cell transcriptomics (single-cell RNA sequencing [scRNA-seq]) and functional phenotyping to elucidate how the antigen-specific CD4 + T cells differentiate in the murine infarcted myocardium and influence tissue repair. Additionally, we transferred proinflammatory versus regulatory predifferentiated TCR-M-cells to dissect how they specially contribute to post–myocardial infarction inflammation. Results: Flow cytometry and scRNA-/TCR-seq analyses revealed that transferred TCR-M cells acquired an induced regulatory phenotype (induced regulatory T cell) in the infarcted myocardium and blunted local inflammation. Myocardial TCR-M cells differentiated into 2 main lineages enriched with either cell activation and profibrotic transcripts (eg, Tgfb1 ) or suppressor immune checkpoints (eg, Pdcd1 ), which we also found in human myocardial tissue. These cells produced high levels of LAP (latency-associated peptide) and inhibited IL-17 (interleukin-17) responses. Endogenous myosin-specific T-helper cells, identified using genetically barcoded tetramers, also accumulated in infarcted hearts and exhibited a regulatory phenotype. Notably, TCR-M cells that were predifferentiated toward a regulatory phenotype in vitro maintained stable in vivo FOXP3 (Forkhead box P3) expression and anti-inflammatory activity whereas T H 17 partially converted toward a regulatory phenotype in the injured myocardium. Overall, the myosin-specific Tregs dampened post–myocardial infarction inflammation, suppressed neighboring T cells, and were associated with improved cardiac function. Conclusions: These findings provide novel evidence that the heart and its draining lymph nodes actively shape local immune responses by promoting the differentiation of antigen-specific Tregs poised with suppressive function.

Background: The insulin-like growth factor 1 (IGF1) pathway is a key regulator of cellular metabolism and aging. Although its inhibition promotes longevity across species, the effect of attenuated IGF1 signaling on cardiac aging remains controversial. Methods: We performed a lifelong study to assess cardiac health and lifespan in 2 cardiomyocyte-specific transgenic mouse models with enhanced versus reduced IGF1 receptor (IGF1R) signaling. Male mice with human IGF1R overexpression or dominant negative phosphoinositide 3-kinase mutation were examined at different life stages by echocardiography, invasive hemodynamics, and treadmill coupled to indirect calorimetry. In vitro assays included cardiac histology, mitochondrial respiration, ATP synthesis, autophagic flux, and targeted metabolome profiling, and immunoblots of key IGF1R downstream targets in mouse and human explanted failing and nonfailing hearts, as well. Results: Young mice with increased IGF1R signaling exhibited superior cardiac function that progressively declined with aging in an accelerated fashion compared with wild-type animals, resulting in heart failure and a reduced lifespan. In contrast, mice with low cardiac IGF1R signaling exhibited inferior cardiac function early in life, but superior cardiac performance during aging, and increased maximum lifespan, as well. Mechanistically, the late-life detrimental effects of IGF1R activation correlated with suppressed autophagic flux and impaired oxidative phosphorylation in the heart. Low IGF1R activity consistently improved myocardial bioenergetics and function of the aging heart in an autophagy-dependent manner. In humans, failing hearts, but not those with compensated hypertrophy, displayed exaggerated IGF1R expression and signaling activity. Conclusions: Our findings indicate that the relationship between IGF1R signaling and cardiac health is not linear, but rather biphasic. Hence, pharmacological inhibitors of the IGF1 pathway, albeit unsuitable for young individuals, might be worth considering in older adults.

Background Cardiac tumours are rare but affected patients may present with symptoms mimicking other cardiac diseases. The most frequent symptoms include heart failure, arrhythmias, or embolic phenomena. Case summary A 39-year-old man with a history of extranodal NK/T-cell lymphoma of the nasal type (ENKTL-NT) in clinical remission presented at our department with incessant ventricular tachycardia. The arrhythmia could only be controlled with a combination of intravenously administered beta-blockers, ajmaline, and amiodarone. Diagnostic workup excluded ischaemia, but imaging revealed a tumour located in the apex of the left ventricle. Endomyocardial biopsy confirmed the diagnosis of cardiac relapse of ENKTL-NT. Upon chemotherapy no further arrhythmias developed. Discussion Many malignancies can metastasize into the heart. Multimodal imaging including echocardiography, cardiac magnetic resonance imaging, and a positron-emission tomography computed tomography paved the way to the diagnosis that was finally established by endomyocardial biopsy. In the present case, a cardiac metastasis from an ENKTL-NT presented with incessant ventricular tachycardia.

Mesenchymal stem cell (MSC) therapy has gained significant traction in the context of cardiovascular repair, and have been proposed to exert their regenerative effects via the secretion of paracrine factors. In this systematic review, we examined the literature and consolidated available evidence for the “paracrine hypothesis”. Two Ovid SP databases were searched using a strategy encompassing paracrine mediated MSC therapy in the context of ischemic heart disease. This yielded 86 articles which met the selection criteria for inclusion in this study. We found that the MSCs utilized in these articles were primarily derived from bone marrow, cardiac tissue, and adipose tissue. We identified 234 individual protective factors across these studies, including VEGF, HGF, and FGF2; which are proposed to exert their effects in a paracrine manner. The data collated in this systematic review identifies secreted paracrine factors that could decrease apoptosis, and increase angiogenesis, cell proliferation, and cell viability. These included studies have also demonstrated that the administration of MSCs and indirectly, their secreted factors can reduce infarct size, and improve left ventricular ejection fraction, contractility, compliance, and vessel density. Furthering our understanding of the way these factors mediate repair could lead to the identification of therapeutic targets for cardiac regeneration. Graphical abstract

Patients at risk of developing a disease have to be identified at an early stage to enable prevention. One way of early detection is the use of machine learning based prediction models trained on electronic health records.The aim of this project was to develop a software solution to predict cardiovascular and nephrological events using machine learning models. In addition, a risk verification interface for health care professionals was established.In order to meet the requirements, different tools were analysed. Based on this, a software architecture was created, which was designed to be as modular as possible.A software was realised that is able to automatically calculate and display risks using machine learning models. Furthermore, predictions can be verified via an interface adapted to the need of health care professionals, which shows data required for prediction.Due to the modularised software architecture and the status-based calculation process, different technologies could be applied. This facilitates the installation of the software at multiple health care providers, for which adjustments need to be carried out at one part of the software only.

SummaryThe prevalence and significance of cardiac amyloidosis have been considerably underestimated in the past; however, the number of patients diagnosed with cardiac amyloidosis has increased significantly recently due to growing awareness of the disease, improved diagnostic capabilities and demographic trends. Specific therapies that improve patient prognosis have become available for certain types of cardiac amyloidosis. Thus, the earliest possible referral of patients with suspicion of cardiac amyloidosis to an experienced center is crucial to ensure rapid diagnosis, early initiation of treatment, and structured patient care. This requires intensive collaboration across several disciplines, and between resident physicians and specialized centers. The aim of this consensus statement is to provide guidance for the rapid and efficient diagnosis and treatment of light-chain amyloidosis and transthyretin amyloidosis, which are the most common forms of cardiac amyloidosis.

Background Kidney transplant recipients exhibit a dramatically increased cardiovascular (CV) risk. In 2007, Austrian centres implemented a consensus of comprehensive CV screening programme prior to kidney transplantation (KT). The consensus placed a particular emphasis on screening for coronary artery disease (CAD) with cardiac computed tomography (CT) or coronary angiography (CAG) in patients with diabetes mellitus, known CAD or those having multiple conventional CV risk factors. Here, we investigate if this affected risk stratification and post-transplant CV outcomes. Methods In a retrospective chart review, we evaluated 551 KTs performed from 2003 to 2015 in our centre. Patients were categorized into three groups: KT before (2003–07), directly after (2008–11) and 5 years after (2012–15) implementation of the consensus. We analysed clinical characteristics, the rate of cardiac CTs and CAGs prior to KT as well as major adverse cardiac events (MACEs) during a 2-year follow-up after KT. Results The three study groups showed a homogeneous distribution of comorbidities and age. Significantly more cardiac CTs (13.6% versus 10.2% versus 44.8%; P = 0.002) and CAGs (39.6% versus 43.9% versus 56.2%; P = 0.003) were performed after the consensus. Coronary interventions were performed during 42 out of 260 CAGs (16.2%), the cumulative 2-year MACE incidence was 8.7%. Regarding MACE occurrence, no significant difference between the three groups was found. Conclusion CV risk stratification has become more rigorous and invasive after the implementation of the consensus; however, this was not associated with an improvement in CV outcome.

Mortality from ischemic heart disease (IHD) is significantly lower in Japan than in Western countries. The purpose of this study was to investigate differences in circulating microRNA (miRNA) levels related to IHD in Austrians and Japanese. Participants were middle-aged healthy male Austrians (n = 20) and Japanese (n = 20). Total miRNAs in serum from each participant were analyzed using the 3D-Gene miRNA Oligo chip. Twenty-one miRNAs, previously reported as associated with IHD, were compared between Austrians and Japanese. The expression levels of miR-106a-5p, miR-135a-3p, miR-150-3p, miR-16-5p, miR-17-5p. miR-191-5p, miR-320b, miR-451a, miR-486-5p, miR-663b, and miR-92a-3p were significantly higher, while the miR-2861 expression level was significantly lower in Austrians as compared to Japanese. Both in Austrians and Japanese, there were significant positive correlations between serum expression levels of each pair of the above miRNAs except for miR-2861. The expression level of miR-2861 showed significant positive correlations with the expression levels of miR-106a-5p, miR-150-3p, miR-17-5p, miR-486-5p, miR-663b and miR-92a-3p in Austrians but not in Japanese. In pathway analysis, proinflammatory cytokine production in foam cells and collagen synthesis in vascular smooth muscle cells were associated with differentially expressed miRNAs. Difference in miRNA levels may contribute to lower cardiovascular risk in Japan than in Western countries.

Stretch and tachycardia are common triggers for cardiac remodelling in various conditions, but a comparative characterization of their role in the excitation‐transcription coupling (ETC) and early regulation of gene expression and structural changes is lacking. Here, we show that stretch and tachycardia directly induced hypertrophy of neonatal rat cardiac myocytes and also of non‐myocytes. Both triggers induced similar patterns of hypertrophy but had largely distinct gene expression profiles. ACTA1 served as good hypertrophy marker upon stretch, while RCAN1 was found increased in response to tachycardia in a rate‐dependent fashion. Mechanistically, several calcium‐handling proteins, including the sodium‐calcium exchanger (NCX), contributed to ETC. Phosphorylation of the calcium/calmodulin‐dependent protein kinase II (CaMKII) was elevated and occurred downstream of NCX activation upon tachycardia, but not stretch. Microarray profiling revealed that stretch and tachycardia regulated around 33% and 20% genes in a NCX‐dependent manner, respectively. In conclusion, our data show that hypertrophy induction by stretch and tachycardia is associated with different gene expression profiles with a significant contribution of the NCX.

Aims Cardiac involvement in myopathies that primarily affect the skeletal muscle is variable and may be subtle, necessitating sensitive diagnostic approaches. Here, we describe the prevalence of cardiac abnormalities in a cohort of patients with skeletal muscle disease presenting at a tertiary care neuromuscular centre. Methods and results We systematically investigated patients with skeletal myopathies and comprehensively analysed their cardiac phenotype including 24 h electrocardiogram, echocardiography with strain analyses, contrast‐enhanced cardiac magnetic resonance imaging, and, if at increased risk of coronary artery disease, computed tomography coronary angiography. We prospectively screened 91 patients with diverse skeletal myopathies and enrolled 73 patients. The most pronounced cardiac involvement was present in patients with dystrophic myopathies (cardiac abnormalities in 59% of patients). We analysed myotonic dystrophies (n = 29) in more detail and found prolonged QRS (99.4 ± 15.6 vs. 91.5 ± 10.3 ms; P = 0.027) and QTc times (441.1 ± 28.1 vs. 413.0 ± 23.3 ms; P

SummarySurvival in cancer is continuously improving due to evolving oncological treatment. Therefore, cardiovascular short-term and long-term side effects gain crucial importance for overall outcome. Cardiotoxicity not only presents as heart failure, but also as treatment-resistant hypertension, acute coronary ischemia with plaque rupture or vasospasm, thromboembolism, arrhythmia, pulmonary hypertension, diastolic dysfunction, acute myocarditis and others. Recent recommendations have proposed baseline cardiac risk assessment and surveillance strategies. Major challenges are the availability of monitoring and imaging resources, including echocardiography with speckle tracking longitudinal strain (GLS), serum biomarkers such as natriuretic peptides (NT-proBNP) and highly sensitive cardiac troponins. This Austrian consensus encompasses cardiotoxicity occurrence in frequent antiproliferative cancer drugs, radiotherapy, immune checkpoint inhibitors and cardiac follow-up considerations in cancer survivors in the context of the Austrian healthcare setting. It is important to optimize cardiovascular risk factors and pre-existing cardiac diseases without delaying oncological treatment. If left ventricular ejection fraction (LVEF) deteriorates during cancer treatment (from >10% to 15% change in GLS), early initiation of cardioprotective therapies (angiotensin-converting enzyme inhibitors, angiotensin or beta receptor blockers) is recommended, and LVEF should be reassessed before discontinuation. Lower LVEF cut-offs were recently shown to be feasible in breast cancer patients to enable optimal anticancer treatment. Interdisciplinary cardio-oncology cooperation is pivotal for optimal management of cancer patients.

Introduction: Heart failure (HF) is a global issue and approximately 50% of patients are classified as having HF with preserved Ejection Fraction (HFpEF), with no FDA approved therapies available. We previously characterized a large animal model that recapitulates key features of HFpEF and tested the effects of suberanilohydroxamic acid (SAHA, pan-HDAC inhibitor), which reversed and prevented the development of cardiopulmonary dysfunction. Parallel studies in cardiac tissue from humans and large mammals were designed to evaluate the effects of SAHA at the cellular level. Hypothesis: SAHA treatment will improve cardiomyocyte function. Methods: Adult feline ventricular cardiomyocytes (AFVM) were isolated from male domestic short hair cats and treated with 2.5μM SAHA or vehicle (DMSO) for 90 minutes, then incubated with a calcium (Ca 2+ ) indicator (Fluo-4AM) and electrically stimulated (0.5Hz) to record Ca 2+ transients and contractions. Human left ventricle (LV) trabeculae isolated from non-failing donor hearts were treated with 10μM SAHA or vehicle for 120 minutes while being electrically stimulated (1Hz) to record developed force and relaxation parameters. Skinned myocytes were isolated from treated AFVM and human trabeculae to assess myofilament Ca 2+ sensitivity and passive stiffness. Mass spectrometry (MS) was performed on AFVM skinned myocytes to identify novel acetylation sites. Results: There was no difference in AFVM peak Ca 2+ transients with SAHA treatment, but calcium removal was increased (tau, time to 30% baseline). There was a significant increase in contractility (fractional shortening) and relaxation kinetics (time to 50% baseline, return velocity). Trabeculae treated with SAHA had decreased diastolic tension and an increase in developed force. Skinned myocytes were isolated from treated AFVMs and trabeculae and both had a significant improvement in myofilament Ca 2+ sensitivity and significant decrease in passive stiffness with SAHA. MS of AFVM skinned myocytes revealed increased acetylation of the myosin regulatory light chain, driven by lysine 115. Conclusions: These findings suggest that SAHA may have an important role in regulating cardiac function via the cardiomyocyte and myofilament in feline and human myocardium.

Accumulating evidence suggests that individuals with sarcomeric hypertrophic cardiomyopathy (HCM) carrying MYH7 mutations may have a worse prognosis than MYBPC3 mutation carriers. Myocardial deformation analysis is superior to standard echocardiography in detecting subtle myocardial dysfunction and scar formation, but studies evaluating the association with HCM genotype are scarce. We therefore aimed to compare myocardial strain parameters between MYBPC3 and MYH7 mutation carriers with proven HCM. Participants of the prospective Graz HCM Registry carrying at least one causative mutation in MYBPC3 (n = 39) or MYH7 (n = 18) were enrolled. MYBPC3 mutation carriers were older, predominantly male and more often treated with an implantable cardioverter-defibrillator (39% vs. 0%; p = 0.002). Using analyses of covariance, there were no significant differences between MYBPC3 and MYH7 mutation carriers with regard to left ventricular global longitudinal strain (estimated marginal means ± standard deviation: −16.9 ± 0.6% vs. −17.3 ± 0.9%; p = 0.807) and right ventricular 6-segments endocardial strain (−24.3 ± 1.0% vs. 26.3 ± 1.5%; p = 0.285). Our study suggests, that myocardial deformation analysis may not be helpful in concluding on the underlying HCM genotype, and vice versa.

Accumulating evidence suggests that individuals with sarcomeric hypertrophic cardiomyopathy (HCM) carrying MYH7 mutations may have a worse prognosis than MYBPC3 mutation carriers. Myocardial deformation analysis is superior to standard echocardiography in detecting subtle myocardial dysfunction and scar formation, but studies evaluating the association with HCM genotype are scarce. We therefore aimed to compare myocardial strain parameters between MYBPC3 and MYH7 mutation carriers with proven HCM. Participants of the prospective Graz HCM Registry carrying at least one causative mutation in MYBPC3 (n = 39) or MYH7 (n = 18) were enrolled. MYBPC3 mutation carriers were older, predominantly male and more often treated with an implantable cardioverter-defibrillator (39% vs. 0%; p = 0.002). Using analyses of covariance, there were no significant differences between MYBPC3 and MYH7 mutation carriers with regard to left ventricular global longitudinal strain (estimated marginal means ± standard deviation: −16.9 ± 0.6% vs. −17.3 ± 0.9%; p = 0.807) and right ventricular 6-segments endocardial strain (−24.3 ± 1.0% vs. 26.3 ± 1.5%; p = 0.285). Our study suggests, that myocardial deformation analysis may not be helpful in concluding on the underlying HCM genotype, and vice versa.

Natriuretic peptide plasma levels help to manage patients with severe aortic stenosis (AS). The role of troponin plasma levels in this patient cohort remains speculative. A consortium of 4 university hospital centers in Austria analyzed retrospectively 3,595 patients admitted for valve replacement because of severe AS since 2007. The aim was to compare the additive preprocedural value of high-sensitivity troponin T (hsTnT) to N-terminal pro brain natriuretic peptide (NT-proBNP) plasma levels in predicting postoperative long-term survival in a large cohort undergoing either surgical (57.8%) or transcatheter (42.2%) aortic valve replacement. During a median follow-up of 2.93 (1.91 to 4.92) years, 919 patients (25.6%) died, in them 556 (15.5%) due to cardiovascular causes. Both normal hsTnT (

Patients with major adverse cardiovascular events (MACE) such as myocardial infarction or stroke suffer from frequent hospitalizations and have high mortality rates. By identifying patients at risk at an early stage, MACE can be prevented with the right interventions.The aim of this study was to develop machine learning-based models for the 5-year risk prediction of MACE.The data used for modelling included electronic medical records of more than 128,000 patients including 29,262 patients with MACE. A feature selection based on filter and embedded methods resulted in 826 features for modelling. Different machine learning methods were used for modelling on the training data.A random forest model achieved the best calibration and discriminative performance on a separate test data set with an AUROC of 0.88.The developed risk prediction models achieved an excellent performance in the test data. Future research is needed to determine the performance of these models and their clinical benefit in prospective settings.

Many cardiac insults causing atrial remodeling are linked to either stretch or tachycardia, but a comparative characterization of their effects on early remodeling events in human myocardium is lacking. Here, we applied isometric stretch or sustained tachycardia at 2.5 Hz in human atrial trabeculae for 6 h followed by microarray gene expression profiling. Among largely independent expression patterns, we found a small common fraction with the microRNA miR-1183 as the highest up-regulated transcript (up to 4-fold). Both, acute stretch and tachycardia induced down-regulation of the predicted miR-1183 target genes ADAM20 and PLA2G7. Furthermore, miR-1183 was also significantly up-regulated in chronically remodeled atrial samples from patients with persistent atrial fibrillation (3-fold up-regulation versus sinus rhythm samples), and in ventricular myocardium from dilative cardiomyopathy hearts (2-fold up-regulation) as compared to non-failing controls. In sum, although stretch and tachycardia show distinct transcriptomic signatures in human atrial myocardium, both cardiac insults consistently regulate the expression of miR-1183 and its downstream targets in acute and chronic remodeling. Thus, elevated expression of miR-1183 might serve as a tissue biomarker for atrial remodeling and might be of potential functional significance in cardiac disease.

Aims Autophagy protects against the development of cardiac hypertrophy and failure. While aberrant Ca2+ handling promotes myocardial remodelling and contributes to contractile dysfunction, the role of autophagy in maintaining Ca2+ homeostasis remains elusive. Here, we examined whether Atg5 deficiency-mediated autophagy promotes early changes in subcellular Ca2+ handling in ventricular cardiomyocytes, and whether those alterations associate with compromised cardiac reserve capacity, which commonly precedes the onset of heart failure. Methods and results RT–qPCR and immunoblotting demonstrated reduced Atg5 gene and protein expression and decreased abundancy of autophagy markers in hypertrophied and failing human hearts. The function of ATG5 was examined using cardiomyocyte-specific Atg5-knockout mice (Atg5−/−). Before manifesting cardiac dysfunction, Atg5−/− mice showed compromised cardiac reserve in response to β-adrenergic stimulation. Consequently, effort intolerance and maximal oxygen consumption were reduced during treadmill-based exercise tolerance testing. Mechanistically, cellular imaging revealed that Atg5 deprivation did not alter spatial and functional organization of intracellular Ca2+ stores or affect Ca2+ cycling in response to slow pacing or upon acute isoprenaline administration. However, high-frequency stimulation exposed stunted amplitude of Ca2+ transients, augmented nucleoplasmic Ca2+ load, and increased CaMKII activity, especially in the nuclear region of hypertrophied Atg5−/− cardiomyocytes. These changes in Ca2+ cycling were recapitulated in hypertrophied human cardiomyocytes. Finally, ultrastructural analysis revealed accumulation of mitochondria with reduced volume and size distribution, meanwhile functional measurements showed impaired redox balance in Atg5−/− cardiomyocytes, implying energetic unsustainability due to overcompensation of single mitochondria, particularly under increased workload. Conclusion Loss of cardiac Atg5-dependent autophagy reduces mitochondrial abundance and causes subtle alterations in subcellular Ca2+ cycling upon increased workload in mice. Autophagy-related impairment of Ca2+ handling is progressively worsened by β-adrenergic signalling in ventricular cardiomyocytes, thereby leading to energetic exhaustion and compromised cardiac reserve.

Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent and intractable form of cardiac decompensation commonly associated with diastolic dysfunction. Here, we show that diastolic dysfunction in patients with HFpEF is associated with a cardiac deficit in nicotinamide adenine dinucleotide (NAD+). Elevating NAD+ by oral supplementation of its precursor, nicotinamide, improved diastolic dysfunction induced by aging (in 2-year-old C57BL/6J mice), hypertension (in Dahl salt-sensitive rats), or cardiometabolic syndrome (in ZSF1 obese rats). This effect was mediated partly through alleviated systemic comorbidities and enhanced myocardial bioenergetics. Simultaneously, nicotinamide directly improved cardiomyocyte passive stiffness and calcium-dependent active relaxation through increased deacetylation of titin and the sarcoplasmic reticulum calcium adenosine triphosphatase 2a, respectively. In a long-term human cohort study, high dietary intake of naturally occurring NAD+ precursors was associated with lower blood pressure and reduced risk of cardiac mortality. Collectively, these results suggest NAD+ precursors, and especially nicotinamide, as potential therapeutic agents to treat diastolic dysfunction and HFpEF in humans. This study was thankfully supported by the European Research Area Network on Cardiovascular Diseases (ERACVD) through the MINOTAUR consortium: S.S. (The Austrian Science Fund – FWF, I3301-B31), G.K. (Agence National de la Recherche – ANR), W.A.L. (Bundesministerium für Bildung und Forschung – BMBF), J.A.C. (Instituto de Salud Carlos III – ISCIII, AC16/00045) and A.L.M. (Portuguese Foundation for Science and Technology – FCT). M. Abdellatif acknowledges funding received from the European Society of Cardiology in form of an ESC Research Grant and from the Austrian Society of Cardiology (Präsidentenstipendium der ÖKG). The Austrian Science Fund supports S.F. (P27166-B23), A.P. (I3165, P29328-B26) and F.M. (P27893, P31727). S.S., J.V., F.M. and S.L.H. acknowledge support from the BioTechMed–Graz. G.K. is supported by the Ligue contre le Cancer (équipe labellisée); Association pour la recherche sur le cancer (ARC); Association Ruban Rose, Cancéropôle Ile-de-France; Chancelerie des universités de Paris (Legs Poix), Fondation pour la Recherche Médicale (FRM); Institut National du Cancer (INCa); Inserm (HTE); Inserm Transfert; Institut Universitaire de France; LeDucq Foundation; the LabEx Immuno-Oncology (ANR-18-IDEX-0001); the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM). J.A.C. acknowledges funding from the Ministerio de Ciencia e Innovación (MCIN) through grant BIO2017-83640-P (AEI/FEDER, UE) and the Comunidad de Madrid (consortium Tec4Bio-CM, S2018/ NMT-4443, FEDER). A.S. acknowledges support from BioPersMed Graz. S.K. receives funding from the Austrian Research Promotion Agency FFG (VASCage; Nr. 868624). The Bruneck Study was supported by the Pustertaler Verein zur Prävention von Herz-und Hirngefäßerkrankungen, Gesundheitsbezirk Bruneck, and the Assessorat für Gesundheit, Province of Bolzano, Italy. Sí

AIMS: We assessed the outcome of hospitalized coronavirus disease 2019 (COVID-19) patients with heart failure (HF) compared with patients with other cardiovascular disease and/or risk factors (arterial hypertension, diabetes, or dyslipidaemia). We further wanted to determine the incidence of HF events and its consequences in these patient populations. METHODS AND RESULTS: International retrospective Postgraduate Course in Heart Failure registry for patients hospitalized with COVID-19 and CArdioVascular disease and/or risk factors (arterial hypertension, diabetes, or dyslipidaemia) was performed in 28 centres from 15 countries (PCHF-COVICAV). The primary endpoint was in-hospital mortality. Of 1974 patients hospitalized with COVID-19, 1282 had cardiovascular disease and/or risk factors (median age: 72 [interquartile range: 62-81] years, 58% male), with HF being present in 256 [20%] patients. Overall in-hospital mortality was 25% (n = 323/1282 deaths). In-hospital mortality was higher in patients with a history of HF (36%, n = 92) compared with non-HF patients (23%, n = 231, odds ratio [OR] 1.93 [95% confidence interval: 1.44-2.59], P

Background and purpose Cardiac remodeling can be caused by a variety of insults linked to either stretch or tachycardia as a triggering mechanism. We aimed to investigate similarities and differences of the transcriptomic profiles in response to either acute stretch or tachycardia in isolated human atrial myocardium. In addition, we tested the highest acutely regulated target for its chronic regulation in human tissue with atrial or ventricular cardiac remodeling. Methods For acute trigger testing we applied either stretch (high pre- and afterload) or sustained tachycardia (2.5 Hz) for 6 hours in isolated atrial human trabeculae from cardiac surgery patients (all in sinus rhythm, SR). We performed gene expression profiling by RNA microarrays (n=5 per group) as a remodeling readout. For chronic regulation we performed qPCR of selected genes of interest in right atrial appendage tissue obtained from cardiac surgery patients with persistent atrial fibrillation compared to control patients with SR (n=6 per group), and also in ventricular tissue samples from failing hearts (from transplanted dilative cardiomyopathy patients) or non-failing control hearts (from multi-organ donors denied for transplantation), n=6 per group. Results The expression patterns of stretch and tachycardia were largely independent with 1305 transcripts regulated solely by stretch and 1837 transcripts by tachycardia with p Conclusion Stretch and tachycardia show distinct transcriptomic signatures in human atrial trabeculae but share the strongest upregulated gene MIR1183 and consistent regulation of its downstream targets. This is present in an acute as well as chronic remodeling setting. Expression levels of MIR1183 might serve as a biomarker for atrial remodeling and to some extend ventricular remodeling and have potential functional significance in cardiac disease. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Medical University of Graz

Introduction Recent studies have demonstrated the predictive value of preprocedural cardiac biomarkers, such as N-terminal pro brain natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT), in patients with severe aortic valve stenosis undergoing valve replacement. Nonetheless, it remains still unclear whether hsTnT may be influenced by gender-specific differences. Purpose The aim of this subanalysis was to evaluate sex-related differences of preprocedural hsTnT in predicting postoperative long-term survival in a large cohort undergoing either surgical or transcatheter aortic valve replacement. Methods The TASS-2 group, a consortium of four university hospital centers, analysed 3595 consecutively enrolled patients admitted for valve implantation because of severe aortic stenosis between 2007 and 2017. Results The study cohort consisted of 1728 (48.1%) female and 1867 (51.9%) male patients. During a median follow-up of 2.9 years, cardiovascular mortality was found in 556 (15.5%) patients, amongst whom were 292 (16.9%) women and 264 (14.1%) men. All-cause mortality was detected in 919 (25.6%) patients dividing into 462 (26.7%) women and 457 (24.5%) men. Preprocedural hsTnT was significantly higher (p50 ng/l). Cardiovascular and all-cause mortality were significantly increased with higher hsTnT plasma levels in women (p In two separate multivariate cox regression models, one for either gender - adjusting for STS risk score, NT-proBNP plasma levels, degree of left ventricular systolic dysfunction, atrial fibrillation, age, renal function, chronic obstructive pneumonic disease, arterial hypertension, diabetes mellitus, concomitant significant coronary artery disease and type of procedure – pre-procedural hsTnT was a strong independent predictor for postoperative cardiovascular mortality with an hazard ratio [HR] of 3.34, 95% confidence interval [CI] 1.03–10.80, P=0.044 for mildly to moderately elevated hsTnT (14–50 ng/l) and an HR of 3.98, CI 1.19–13.30, P=0.025 for severely elevated hsTnT (>50 ng/l) in women, whereas an hazard ratio [HR] 4.09, 95% confidence interval [CI] 0.55–29.99, P=0.166 for mildly to moderately elevated hsTnT (14–50 ng/l) and an HR 7.48, CI 0.99–56.12, P=0.050 for severely elevated hsTnT (>50 ng/l) in men was yielded. Conclusion Long-term postoperative survival in patients with severe AS admitted for valve implantation was independently predicted by hsTnT, irrespective of gender. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Tiroler Wissenschaftsförderung (Innsbruck, Austria)

Aims Latent cytomegalovirus (CMV) infection is associated with adverse cardiovascular outcomes. Virus-specific CX3CR1+ effector memory T-cells may be instrumental in this process due to their pro-inflammatory properties. We investigated the role of CX3CR1 (fractalkine receptor) in CMV-related lymphocyte kinetics and cardiac remodeling in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI). Methods and Results We retrospectively analysed lymphocyte count, troponin, and survival in 4874 STEMI/pPCI patients, evaluated lymphocyte kinetics during reperfusion in a prospective cohort, and obtained sequential cardiac MRI (cMRI) to assess remodeling. Pre-reperfusion lymphopenia independently predicted mortality at 7.5 years. Prior to reperfusion, CCR7+ T-lymphocytes appeared to be depleted. After reperfusion, T-lymphocytes expressing CX3CR1 were depleted predominantly in CMV-seropositive patients. During ischaemia/reperfusion, a drop in CX3CR1+ T-lymphocytes was significantly linked with microvascular obstruction in CMV+ patients, suggesting increased fractalkine-receptor interaction. At 12 weeks, CMV+ patients displayed adverse LV remodeling. Conclusion We show that lymphopenia occurs before and after reperfusion in STEMI by different mechanisms and predicts long-term outcome. In CMV+ patients, increased fractalkine induction and sequestration of CX3CR1+ T-cells may contribute to adverse remodeling, suggesting a pro-inflammatory pathomechanism which presents a novel therapeutic target.

The protein titin determines cardiomyocyte contraction and truncating variants in the titin gene (TTN) are the most common cause of dilated cardiomyopathy (DCM). Different to truncations, missense variants inTTNare currently classified as variants of uncertain significance due to their high frequency in the population and the absence of functional annotation. Here, we report the regulatory role of conserved, mechanically active titin cysteines, which, contrary to current views, we uncover to be reversibly oxidized in basal conditions leading to isoform- and force-dependent modulation of titin stiffness and dynamics. Building on our functional studies, we demonstrate that missense mutations targeting a conserved titin cysteine alter myocyte contractile function and cause DCM in humans. Our findings have a direct impact on genetic counselling in clinical practice.One sentence summaryMutations targeting cysteines key to the mechanoredox control of titin cause human dilated cardiomyopathy

Hereby, the supplemental data of the research article “Long-Term Prognostic Value of High-Sensitivity Troponin T added to N-Terminal Pro Brain Natriuretic Peptide Plasma Levels before Valve Replacement for Severe Aortic Stenosis” are presented [1]. It offers enhanced input on the predictive value of these biomarkers considering the influence of the presence of concomitant coronary artery disease (CAD) in various severities as well as an additional cox proportional hazard model on cardiovascular mortality. Furthermore, the receiver operating characteristic (ROC) curves are shown as figures. The material described increases therefore the understanding of the predictive value of these already routinely available biomarkers and reduces the risk of potential bias due to possible confounding factors. It also underlines the urge for a multi-factorial approach in diagnostics to detect the optimal point for referral to valve replacement other than just symptomatic status, an observed reduction in left ventricular ejection fraction or the presence of CAD with the necessity for coronary artery bypass grafting (CABG) [2]. The data of the 3595 patients were gathered retrospectively at a consortium of four university hospital centers in Austria and combined with prospectively collected data on cardiovascular and all-cause mortality. Keywords: High sensitivity troponin T, N-terminal pro brain natiuretic peptide, Severe aortic stenosis, Valve replacement, Survival, Risk stratification