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Background Non-ischemic dilated cardiomyopathy (DCM) can be complicated by sustained ventricular arrhythmias (SVA) and sudden cardiac death (SCD). By now, left-ventricular ejection fraction (LV-EF) is the main guideline criterion for primary prophylactic ICD implantation, potentially leading either to overtreatment or failed detection of patients at risk without severely impaired LV-EF. The aim of the European multi-center study DETECTIN-HF was to establish a clinical risk calculator for individualized risk stratification of DCM patients. Methods 1393 patients (68% male, mean age 50.7 ± 14.3y) from four European countries were included. The outcome was occurrence of first potentially life-threatening ventricular arrhythmia. The model was developed using Cox proportional hazards, and internally validated using cross validation. The model included seven independent and easily accessible clinical parameters sex, history of non-sustained ventricular tachycardia, history of syncope, family history of cardiomyopathy, QRS duration, LV-EF, and history of atrial fibrillation. The model was also expanded to account for presence of LGE as the eight8h parameter for cases with available cMRI and scar information. Results During a mean follow-up period of 57.0 months, 193 (13.8%) patients experienced an arrhythmic event. The calibration slope of the developed model was 00.97 (95% CI 0.90–1.03) and the C-index was 0.72 (95% CI 0.71–0.73). Compared to current guidelines, the model was able to protect the same number of patients (5-year risk ≥8.5%) with 15% fewer ICD implantations. Conclusions This DCM-SVA risk model could improve decision making in primary prevention of SCD in non-ischemic DCM using easily accessible clinical information and will likely reduce overtreatment.

Background The development of Precision Medicine strategies requires high-dimensional phenotypic and genomic data, both of which are highly privacy-sensitive data types. Conventional data management systems lack the capabilities to sufficiently handle the expected large quantities of such sensitive data in a secure manner. PROMISE is a genetic data management concept that implements a highly secure platform for data exchange while preserving patient interests, privacy, and autonomy. Methods The concept of PROMISE to democratize genetic data was developed by an interdisciplinary team. It integrates a sophisticated cryptographic concept that allows only the patient to grant selective access to defined parts of his genetic information with single DNA base-pair resolution cryptography. The PROMISE system was developed for research purposes to evaluate the concept in a pilot study with nineteen cardiomyopathy patients undergoing genotyping, questionnaires, and longitudinal follow-up. Results The safety of genetic data was very important to 79%, and patients generally regarded the data as highly sensitive. More than half the patients reported that their attitude towards the handling of genetic data has changed after using the PROMISE app for 4 months (median). The patients reported higher confidence in data security and willingness to share their data with commercial third parties, including pharmaceutical companies (increase from 5 to 32%). Conclusion PROMISE democratizes genomic data by a transparent, secure, and patient-centric approach. This clinical pilot study evaluating a genetic data infrastructure is unique and shows that patient’s acceptance of data sharing can be increased by patient-centric decision-making. Graphic abstract

Aims Patients with non‐ischaemic dilated cardiomyopathy (DCM) are at increased risk of sudden cardiac death. Identification of patients that may benefit from implantable cardioverter‐defibrillator implantation remains challenging. In this study, we aimed to determine predictors of sustained ventricular arrhythmias in patients with DCM. Methods and results We searched MEDLINE/Embase for studies describing predictors of sustained ventricular arrhythmias in patients with DCM. Quality and bias were assessed using the Quality in Prognostic Studies tool, articles with high risk of bias in ≥2 areas were excluded. Unadjusted hazard ratios (HRs) of uniformly defined predictors were pooled, while all other predictors were evaluated in a systematic review. We included 55 studies (11 451 patients and 3.7 ± 2.3 years follow‐up). Crude annual event rate was 4.5%. Younger age [HR 0.82; 95% CI (0.74–1.00)], hypertension [HR 1.95; 95% CI (1.26–3.00)], prior sustained ventricular arrhythmia [HR 4.15; 95% CI (1.32–13.02)], left ventricular ejection fraction on ultrasound [HR 1.45; 95% CI (1.19–1.78)], left ventricular dilatation (HR 1.10), and presence of late gadolinium enhancement [HR 5.55; 95% CI (4.02–7.67)] were associated with arrhythmic outcome in pooled analyses. Prior non‐sustained ventricular arrhythmia and several genotypes [mutations in Phospholamban (PLN), Lamin A/C (LMNA), and Filamin‐C (FLNC)] were associated with arrhythmic outcome in non‐pooled analyses. Quality of evidence was moderate, and heterogeneity among studies was moderate to high. Conclusions In patients with DCM, the annual event rate of sustained ventricular arrhythmias is approximately 4.5%. This risk is considerably higher in younger patients with hypertension, prior (non‐)sustained ventricular arrhythmia, decreased left ventricular ejection fraction, left ventricular dilatation, late gadolinium enhancement, and genetic mutations (PLN, LMNA, and FLNC). These results may help determine appropriate candidates for implantable cardioverter‐defibrillator implantation.

Background Postcardiac injury syndrome (PCIS) is an inflammatory complication that derives from injury to the epicardium, myocardium, or endocardium. It occurs after trauma, myocardial infarction, percutaneous coronary intervention, cardiac surgery, intracardiac ablation, and implantation of cardiac implantable electronic device (CIED). In this study we assessed the incidence of PCIS after CIED implantation and its possible risk factors. Material and methods All patients who received CIED implantation at Heidelberg University Hospital between 2000 and 2014 were evaluated (n = 4989 patients). Clinical data including age, sex, underlying cardiac disease, type of implanted CIED, location of electrode implantation, clinical symptoms, time of symptom onset of PCIS, therapy, and outcome were extracted and analyzed. Results We identified 19 cases of PCIS in 4989 patients, yielding an incidence of 0.38%. The age of patients with PCIS ranged from 39 to 86 years. Dilated cardiomyopathy (DCM) as underlying cardiac disease and right atrial (RA) lead implantation had a significant association with occurrence of PCIS (p = 0.045 in DCM and p Conclusion To the best of our knowledge, this is the largest cohort evaluating the incidence of PCIS after CIED implantation. The data show that PCIS is a rare complication after CIED implantation and occurs more frequently in patients with DCM and those with RA lead implantation. Although rare and mostly benign, PCIS can lead to potentially lethal complications and physicians must be aware of its symptoms.

We report a rare case of concomitant hypertrophic cardiomyopathy and cardiac myxoma without LEOPARD syndrome. Additionally, 6 similar cases were systemically reviewed, and the characteristics of this first-ever studied patient group were summarized. (Level of Difficulty: Beginner.), Graphical abstract, This article reports a rare case of concomitant hypertrophic cardiomyopathy and cardiac myxoma without LEOPARD syndrome. Six similar cases were reviewed…

Hypertrophic obstructive cardiomyopathy (HOCM) increases the risk for mother and fetus during pregnancy. Alcohol septal ablation (ASA) is an established procedure in nonpregnant patients with HOCM. In this report, we present a case of a 29-year-old woman in her 29th gestational week with decompensated HOCM undergoing a successful ASA. (Level of Difficulty: Advanced.), Graphical abstract, Hypertrophic obstructive cardiomyopathy (HOCM) increases the risk for mother and fetus during pregnancy…

Cardiac sarcoidosis is a chronic inflammatory disease with a large spectrum of symptoms that can mimic diseases such as dilated, hypertrophic, or arrhythmogenic cardiomyopathies. It can be asymptomatic but can also present with ventricular arrhythmias, conduction disease, and heart failure (HF) or even sudden cardiac death (SCD). We present here the case of a patient transplanted due to end‐stage arrhythmogenic right ventricular cardiomyopathy (ARVC), fulfilling the task force criteria. A few years after successful heart transplantation (HTX), the patient developed similar symptoms and morphofunctional changes of the heart, which led to critical re‐evaluation of his primary diagnosis.

The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young, otherwise healthy, individuals. We conducted genome-wide association studies and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left ventricular (LV) traits (19,260 UK Biobank participants with structurally normal hearts). We identified 16 loci associated with HCM, 13 with DCM and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased LV contractility with HCM risk. A polygenic risk score explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that polygenic risk score may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects.

Introduction Myocardial fibrosis occurs during pathological remodeling of the heart and can be associated with worse outcome in affected patients. Genetic background is also known to affect patients' survival. In this study we sought to estimate patients' overall fibrosis burden by combining independent modalities including left ventricular endomyocardial biopsy (LV-EMB), circulating biomarkers, and cMRI. We also aimed to use patients' genetics information to predict outcome. Furthermore, we investigated the correlation between cardiac fibrosis and genetic variations to detect novel susceptibility loci for fibrosis in DCM. Methods A total number of 542 DCM patients were included. Collagen volume fraction (CVF) was automatically estimated from biopsies. 13 circulating fibrosis biomarkers were measured using Human Magnetic Luminex Screening Assays, and the cMRIs were screened for presence of LGE. Whole exome sequencing (WES) was performed in 410 patients of the cohort using illumina HiSeq 2000. Common (MAF ≥0.05 in the study population OR gnomAD NFE AF ≥0.01) and non-common missense variants (MAF Results The median follow-up time was 43.2 months (2084 patient-years). Sixty-two patients reached the composite end point and 55 died. LV-EMB proved to be a safe procedure with a total complication rate of 2.3%. Machine learning based characterization of biopsies was highly accurate. Although the 3 different modalities did not significantly correlate with one another, the extent of CVF, levels of MMP-2, TIMP-1, OPN, and GDF-15, and presence of LGE were each significantly associated with worse outcome. Four possible susceptibility loci for cardiac fibrosis in DCM were introduced and underwent eQTL analyses. Rare missense variants in a list of 11 DCM-related genes showed to be associated with the 2 outcome measures or fibrosis burden. Conclusions LV-EMB, fibrosis biomarkers, and cMRI likely capture different aspects of a detrimental fibrosis process and may be combined to estimate patients' prognosis and monitor therapeutic success. Phenotype-genotype association studies help elucidate novel disease pathomechanisms and individualize patients' treatment. Funding Acknowledgement Type of funding source: Other. Main funding source(s): German Centre for Cardiovascular Research: DZHK

Background Cardiac troponins are the preferred biomarkers of acute myocardial infarction. Despite superior sensitivity, serial testing of Troponins to identify patients suffering acute coronary syndromes is still required in many cases to overcome limited specificity. Moreover, unstable angina pectoris relies on reported symptoms in the troponin-negative group. In this study, we investigated genome-wide miRNA levels in a prospective cohort of patients with clinically suspected ACS and determined their diagnostic value by applying an in silico neural network. Methods PAXgene blood and serum samples were drawn and hsTnT was measured in patients at initial presentation to our Chest-Pain Unit. After clinical and diagnostic workup, patients were adjudicated by senior cardiologists in duty to their final diagnosis: STEMI, NSTEMI, unstable angina pectoris and non-ACS patients. ACS patients and a cohort of healthy controls underwent deep transcriptome sequencing. Machine learning was implemented to construct diagnostic miRNA classifiers. Results We developed a neural network model which incorporates 34 validated ACS miRNAs, showing excellent classification results. By further developing additional machine learning models and selecting the best miRNAs, we achieved an accuracy of 0.96 (95% CI 0.96–0.97), sensitivity of 0.95, specificity of 0.96 and AUC of 0.99. The one-point hsTnT value reached an accuracy of 0.89, sensitivity of 0.82, specificity of 0.96, and AUC of 0.96. Conclusions Here we show the concept of neural network based biomarkers for ACS. This approach also opens the possibility to include multi-modal data points to further increase precision and perform classification of other ACS differential diagnoses.

Background Patients with non-ischemic dilated cardiomyopathy (NIDCM) are at increased risk of ventricular arrhythmias and sudden cardiac death (SCD). However, identifying patients at high risk for life-threatening ventricular arrhythmia (LTVA) who may benefit from an implantable cardioverter defibrillator (ICD) remains challenging. Methods We searched MEDLINE and EMBASE for prognostic studies describing predictors of LTVA (defined as sustained ventricular tachycardia (VT), haemodynamically unstable VT, ventricular fibrillation, (aborted) SCD or appropriate ICD intervention) in patients with NIDCM. We excluded articles with composite heart failure and arrhythmic endpoints but lacking (subgroup) analysis for LTVA. Study quality and risk of bias was assessed using the QUIPS-tool, and articles with high risk of bias in ≥2 areas were excluded from analysis. Univariable hazard ratios of reported predictors were pooled from the remaining studies in a meta-analysis using a random-effects model and presented with 95% confidence interval (CI). Results Out of 1996 unique citations, 51 studies were included comprising 9798 patients with 1493 arrhythmic events. 28 studies were pooled for meta-analysis (mean age 55±4.1 years, 72% male) with a mean follow-up of 3.7±1.9 years. Crude event rate was 4.3% (95% CI 4.02–4.57) per year. From our meta-analysis, hypertension (HR 1.95; CI [1.26–3.00]), history of out of hospital cardiac arrest or sustained VT (HR 4.15; CI [1.32–13.02]), T-wave alternans (HR 6.50; CI [2.46–17.14]), LVEDV per 10ml/m2 increase (HR 1.10; CI [1.10–1.10]), LVESV per 10ml/m2 increase (HR 1.10; CI [1.00–1.22]) and delayed gadolinium enhancement (HR 5.55; CI [4.02–7.67]) were significantly associated with LTVA (figure). The quality of evidence was moderate and there was significant heterogeneity (median i2 57%; IQR 76%) among studies. Additionally from data that could not be pooled, decreased LVEF, history of nsVT and decreased heart rate variability were significantly associated with LTVA. Summary of meta-analysis results Conclusion The risk of LTVA in NIDCM is 4.3% per year and is considerably higher in patients with hypertension, history of LTVA, decreased LVEF, high LVEDV, high LVESV, T-wave alternans, history of nsVT, decreased heart rate variability and delayed gadolinium enhancement. These results may help determine appropriate candidates for ICD implantation. The high heterogeneity in reported results indicate the need for future multicentre studies to further improve risk stratification in NIDCM. Acknowledgement/Funding ERA-CVD JTC2016: DETECTIN-HF, 680969 & Dutch Heart Foundation (2016T096)

Background The diagnosis of cardiac hypertrabecularization has increased considerably in recent years. Whether or not the non-compaction is a pathological condition or a physiological trait is still highly debated. We performed a meta-analysis and systematic review on more than 7,000 adult individuals with left ventricular non-compaction to provide a comprehensive overview on its clinical outcome as well as its genetic background. Methods We first retrieved PubMed/Medline literatures in English language between 2000 to 2018 on clinical outcome and genotype of patients with non-compaction. Altogether, 35 studies with non-compaction cardiomyopathy patients passed the selection criteria and were extensively reviewed and meta-analyzed. Furthermore, we summarized the results of 8 major studies, which investigated the non-compaction in athletes, pregnant women, patients with sickle cell disease, or in individuals from population-based cohorts. Results About 60% of the patients with left-ventricular non-compaction cardiomyopathy were male. The diagnosis was mostly made in the mid of patients' 5th decade. Seven percent of patients had congenital heart diseases (CHD) including atrial/ventricular septum defect or Ebstein anomaly. Around 25% of the patients had positive family history for cardiomyopathy. Frequent phenotypic manifestations were heart rhythm abnormalities including conduction disease (26%), supraventricular tachycardia (17%), and sustained or non-sustained ventricular tachycardia (18%). Neuromuscular disease was a reported comorbidity with a mean frequency of 5%. Three important outcome measures including systemic thromboembolic events (9%), heart transplantation (4%), and adequate ICD therapy (15%) were reported. The genetics of non-compaction cardiomyopathy showed TTN to be the most frequently mutated gene (11%), followed by MYH7 (9%), MYBPC3 (5%), and CASQ2, LDB3 (3% each). TPM1, MIB1, ACTC1, and LMNA mutations had an average frequency of 2% each followed by PLN, HCN4, TAZ, DTNA, TNNT2, and RBM20 (1% each). Eight studies that investigated the occurrence of non-compacted myocardial regions in apparently heart healthy individuals applied different, established imaging-based diagnostic criteria for non-compaction and could confirm its presence in a wide range of 1.3% to 37%. Conclusion This meta-analysis summarizes the clinical presentation of left ventricular non-compaction in a large dataset and indicates that its presence often leads to unfavourable outcome, but can also be observed in heart healthy individuals. Multimodal diagnostic workflows are needed for comprehensive understanding of these individuals and for distinguishing between benign morphological trait and manifest cardiomyopathy.

Background Post cardiac injury syndrome (PCIS) is an inflammatory process, which occurs in the setting of injury to the pericardium, epicardium or myocardium. It may follow cardiac surgery, myocardial infarction, trauma, intracardiac ablation, percutaneous coronary intervention, and implantation of heart rhythm devices (HRD). In this study we aimed to assess the incidence of PCIS after HRD implantation and its possible risk factors. Material and methods All patients who received HRD implantation at our University Hospital between the years 2000 to 2014 were evaluated (n=4,989 patients) for developing PCIS. Clinical data including age, sex, underlying cardiac disease, type of implanted HRD, location of electrode implantation, clinical symptoms, time of symptom onset of PCIS, therapy, and outcome were extracted and analysed. Results 19 cases of PCIS were identified in altogether 4,989 patients resulting in an incidence of 0.38%. The age in patients with PCIS ranged from 39 to 86 years. Dilated cardiomyopathy (DCM) as underlying cardiac disease and right atrial (RA) lead implantation showed significant association to occurrence of PCIS (p=0.045 in DCM and p Conclusion To the best of our knowledge, this is the thus far largest cohort evaluating the incidence of PCIS after HRD implantation. PCIS remains a rare, but potentially lethal complication of heart rhythm device implantation. It should be considered particularly in patients with right atrial lead active fixation and DCM as underlying cardiac disease.

Introduction: Familial dilated cardiomyopathy (DCM) is clinically variable and has been associated with mutations in more than 50 genes. Rapid improvements in DNA sequencing have led to the identification of diverse rare variants with unknown significance (VUS), which underlines the importance of functional analyses. In this study, by investigating human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we evaluated the pathogenicity of the p.C335R sodium voltage-gated channel alpha subunit 5 (SCN5a) variant in a large family with familial DCM and conduction disease. Methods: A four-generation family with autosomal dominant familial DCM was investigated. Next-generation sequencing (NGS) was performed in all 16 family members. Clinical deep phenotyping, including endomyocardial biopsy, was performed. Skin biopsies from two patients and one healthy family member were used to generate human-induced pluripotent stem cells (iPSCs), which were then differentiated into cardiomyocytes. Patch-clamp analysis with Xenopus oocytes and iPSC-CMs were performed. Results: A SCN5a variant (c.1003T>C; p.C335R) could be detected in all family members with DCM or conduction disease. A novel truncating TTN variant (p.Ser24998LysfsTer28) could also be identified in two family members with DCM. Family members with the SCN5a variant (p.C335R) showed significantly longer PQ and QRS intervals and lower left ventricular ejection fractions (LV-EF). All four patients who received CRT-D were non-responders. Electrophysiological analysis with Xenopus oocytes showed a loss of function in SCN5a p.C335R. Na+ channel currents were also reduced in iPSC-CMs from DCM patients. Furthermore, iPSC-CM with compound heterozygosity (SCN5a p.C335R and TTNtv) showed significant dysregulation of sarcomere structures, which may be contributed to the severity of the disease and earlier onset of DCM. Conclusion: The SCN5a p.C335R variant is causing a loss of function of peak INa in patients with DCM and cardiac conduction disease. The co-existence of genetic variants in channels and structural genes (e.g., SCN5a p.C335R and TTNtv) increases the severity of the DCM phenotype.

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease, which goes along with increased risk for sudden cardiac death (SCD). Despite the knowledge about the different causal genes, the relationship between individual genotypes and phenotypes is incomplete. We retrieved PubMed/Medline literatures on genotype–phenotype associations in patients with HCM and mutations in MYBPC3, MYH7, TNNT2, and TNNI3. Altogether, 51 studies with 7675 HCM patients were included in our meta-analysis. The average frequency of mutations in MYBPC3 (20%) and MYH7 (14%) was higher than TNNT2 and TNNI3 (2% each). The mean age of HCM onset for MYH7 mutation positive patients was the beginning of the fourth decade, significantly earlier than patients without sarcomeric mutations. A high male proportion was observed in TNNT2 (69%), MYBPC3 (62%) and mutation negative group (64%). Cardiac conduction disease, ventricular arrhythmia and heart transplantation (HTx) rate were higher in HCM patients with MYH7 mutations in comparison to MYBPC3 (p

Left ventricular non-compaction has been increasingly diagnosed in recent years. However, it is still debated whether non-compaction is a pathological condition or a physiological trait. In this meta-analysis and systematic review, we compare studies, which investigated these two different perspectives. Furthermore, we provide a comprehensive overview on the clinical outcome as well as genetic background of left ventricular non-compaction cardiomyopathy in adult patients. We retrieved PubMed/Medline literatures in English language from 2000 to 19/09/2018 on clinical outcome and genotype of patients with non-compaction. We summarized and extensively reviewed all studies that passed selection criteria and performed a meta-analysis on key phenotypic parameters. Altogether, 35 studies with 2271 non-compaction patients were included in our meta-analysis. The mean age at diagnosis was the mid of their fifth decade. Two-thirds of patients were male. Congenital heart diseases including atrial or ventricular septum defect or Ebstein anomaly were reported in 7% of patients. Twenty-four percent presented with family history of cardiomyopathy. The mean frequency of neuromuscular diseases was 5%. Heart rhythm abnormalities were reported frequently: conduction disease in 26%, supraventricular tachycardia in 17%, and sustained or non-sustained ventricular tachycardia in 18% of patients. Three important outcome measures were reported including systemic thromboembolic events with a mean frequency of 9%, heart transplantation with 4%, and adequate ICD therapy with 15%. Nine studies investigated the genetics of non-compaction cardiomyopathy. The most frequently mutated gene was TTN with a pooled frequency of 11%. The average frequency of MYH7 mutations was 9%, for MYBPC3 mutations 5%, and for CASQ2 and LDB3 3% each. TPM1, MIB1, ACTC1, and LMNA mutations had an average frequency of 2% each. Mutations in PLN, HCN4, TAZ, DTNA, TNNT2, and RBM20 were reported with a frequency of 1% each. We also summarized the results of eight studies investigating the non-compaction in altogether 5327 athletes, pregnant women, patients with sickle cell disease, as well as individuals from population-based cohorts, in which the presence of left ventricular hypertrabeculation ranged from 1.3 to 37%. The summarized data indicate that non-compaction may lead to unfavorable outcome in different cardiomyopathy entities. The presence of key features in a multimodal diagnostic approach could distinguish between benign morphological trait and manifest cardiomyopathy.

Routine genetic testing in Dilated Cardiomyopathy (DCM) has recently become reality using Next-Generation Sequencing. Several studies have explored the relationship between genotypes and clinical phenotypes to support risk estimation and therapeutic decisions, however, most studies are small or restricted to a few genes. This study provides to our knowledge the first systematic meta-analysis on genotype-phenotype associations in DCM. We retrieved PubMed/Medline literature on genotype–phenotype associations in patients with DCM and mutations in LMNA, PLN, RBM20, MYBPC3, MYH7, TNNT2 and TNNI3. We summarized and extensively reviewed all studies that passed selection criteria and performed a meta-analysis on key phenotypic parameters. Together, 48 studies with 8097 patients were included. Furthermore, we reviewed recent studies investigating genotype-phenotype associations in DCM patients with TTN mutations. The average frequency of mutations in the investigated genes was between 1 and 5 %. The mean age of DCM onset was the beginning of the fifth decade for all genes. Heart transplantation (HTx) rate was highest in LMNA mutation carriers (27 %), while RBM20 mutation carriers were transplanted at a markedly younger age (mean 28.5 years). While 73 % of DCM patients with LMNA mutations showed cardiac conduction diseases, low voltage was the reported ECG hallmark in PLN mutation carriers. The frequency of ventricular arrhythmia in DCM patients with LMNA (50 %) and PLN (43 %) mutations was significantly higher. The penetrance of DCM phenotype in subjects with TTN truncating variants increased with age and reached 100 % by age of 70. A pooled analysis of available genotype-phenotype data shows a higher prevalence of sudden cardiac death (SCD), cardiac transplantation, or ventricular arrhythmias in LMNA and PLN mutation carriers compared to sarcomeric gene mutations. This study will further support the clinical interpretation of genetic findings.

BACKGROUND Biomarkers are well established for diagnosis of myocardial infarction [cardiac troponins, high-sensitivity cardiac troponins (hs-cTn)], exclusion of acute and chronic heart failure [B-type natriuretic peptide (BNP), N-terminal proBNP (NT-proBNP)] and venous thromboembolism (d-dimers). Several studies have demonstrated acute increases in cardiac biomarkers and altered cardiac function after strenuous sports that can pretend a cardiovascular emergency and interfere with state-of-the-art clinical assessment. METHODS We performed a systematic review and metaanalysis of biomarker and cardiovascular imaging changes after endurance exercise. We searched for observational studies published in the English language from 1997 to 2014 that assessed these biomarkers or cardiac function and morphology directly after endurance exercise. Of 1787 identified abstracts, 45 studies were included. RESULTS Across all studies cardiac troponin T (cTnT) exceeded the cutoff value (0.01 ng/mL) in 51% (95% CI, 37%–64%) of participants. The measured pooled changes from baseline for high-sensitivity cTnT (hs-cTnT) were +26 ng/L (95% CI, 5.2–46.0), for cTnI +40 ng/L (95% CI, 21.4; 58.0), for BNP +10 ng/L (95% CI, 4.3; 16.6), for NT-proBNP +67 ng/L (95% CI, 49.9; 84.7), and for d-dimer +262 ng/mL (95% CI, 165.9; 358.7). Right ventricular end diastolic diameter increased and right ventricular ejection fraction as well as the ratio of the early to late transmitral flow velocities decreased after exercise, while no significant changes were observed in left ventricular ejection fraction. CONCLUSIONS Current cardiovascular biomarkers (cTnT, hs-cTnT, BNP, NT-proBNP, and d-dimer) that are used in clinical diagnosis of pulmonary embolism, acute coronary syndrome, and heart failure are prone to alterations due to strenuous exercise. Hence, it is necessary to take previous physical exercise into account when a cardiac emergency is suspected.

About 30% of HF patients suitable for CRT do not respond to therapy. Estimating CRT response preoperatively would allow improved patient selection. The ability of a patient-specific computer heart model to introduce new preoperative biomarkers of CRT response was studied. cMRI and 12-lead ECGs were

Genetic variants contribute to several steps during heart failure pathophysiology. The mechanisms include frequent polymorphisms that increase the susceptibility to heart failure in the general population and rare variants as causes of an underlying cardiomyopathy. In this review, we highlight recent discoveries made by genetic approaches and provide an outlook onto the role of epigenetic modifiers of heart failure.

This systematic review with meta-analysis sought to determine protective effects of erythropoietin on clinical outcomes following percutaneous coronary intervention (PCI). Medline, Embase, Elsevier and Sciences online database as well as Google scholar literature were used for selecting appropriate studies with randomized controlled design. The effect sizes measured were odds ratio (OR) for categorical variables and weighted mean difference (WMD) with 95% confidence interval for calculating differences between mean values of duration of hospitalization in intervention and control groups. Values of P 2 >50% indicated significant heterogeneity between the studies. The literature searches of all major databases retrieved 973 studies. After screening, a total of 15 trials that reported outcomes were identified. Pooled analysis was performed on left ventricular ejection fraction (WMD of −0.047; 95% CI: −0.912 to 0.819; P =0.9), left ventricular end diastolic volume (WMD of −0.363; 95% CI: −3.902 to 3.175; P =0.8), left ventricular end systolic volume (WMD of 0.346; 95% CI: −2.533 to 3.226; P =0.8), infarct size (WMD of −0.446; 95% CI: −2.352 to −1.460; P =0.6), stroke (OR of 2.1; 95% CI: 0.58 to 7.54; P =0.2), re-myocardial infarction (OR of 1.06; 95% CI: 0.52 to 2.185; P =0.8), heart failure (OR of 0.53; 95% CI: 0.259 to 1.105; P =0.09), mortality (OR of 0.56; 95% CI: 0.27 to 1.19; P =0.13), thrombosis (OR of 0.774; 95% CI: 0.41 to 1.45; P =0.4), major adverse cardiovascular events (OR of 0.926; 95% CI: 0.63 to 1.35; P =0.6). Short-term administration of EPO in patients with myocardial infarction (MI) undergoing PCI does not result in improvement in cardiac function, reduction of infarct size and all-cause mortality. Low dose EPO therapy may not be the choice of treatment for the patients with MI, while higher doses might be more effective.

Post cardiac injury syndrome (PCIS) is an inflammatory process that occurs in the setting of injury to the pericardium, epicardium or myocardium. It may follow cardiac surgery, myocardial infarction, trauma, intracardiac ablation, percutaneous coronary intervention or implantation of a pacemaker or cardioverter–defibrillator. In this paper, we report the first case of PCIS after implantation of a “Cardiac Resynchronization Therapy Defibrillator” (CRT-D) device and review systematically the available literature. To obtain information on PCIS after implantation of heart rhythm devices (HRD), we performed a systematic review of Medline, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL). The collected data included age, gender, initial diagnosis, procedure type, time to PCIS, symptoms, clinical manifestations, therapy and outcome. Included were reports in English, French and Spanish. In our systematic review, we found PCIS after HRD implantation in 17 additional cases. The age ranged from 23 to 84 years. Symptoms developed within 1 day–4 months after implantation. The use of active-fixation atrial leads was reported in nine cases. Fever, dyspnoea, chest pain, tachypnoea, tachycardia, palpitation, malaise, ankle edema, dry cough, night sweats, nausea and vomiting were reported as associated symptoms. PCIS should be considered as a rare, but serious complication of HRD implantation, may cause recurrent hospitalization and can be life threatening. The incidence and possible causes of PCIS after HRD, such as active fixation leads and specific lead positions as well as its treatment deserve further investigation in prospective studies.

Aims: In this study, we aimed to clinically and genetically characterize LVNC patients and investigate the prevalence of variants in known and novel LVNC disease genes. Introduction: Left ventricular non-compaction cardiomyopathy (LVNC) is an increasingly recognized cause of heart failure, arrhythmia, thromboembolism, and sudden cardiac death. We sought here to dissect its genetic causes, phenotypic presentation and outcome. Methods and results: In our registry with follow-up of in the median 61 months, we analysed 95 LVNC patients (68 unrelated index patients and 27 affected relatives; definite familial LVNC = 23.5%) by cardiac phenotyping, molecular biomarkers and exome sequencing. Cardiovascular events were significantly more frequent in LVNC patients compared with an age-matched group of patients with non-ischaemic dilated cardiomyopathy (hazard ratio = 2.481, P = 0.002). Stringent genetic classification according to ACMG guidelines revealed that TTN, LMNA, and MYBPC3 are the most prevalent disease genes (13 patients are carrying a pathogenic truncating TTN variant, odds ratio = 40.7, Confidence interval = 21.6-76.6, P

Aims Non-ischaemic heart failure is one of the today's most prevalent cardiovascular disorders. Since modern pharmacotherapy has proved to be very effective in delaying disease progression and preventing death, imaging modalities and molecular biomarkers play an important role in early identification and clinical management as well as risk assessment of patients. The present study evaluated for the first time whole peripheral blood miRNAs as novel biomarker candidates for non-ischaemic heart failure with reduced ejection fraction (HF-REF). Methods and results We assessed genome-wide miRNA expression profiles in 53 HF-REF patients and 39 controls. We could identify and validate several miRNAs that show altered expression levels in non-ischaemic HF-REF, discriminating cases from controls both as single markers or when combined in a multivariate signature. In addition, we demonstrate that the miRNAs of this signature significantly correlate with disease severity as indicated by left ventricular ejection fraction. Conclusion Our data further denote that miRNAs are potential biomarkers for systolic heart failure. Since their detection levels in whole blood are also related to the degree of left ventricular dysfunction, they may serve as objective molecular tools to assess disease severity and prognosis.

To investigate the association of right ventricular long axis strain (RV-LAS), a parameter of longitudinal function, with outcome in patients with non-ischaemic dilated cardiomyopathy (NIDCM).In 441 patients with NIDCM, RV-LAS was analysed retrospectively by measuring the length between the epicardial border of the left ventricular apex and the middle of a line connecting the origins of the tricuspidal valve leaflets in end-diastole and end-systole on non-contrast standard cine sequences.The primary endpoint (cardiac death or heart transplantation) occurred in 41 patients, whereas 95 reached the combined endpoint (including cardiac decompensation and sustained ventricular arrhythmias) during a median follow-up of 4.2 years. Kaplan-Meier survival curves showed a poor outcome in patients with RV-LAS values below -10% (log-rank, p 0.0001). In a risk stratification model RV-LAS improved prediction of outcome in addition to RV ejection fraction (RVEF) and presence of late gadolinium enhancement. Assessment of RV-LAS offered incremental information compared to clinical symptoms, biomarkers and RVEF. Even in the subgroup with normal RVEF (45%, n = 213) reduced RV-LAS was still associated with poor outcome.Assessment of RV-LAS is an independent indicator of outcome in patients with NIDCM and offers incremental information beyond clinical and cardiac MR parameters.• Impaired right ventricular longitudinal function (RV-LAS) is associated with poorer cardiac outcomes. • Poor outcome is associated with decreased RV-LAS even in patients with RVEF45%. • Addition of RV-LAS to known risk factors enhances the power prognostic information.

MicroRNAs (miRNAs) are important regulators of adaptive and maladaptive responses in cardiovascular diseases and hence are considered to be potential therapeutical targets. However, their role as novel biomarkers for the diagnosis of cardiovascular diseases still needs to be systematically evaluated. We assessed here for the first time whole-genome miRNA expression in peripheral total blood samples of patients with acute myocardial infarction (AMI). We identified 121 miRNAs, which are significantly dysregulated in AMI patients in comparison to healthy controls. Among these, miR-1291 and miR-663b show the highest sensitivity and specificity for the discrimination of cases from controls. Using a novel self-learning pattern recognition algorithm, we identified a unique signature of 20 miRNAs that predicts AMI with even higher power (specificity 96%, sensitivity 90%, and accuracy 93%). In addition, we show that miR-30c and miR-145 levels correlate with infarct sizes estimated by Troponin T release. The here presented study shows that single miRNAs and especially miRNA signatures derived from peripheral blood, could be valuable novel biomarkers for cardiovascular diseases.

BackgroundDespite modern pharmacotherapy and advanced implantable cardiac devices, overall prognosis and quality of life of HF patients remain poor. This is in part due to insufficient patient stratification and lack of individualized therapy planning, resulting in less effective treatments and a significant number of non-responders.Methods and resultsState-of-the-art clinical phenotyping was acquired, including magnetic resonance imaging (MRI) and biomarker assessment. An individualized, multi-scale model of heart function covering cardiac anatomy, electrophysiology, biomechanics and hemodynamics was estimated using a robust framework. The model was computed on n=46 HF patients, showing for the first time that advanced multi-scale models can be fitted consistently on large cohorts. Novel multi-scale parameters derived from the model of all cases were analyzed and compared against clinical parameters, cardiac imaging, lab tests and survival scores to evaluate the explicative power of the model and its potential for better patient stratification. Model validation was pursued by comparing clinical parameters that were not used in the fitting process against model parameters.ConclusionThis paper illustrates how advanced multi-scale models can complement cardiovascular imaging and how they could be applied in patient care. Based on obtained results, it becomes conceivable that, after thorough validation, such heart failure models could be applied for patient management and therapy planning in the future, as we illustrate in one patient of our cohort who received CRT-D implantation.

Left ventricular noncompaction cardiomyopathy (LVNC) is an increasingly recognized cause of heart failure, arrhythmias, thrombembolic events, and sudden cardiac death. To better understand the contribution of genetic factors to this disease, allowing a better diagnosis, counseling of affected families and estimation of prognosis, we have performed whole-exome deep-sequencing on a cohort of in 104 subjects (67 unrelated LVNC probands, 26 affected relatives form 15 families and 11 additional healthy relatives). By annotating the detected variants with mutation databases (HGMD), we were able to for the first time show an overlap between the distinct causes of LVNC and other genetic cardiomyopathies, as 8 mutations were previously reported to cause hypertrophic cardiomyopathy (HCM), 9 dilated cardiomyopathy (DCM) and 6 arrhythmogenic right ventricular cardiomyopathy (ARVC). Besides already known genetic causes, we identified a number of genes contributing to different pathways, so far not discussed to be of relevance for LVNC. From those, TTN truncating mutations were very frequent, affecting 17.9% of all index patients and one fifth of the familial cases. For two genes, which have already been linked to cardiac noncompaction in animal models, we are first to describe a relevant number of patients carrying mutations in these genes NCOR2 (frequency = 7.5%) and XIRP2 (4.5%). By performing segregation and linkage analyses, as well as in vivo studies, we provide for the first time evidence for a gene that was previously not known to cause a human disease, Compactin1. In conclusion, we show that LVNC has a substantial genetic component and suggest new candidate genes for a functional dissection of their contribution to cardiac development and as potential therapeutic target.

Background This systematic review with meta-analysis sought to determine the efficacy and safety of intramyocardial transplantation of bone marrow stem cells during coronary artery bypass graft surgery on postoperative cardiac functional parameters such as left ventricular ejection fraction and left ventricular end-diastolic volume. Methods Medline/PubMed, Embase, Elsevier, Sciences online database, and Google Scholar literature search were searched. The effect sizes measured were risk ratio for categorical variables and weighted mean difference with 95% confidence interval for calculating differences between mean values of baseline and follow-up cardiac functional parameters. A value of p 2 > 50%, indicated significant heterogeneity among studies. The literature search retrieved 2900 studies from screened databases, of which 2866 (98.6%) were excluded and 34 (619 patients) were included for scoping review. The final analysis included 9 studies (335 patients). Results Pooled effects estimates of left ventricular ejection fraction and left ventricular end-diastolic volume showed that bone marrow stem cell transplantation had a weighted mean difference of 4.06 (95% confidence interval: 0.41–7.72; p = 0.02) and 7.06 (95% confidence interval: −8.58–22.7; p = 0.3), respectively. Conclusions Intramyocardial transplantation of bone marrow stem cells improves cardiac functional parameters, significantly increasing left ventricular ejection fraction with a nonsignificant reduction in left ventricular end-diastolic volume. Also, this therapeutic method has no life-threatening complications and was therefore found to be an effective and safe method.

Recent advances in computational electrophysiology (EP) models make them attractive for clinical use. We propose a novel data-driven approach to calibrate an EP model from standard 12-lead electrocardiograms (ECG), which are in contrast to invasive or dense body surface measurements widely available in clinical routine. With focus on cardiac depolarization, we first propose an efficient forward model of ECG by coupling a mono-domain, Lattice-Boltzmann model of cardiac EP to a boundary element formulation of body surface potentials. We then estimate a polynomial regression to predict myocardium, left ventricle and right ventricle endocardium electrical diffusion from QRS duration and ECG electrical axis. Training was performed on 4,200 ECG simulations, calculated in ≈3s each, using different diffusion parameters on 13 patient geometries. This allowed quantifying diffusion uncertainty for given ECG parameters due to the ill-posed nature of the ECG problem. We show that our method is able to predict myocardium diffusion within the uncertainty range, yielding a prediction error of less than 5ms for QRS duration and 2° for electrical axis. Prediction results compared favorably with those obtained with a standard optimization procedure, while being 60 times faster. Our data-driven model can thus constitute an efficient preliminary step prior to more refined EP personalization.