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Aims Atrial fibrillation (AF) after heart transplantation (HTX) is associated with worse clinical outcomes. The current study aimed to analyse the association between AF before HTX and AF within 30 days after HTX. Methods and results This study included 639 adults who received HTX at Heidelberg Heart Center. Patients were subdivided into four groups depending on the status of AF before and after HTX. Analyses comprised recipient and donor data, medication, echocardiographic features, permanent pacemaker implantation, stroke, and mortality after HTX. Three hundred thirty‐two patients (52.0%) had neither AF before nor after HTX, 15 patients (2.3%) had no AF before HTX but showed AF after HTX, 219 patients (34.3%) showed AF before HTX but had no AF after HTX, and 73 patients (11.4%) had AF before and after HTX. Patients with AF before and after HTX had a higher 1 year post‐transplant mortality (39.7%) than patients without AF before or after HTX (18.1%, P

Aims Right bundle branch block (RBBB) after heart transplantation (HTX) is a common finding, but its impact on post‐transplant survival remains uncertain. This study investigated the post‐transplant outcomes of patients with complete RBBB (cRBBB) ≤ 30 days after HTX. Methods This registry study analysed 639 patients receiving HTX at Heidelberg Heart Center between 1989 and 2019. Patients were stratified by diagnosis of cRBBB ≤ 30 days after HTX. Analysis included recipient and donor data, medication, echocardiographic features, graft rejections, atrial fibrillation, heart rates, permanent pacemaker implantation and mortality after HTX including causes of death. Results One hundred thirty‐nine patients showed cRBBB ≤ 30 days after HTX (21.8%), 20 patients with pre‐existing cRBBB in the donor heart (3.2%) and 119 patients with newly acquired cRBBB (18.6%). Patients with newly acquired cRBBB had a worse 1‐year post‐transplant survival (36.1%, P

Aims Amiodarone and digitalis are frequently used drugs in patients with heart failure. Both have separately been linked to reduced post‐transplant survival, but their combined impact on mortality after HTX remains uncertain. This study investigated the effects of combined amiodarone and digitalis use before HTX on post‐transplant outcomes. Methods and results This registry study analysed 600 patients receiving HTX at Heidelberg Heart Center between 1989 and 2016. Patients were stratified by amiodarone and digitalis use before HTX. Analysis included patient characteristics, medication, echocardiographic features, heart rates, permanent pacemaker implantation, atrial fibrillation, and post‐transplant survival including causes of death. One hundred eighteen patients received amiodarone before HTX (19.7%), hereof 67 patients with digitalis (56.8%) and 51 patients without digitalis before HTX (43.2%). Patients with and without amiodarone before HTX showed a similar 1 year post‐transplant survival (72.0% vs. 78.4%, P = 0.11), but patients with combined amiodarone and digitalis before HTX had a worse 1 year post‐transplant survival (64.2%, P = 0.01), along with a higher percentage of death due to transplant failure (P = 0.03). Echocardiographic analysis of these patients showed a higher percentage of an enlarged right ventricle (P = 0.02), left atrium (P = 0.02), left ventricle (P = 0.03), and a higher rate of reduced left ventricular ejection fraction (P = 0.03). Multivariate analysis indicated combined amiodarone and digitalis use before HTX as a significant risk factor for 1 year mortality after HTX (hazard ratio: 1.69; 95% confidence interval: 1.02–2.77; P = 0.04). Conclusions Combined pre‐transplant amiodarone and digitalis therapy is associated with increased post‐transplant mortality.

Aims Severely elevated pre‐transplant pulmonary vascular resistance (PVR) has been linked to adverse effects after heart transplantation (HTX). The impact of a moderately increased PVR before HTX on post‐transplant outcomes remains uncertain. The aim of this study was to investigate the effects of an elevated pre‐transplant PVR ≥ 300 dyn·s·cm−5 (≥3.75 Wood units) on outcomes after HTX. Methods and results This observational retrospective single‐centre study included 561 patients receiving HTX at Heidelberg Heart Center between 1989 and 2015. Patients were stratified by degree of pre‐transplant PVR. Analyses covered demographics, post‐transplant medication, mortality and causes of death after HTX, early post‐transplant atrial fibrillation (AF), and length of the initial hospital stay after HTX. Ninety‐four patients (16.8%) had a PVR ≥ 300 dyn·s·cm−5 (≥3.75 Wood units). These patients had a higher rate of early post‐transplant AF [20.2 vs. 10.7%, difference: 9.5%, 95% confidence interval (CI): 0.9–18.1%, P = 0.01] and an increased 30 day post‐transplant mortality (25.5 vs. 6.4%, hazard ratio: 4.4, 95% CI: 2.6–7.6, P < 0.01), along with a higher percentage of death due to transplant failure (21.2 vs. 4.1%, difference: 17.1%, 95% CI: 8.7–25.5%, P < 0.01). Multivariate analysis revealed a PVR ≥ 300 dyn·s·cm−5 (≥3.75 Wood units) as a significant risk factor for increased 30 day mortality after HTX (hazard ratio: 4.4, 95% CI: 2.5–7.6, P < 0.01). Kaplan–Meier estimator showed a lower 2 year survival after HTX (P < 0.01) in patients with a PVR ≥ 300 dyn·s·cm−5 (≥3.75 Wood units). Conclusions Elevated pre‐transplant PVR ≥ 300 dyn·s·cm−5 (≥3.75 Wood units) is associated with early post‐transplant AF and increased mortality after HTX.

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.

Aims Upon suspicion of infective endocarditis, the causative microorganism must be identified to optimize treatment. Blood cultures and culturing of removed valves are the mainstay of this diagnosis and should be complemented by growth-independent methods. We assessed the diagnostic benefit of examining removed endocarditis valves by broad-range bacterial PCR to detect causative bacteria in cases where culturing was not available, negative, or inconclusive because a skin commensal was detected, in patients from our clinical routine practice. Methods and results Patients from Heidelberg University Hospital with suspicion of endocarditis, followed by valve replacement and analysis by 16S rDNA PCR, between 2015 and 2018, were evaluated. 146 patients with definite infective endocarditis, confirmed by the valve macroscopics and/or histology, were included. Valve PCRs were compared to corresponding blood and valve culture results. Overall, valve PCR yielded an additional diagnostic benefit in 34 of 146 cases (23%) and was found to be more sensitive than valve culture. In 19 of 38 patients with both negative blood and valve cultures, valve PCR was the only method rendering a pathogen. In 23 patients with positive blood cultures detecting skin commensals, 4 patients showed discordant valve PCR results, detecting a more plausible pathogen, and in 11 of 23 cases, valve PCR confirmed commensals in blood culture as true pathogens. Only the remaining 8 patients had negative valve PCRs. Conclusion Valve PCR was found to be a valuable diagnostic tool in surgical endocarditis cases with negative blood cultures or positive blood cultures of unknown significance. Trial registration S-440/2017 on 28.08.2017 retrospectively registered. Graphic abstract Subdividing of all infective endocarditis patients in this study, showing that valve PCR yields valuable information for patients with skin commensals in blood cultures, which were either confirmed by the same detection in valve PCR or refuted by the detection of a different and typical pathogen in valve PCR. Additionally, benefit was determined in patients with negative or not available blood cultures and only positive detection in valve PCR. +: Positive; −: negative; n/a: not available results

Background Cardiac graft denervation causes inadequate sinus tachycardia in patients after heart transplantation (HTX) which is associated with reduced survival. This study investigated the 5-year results of heart rate control with ivabradine or metoprolol succinate in patients after HTX. Methods This registry study analyzed 104 patients receiving either ivabradine (n = 50) or metoprolol succinate (n = 54) within 5 years after HTX. Analysis included patient characteristics, medication, echocardiographic features, cardiac catheterization data, cardiac biomarkers, heart rates, and post-transplant survival including causes of death. Results Demographics and post-transplant medication revealed no significant differences except for ivabradine and metoprolol succinate use. At 5-year follow-up, patients with ivabradine had a significantly lower heart rate (73.3 bpm) compared to baseline (88.6 bpm; P P P P P P P P P Conclusion Patients receiving ivabradine showed a superior heart rate reduction and a better left ventricular diastolic function along with an improved 5-year survival after HTX.

Background: Cardiac amyloidosis, caused by deposition of immunoglobulin light chains (AL) or transthyretin (ATTR), carries a poor prognosis. Established risk scores for amyloidosis may not predict outcomes in those patients who develop advanced heart failure and who are potential candidates for heart transplantation. Here, we aimed to identify predictive parameters for patients with severe heart failure due to amyloidosis. Methods: Out of > 1000 patients with cardiac amyloidosis (AL or ATTR) admitted to our centre between September 1998 and January 2016, a cohort of 120 patients with a complete cardiac assessment at diagnosis, including right heart catheterization, echocardiography and biomarkers, was analysed retrospectively in this study. Primary endpoint was all-cause mortality. We performed univariate and multivariate Cox regression analysis, generated risk scores to predict outcomes in AL and ATTR amyloidosis and compared those to established risk models for amyloidosis. Results: In the Cox multivariate model, high-sensitivity troponin T (hsTnT; hazard ratio (HR) 1.003; confidence interval (CI) 1.001–1.005; p = 0.009) and mean pulmonary artery pressure (HR 1.061; CI 1.024–1.100; p = 0.001) were found to significantly and independently predict outcomes for AL amyloidosis, whereas QRS duration (HR 1.021; CI 1.004–1.039; p = 0.013), hsTnT (HR 1.021; CI 1.006–1.036; p = 0.006) and N-terminal pro-brain natriuretic peptide (HR 1.0003; CI 1.0001–1.0004; p = 0.002) were the best predictors for ATTR amyloidosis. A simple risk score (“HeiRisk”) including these parameters for AL and ATTR allowed a more precise risk stratification in our patient population compared to established risk models. Conclusions: Risk stratification for cardiac amyloidosis with the newly developed “HeiRisk” score may be superior to other staging systems for patients with advanced heart failure due to amyloid cardiomyopathy.

Impaired left ventricular (LV) longitudinal function (LF) is a known predictor of cardiac events in patients with heart failure, but two-dimensional strain imaging, the reference method to measure myocardial deformation, is not always feasible or available. Therefore, reliable and reproducible alternatives are needed. The aim of the present study was to evaluate unidimensional longitudinal strain (ULS) as a simple echocardiographic parameter for the assessment of LV LF.Two hundred two patients with dilated cardiomyopathy who had their first presentation in the authors' cardiology department, as well as the same number of age- and gender-matched control subjects, were prospectively included in this study. ULS was compared with global longitudinal strain (GLS), the current gold standard for LV LF assessment by echocardiography. Uni- and multivariate Cox regression analyses were conducted to evaluate the prognostic value of ULS.LV LF was higher in the control group compared with patients: GLS -19.5 ± 1.7% versus -12.6 ± 4.8% and ULS -16.3 ± 1.5% versus -10.2 ± 3.9% (P .001 for each). Correlation between ULS and GLS was excellent (r = 0.94), while Bland-Altman plots revealed lower values for ULS (bias -2.76%, limits of agreement ±3.31%). During a mean follow-up time of 39 months, the combined end point of cardiovascular death or hospitalization for acute cardiac decompensation was reached by 28 patients (13.9%). GLS (hazard ratio, 1.21; 95% CI, 1.10-1.34; P .001) and ULS (hazard ratio, 1.24; 95% CI, 1.12-1.39; P .001) had comparable prognostic impact on patient outcomes.ULS might be an alternative echocardiographic method for the assessment of LV LF, with similar diagnostic and prognostic value compared with GLS.

Patients after heart transplantation (HTX) present with sinus tachycardia due to graft denervation. As elevated heart rates negatively affect survival, the aim of this study was to analyze the effects of ivabradine vs metoprolol succinate on heart rate, left ventricular (LV) mass and survival following HTX. This observational retrospective single-center study assessed 84 patients continuously receiving either ivabradine (n = 40) or metoprolol succinate (n = 44) within 2 years after HTX. Patients with dual therapy (ivabradine and metoprolol succinate), other beta blockers, amiodarone, or digitalis were excluded. Patient characteristics, post-transplant medication, heart rates, LV mass, and survival were investigated. Analysis of patient characteristics, immunosuppressive drug regimen, and post-transplant medication showed no significant differences between groups except for ivabradine and metoprolol succinate. Baseline heart rates differed not significantly between patients treated with ivabradine [87.0 beats per minute (bpm)] and metoprolol succinate (86.2 bpm; P = 0.6395). At 2-year follow-up, patients with ivabradine (76.7 bpm) had a significantly lower heart rate compared to baseline (P

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

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.

INTRODUCTION: Fecal microbiota transfer (FMT) is highly effective in the treatment and prevention of recurrent Clostridioides difficile infection (rCDI) with cure rates of about 80% after a single treatment. Nevertheless, the reasons for failure in the remaining 20% remain largely elusive. The aim of the present study was to investigate different potential clinical predictors of response to FMT in Germany. METHODS: Information was extracted from the MicroTrans Registry (NCT02681068), a retrospective observational multicenter study, collecting data from patients undergoing FMT for recurrent or refractory CDI in Germany. We performed binary logistic regression with the following covariates: age, gender, ribotype 027, Eastern Co-operative Oncology Group score, immunosuppression, preparation for FMT by use of proton pump inhibitor, antimotility agents and bowel lavage, previous recurrences, severity of CDI, antibiotic induction treatment, fresh or frozen FMT preparation, and route of application. RESULTS: Treatment response was achieved in 191/240 evaluable cases (79.6%) at day 30 (D30) post FMT and 78.1% at day 90 (D90) post FMT. Assessment of clinical predictors for FMT failure by forward and confirmatory backward-stepwise regression analysis yielded higher age as an independent predictor of FMT failure (p = 0.001; OR 1.060; 95%CI 1.025–1.097). CONCLUSION: FMT in Germany is associated with high cure rates at D30 and D90. No specific pre-treatment, preparation or application strategy had an impact on FMT success. Only higher age was identified as an independent risk factor for treatment failure. Based on these and external findings, future studies should focus on the assessment of microbiota and microbiota-associated metabolites as factors determining FMT success.

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.

Ventricular assist devices (VAD) are increasingly used as long-term treatment for advanced heart failure. However, survival after VAD implantation is still unsatisfactory, and no specific outpatient follow-up algorithms have been formally established. Here, we evaluate the effect of an intensified follow-up protocol (IFUP) on survival rates and VAD-associated complications. This is a retrospective study of 57 patients who received a VAD at our center between February 2013 and December 2017. Inclusion criteria were discharge home after VAD implantation and follow-up in our VAD outpatient clinic. Patients implanted after October 2015 (n = 30) were monitored according to IFUP. This protocol embodied formalized, multi-disciplinary clinical visits every 4–8 weeks including a cardiologist, a cardiothoracic surgeon and a VAD-coordinator and was characterized by optimized anticoagulation and wound management as well as guideline-directed medical therapy. One-year survival in the IFUP patients was 97%, compared to 74% in the pre-IFUP era (p = 0.01). Implementation of IFUP was associated with a 90% risk-reduction for 1-year mortality (relative risk 0.099; p = 0.048). The rate of complications, e.g., device thrombosis and major bleeding, was significantly reduced, resulting in superior event-free survival in the IFUP group (p = 0.003). Furthermore, by implementation of IFUP, a more stable anticoagulation adjustment was achieved as well as an improved adherence to guideline-directed medical therapy. Implementation of an IFUP for VAD patients is associated with a significant decrease in 1-year all-cause mortality. This emphasizes the need for more vigilance in the management of VAD patients by a dedicated multi-disciplinary team.

Background Right ventricular (RV) dysfunction predicts adverse outcome in peripartum cardiomyopathy (PPCM). We recently demonstrated beneficial effects associated with the prolactin release inhibitor bromocriptine at different doses when added to standard heart failure therapy in PPCM. Here, we evaluated for the first time the therapeutic potential of bromocriptine particularly in PPCM patients with RV involvement. Methods In this study, 40 patients with PPCM were included, of whom 24 patients had reduced RV ejection fraction (RVEF

Background The late sodium current inhibitor ranolazine reverses the main electrophysiological and mechanical abnormalities of human hypertrophic cardiomyopathy (HCM) cardiomyocytes in vitro, suggesting potential clinical benefit. We aimed to assess the effect of ranolazine on functional capacity, symptomatic status, diastolic function, and arrhythmias in HCM. Methods and Results In this multicenter, double-blind, phase 2 study, 80 adult patients with nonobstructive HCM (age 53±14 years, 34 women) were randomly assigned to placebo (n=40) or ranolazine 1000 mg bid (n=40) for 5 months. The primary end point was change in peak VO 2 compared with baseline using cardiopulmonary exercise test. Echocardiographic lateral and septal E/E′ ratio, prohormone brain natriuretic peptide levels, 24-hour Holter arrhythmic profile, and quality of life were assessed. Ranolazine was safe and well tolerated. Overall, there was no significant difference in VO 2 peak change at 5 months in the ranolazine versus placebo group (delta 0.15±3.96 versus −0.02±4.25 mL/kg per minute; P =0.832). Ranolazine treatment was associated with a reduction in 24-hour burden of premature ventricular complexes compared with placebo (>50% reduction versus baseline in 61% versus 31%, respectively; P =0.042). However, changes in prohormone brain natriuretic peptide levels did not differ in the ranolazine compared with the placebo group (geometric mean median [interquartile range], −3 pg/mL [−107, 142 pg/mL] versus 78 pg/mL [−71, 242 pg/mL]; P =0.251). Furthermore, E/E′ ratio and quality of life scores showed no significant difference. Conclusions In patients with nonobstructive HCM, ranolazine showed no overall effect on exercise performance, plasma prohormone brain natriuretic peptide levels, diastolic function, or quality of life. The drug showed an excellent safety profile and was associated with reduced premature ventricular complex burden. Late sodium current inhibition does not seem to improve functional capacity in HCM. Clinical Trial Registration: URL: https://www.clinicaltrialsregister.eu . Unique identifier: 2011-004507-20

Aims An anti-angiogenic cleaved prolactin fragment is considered causal for peripartum cardiomyopathy (PPCM). Experimental and first clinical observations suggested beneficial effects of the prolactin release inhibitor bromocriptine in PPCM. ................................................................................................................................................................................................... Methods and results In this multicentre trial, 63 PPCM patients with left ventricular ejection fraction (LVEF) < _35% were randomly assigned to short-term (1W: bromocriptine, 2.5mg, 7 days) or long-term bromocriptine treatment (8W: 5 mg for 2weeks followed by 2.5mg for 6weeks) in addition to standard heart failure therapy. Primary end point was LVEF change (delta) from baseline to 6months assessed bymagnetic resonance imaging. Bromocriptinewas well tolerated. Left ventricular ejection fraction increased from 28± 10% to 49± 12% with a delta-LVEF ofþ21± 11% in the 1W-group, and from 27± 10% to 51 ± 10% with a delta-LVEF ofþ24± 11% in the 8W-group (delta-LVEF: P = 0.381). Full-recovery (LVEF > _50%) was present in 52% of the 1W- and in 68% of the 8W-groupwith no differences in secondary end points between both groups (hospitalizations for heart failure: 1W: 9.7% vs. 8W: 6.5%, P = 0.651). The risk within the 8W-group to fail full-recovery after 6months tended to be lower.No patient in the study needed heart transplantation, LV assist device or died. ................................................................................................................................................................................................... Conclusion Bromocriptine treatment was associated with high rate of full LV-recovery and low morbidity and mortality in PPCM patients compared with other PPCM cohorts not treated with bromocriptine. No significant differences were observed between 1W and 8W treatment suggesting that 1-week addition of bromocriptine to standard heart failure treatment is already beneficial with a trend for better full-recovery in the 8W group.

We sought to determine the ability of quantitative myocardial perfusion reserve index (MPRI) by cardiac magnetic resonance (CMR) and high-sensitive troponin T (hsTnT) for the prediction of cardiac allograft vasculopathy (CAV) and cardiac outcomes in heart transplant (HT) recipients. In 108 consecutive HT recipients (organ age 4.1 ± 4.7 years, 25 [23%] with diabetes mellitus) who underwent cardiac catheterization, CAV grade by International Society for Heart & Lung Transplantation (ISHLT) criteria, MPRI, late gadolinium enhancement (LGE) and hsTnT values were obtained. Outcome data including cardiac death and urgent revascularization (“hard cardiac events”) and revascularization procedures were prospectively collected. During a follow-up duration of 4.2 ± 1.4 years, seven patients experienced hard cardiac events and 11 patients underwent elective revascularization procedures. By multivariable analysis, hsTnT and MPRI both independently predicted cardiac events, surpassing the value of LGE and CAV by ISHLT criteria. Furthermore, hsTnT and MPRI provided complementary value. Thus, patients with high hsTnT and low MPRI showed the highest rates of cardiac events (annual event rate = 14.5%), while those with low hsTnT and high MPRI exhibited excellent outcomes (annual event rate = 0%). In conclusion, comprehensive “bio-imaging” using hsTnT, as a marker of myocardial microinjury, and CMR, as a marker of microvascular integrity and myocardial damage by LGE, may aid personalized risk-stratification in HT recipients.

Left ventricular noncompaction (LVNC) is a cardiomyopathy with hypertrabeculation of the LV, often complicated by heart failure, arrhythmia and thromboembolic events. The features of LVNC are still incompletely characterized due to its late recognition as clinically relevant condition. The aims of this study were to describe echocardiographic and electrophysiologic characteristics of LVNC patients and to assess the effects of chronic β-blocker treatment. Study patients (n = 20; 42.5 [36.3; 52.5] years; 12 men) exhibited reduced LV ejection fraction (median LVEF = 32 %) and an increased LV mass of 210 g. Sinus rhythm was present in 19 patients, whereas one patient was in atrial fibrillation. Baseline heart rate was 77.5 beats per minute. Left bundle branch block was detected in five cases. In a subgroup of patients receiving β-blocker therapy (n = 17), LV mass was reduced from 226 [178; 306] g to 220 [169; 254] g (p = 0.007) at 13 ± 6 months follow-up. By contrast, a subgroup of three patients that were not treated with an anti-β-adrenergic agent showed LV mass increase from 180 [169; 197] g to 199 [185; 213] g (p = 0.023). LVEF and electrocardiographic parameters were not significantly modulated during chronic β-blocker treatment. There was no sustained symptomatic ventricular tachyarrhythmia, thromboembolic event or death in either group. In conclusion, this study reveals reduction of LV mass among LVNC patients during β-blocker therapy. Effects of β-blocker treatment in LVNC require validation in prospective controlled studies.

Transthyretin-related amyloidosis (ATTR) is characterized by a wide heterogeneity of genotypes and predominantly neurological and cardiac phenotypes. This study aims to characterize a cohort of patients with the rare transthyretin (TTR) Val20Ile (p.TTRVal40Ile) variant.This study comprises a single-center cohort of 59 individuals subsequently evaluated for TTRVal20Ile variant due to clinical (n = 13) or predictive (n = 46) reasons. All patients were mainly related to Wagshurst, a small village in the South of Germany. Clinical assessment was performed by neurological evaluation, echocardiography, electrocardiography, cardiac biomarkers, cardiac MRI (n = 13), and (99m)Tc-DPD scintigraphy (n = 16). The rare TTRVal20Ile variant was found in 41 patients; evidence of cardiac amyloidosis was present in 22 patients. Evidence of pulmonary involvement was obtained by (99m)Tc-DPD scintigraphy in eight patients. No further organ involvement was observed in any of the patients carrying TTRVal20Ile variant. Correlation of inter-ventricular septum thickness as well as decrease of left ventricular longitudinal contractility with age was observed. Moreover, thickness of inter-ventricular septum correlated with NT-proBNP plasma levels and decrease in mitral annular plane systolic excursion. Cardiac manifestation started during the early sixth life decade indicated by higher left ventricular septum thickness and NT-proBNP plasma levels as compared to patients in fifth decade of life. All patients of the seventh and eighth life decade (n = 10) presented with cardiac amyloidosis. During median follow-up of 26 (0-108) months, eight patients underwent heart transplantation with 1-year mortality rate of 25%.This large cohort of individuals carrying the TTRVal20Ile mutation reveals a predominantly cardiac phenotype with high penetrance and late onset of symptoms. Cardiac manifestation progressed to end-stage heart failure within a few years, finally requiring heart transplantation with promising long-term survival rates.

Andreas O Doesch,1 Susanne Mueller,1 Christian Erbel,1 Christian A Gleissner,1 Lutz Frankenstein,1 Stefan Hardt,1 Arjang Ruhparwar,2 Philipp Ehlermann,1 Thomas Dengler,3 Hugo A Katus1 1Department of Cardiology, 2Department of Cardiovascular Surgery, University of Heidelberg, Heidelberg, 3SLK Plattenwald Hospital, Bad Friedrichshall, Germany Background: Due to graft denervation, sinus tachycardia is a common problem after heart transplantation, underlining the importance of heart rate control without peripheral effects. However, long-term data regarding the effects of ivabradine, a novel If channel antagonist, are limited in patients after heart transplantation. Methods: In this follow-up analysis, the resting heart rate, left ventricular mass indexed to body surface area (LVMI), tolerability, and safety of ivabradine therapy were evaluated at baseline and after 36 months in 30 heart transplant recipients with symptomatic sinus tachycardia versus a matched control group. Results: During the study period, ivabradine medication was stopped in three patients (10% of total). Further analysis was based on 27 patients with 36 months of drug intake. The mean patient age was 53.3±11.3 years and mean time after heart transplantation was 5.0±4.8 years. After 36 months, the mean ivabradine dose was 12.0±3.4 mg/day. Resting heart rate was reduced from 91.0±10.7 beats per minute before initiation of ivabradine therapy (ie, baseline) to 81.2±9.8 beats per minute at follow-up (P=0.0006). After 36 months of ivabradine therapy, a statistically significant reduction of LVMI was observed (104.3±22.7 g at baseline versus 93.4±18.4 g at follow-up, P=0.002). Hematologic, renal, and liver function parameters remained stable during ivabradine therapy. Except for a lower mycophenolate mofetil dose at follow-up (P=0.02), no statistically significant changes in immunosuppressive drug dosage or blood levels were detected. No phosphenes were observed during 36 months of ivabradine intake despite active inquiry. Conclusion: In line with previously published 12-month data, heart rate reduction with ivabradine remained effective and safe in chronic stable patients after heart transplantation, and also during 36-month long-term follow-up. Further, a significant reduction of LVMI was observed only during ivabradine therapy. Therefore, ivabradine may have a sustained long-term beneficial effect with regard to left ventricular remodeling in heart transplant patients. Keywords: heart transplantation, heart rate control, ivabradine, left ventricular mass

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

Background The clinical effectiveness of fecal microbiota transplant (FMT) for the treatment of recurrent Clostridium difficile infections (rCDI) has been demonstrated in randomized controlled trials. To assess the current status of FMT in Germany with respect to active centers, local standards, clinical effectiveness and safety, the MicroTrans Registry (NCT02681068) was established. Methods In a long-term retrospective multicenter observational study by the German Clinical Microbiome Study Group (GCMSG), primary and secondary cure on day 30 and 90, as well as occurrence of treatment-related adverse events were assessed. In addition to patient demographic data, we provide an overview of the FMT procedures and techniques used at different centers. Results Overall, 133 eligible patients from 33 centers were included, of which 64.7% were female (n = 86). The mean age was 75 years (interquartile range: 59.5-81.5). Administration via the duodenal route (n = 59; 44.4%) was the most frequently applied option, followed by colonic (n = 55; 41.1%), capsule (n = 13; 9.8%), and gastric administration (n = 4; 3.0%). Primary cure on day 30 and 90 was achieved in 84.2% (n = 101/120) and 78.3% (n = 72/92) of patients, respectively. Including re-treatment, secondary response was achieved in 87.5% (d 30; n = 105/120) and 85.9% (d 90; n = 79/92), respectively. Treatment- elated adverse events were documented in 16 patients (12.0%). Conclusion FMT is a safe and effective treatment option for rCDI. However, FMT is currently available only in few centers in Germany, and treatment options vary from one center to another.

Dilated cardiomyopathy (DCM) is a frequent form among the cardiomyopathies and displays a very heterogeneous etiology. It is a familial disease in about one-third of DCM cases [8, 14, 16]. More than 20 DCM candidate genes were already identified [2, 4], but the genetic defects in the large majority of familial cases are still unknown. LMNA is among the most common genes affected in familial DCM and is coding for lamin A/C, which is a ubiquitous component of the nuclear skeleton and involved in the regulation of gene expression. However, there are many other non-cardiac diseases like Emery-Dreifuss muscular dystrophy (EDMD2; OMIM 181350), Limb-girdle muscular dystrophy type 1B (LGMD1B; OMIM 159001), Dunnigantype familial partial lipodystrophy (OMIM 151660), Charcot-Marie-Tooth disease (CMT2B1; OMIM 605588), Hutchinson-Gilford progeria syndrome (HGPS; OMIM 176670) and restrictive dermopathy (OMIM 275210), which can result from defects in this gene and are summarized under the term laminopathies [5]. DCM caused by LMNA mutations is attributed to a characteristic phenotype showing atrial fibrillation, skeletal muscle involvement, cardiac conduction defects and a high incidence of sudden death [3, 9, 20, 25, 26]. Due to these complications, DCM patients with LMNA mutations are reported to have a worse prognosis compared to other DCM patients [23, 28] and a nearly complete disease penetrance with disease expression between 20 and 60 years of age [19]. It is estimated that up to 5% of all DCM cases are caused by LMNA mutations [24]. Here we report about a family with a gene mutation in the lamin A/C gene (LMNA) with the incidence of sudden cardiac death even before the manifestation of dilated cardiomyopathy. A 32-year-old woman presented at the outpatient department after a sudden loss of consciousness for seconds, while she was driving a car on a motorway. There were no prodromi before this event and no diseases in the medical history. However, she reported about a premature death of her father at the age of 42 years, which was interpreted as related to myocardial infarction. There were no abnormal clinical findings and the ECG was interpreted as normal. Echocardiography revealed regular findings, with the exception, that in the apex of the right ventricle a small sacculation was suspected. In regard to the clinical event and family history further thorough examination was initiated (Table 1)

Modified release tacrolimus (TAC) is a new, once-daily oral formulation of the established immunosuppressive agent TAC. Simplification of regimen has been associated with better adherence. This study evaluated patient adherence, as well as safety and efficacy among chronic stable heart transplantation (HT) patients switched from a conventional twice daily calcineurin inhibitor-based regimen (TAC or cyclosporine A [CsA]) to (once daily) modified release TAC.We switched 54 chronic stable patients (41 males and 13 females) from twice daily dosing with conventional TAC or CsA to once daily dosing with modified release TAC. Self-reported adherence was assessed at baseline and at 4 months after the switch using the Basel Assessment of Adherence with Immunosuppressive Medication Scale [BAASIS]), a 4-item validated questionnaire including also a Visual Analogue Scale (VAS). Nonadherence was defined as any self-reported nonadherence on any item.Modified release TAC was discontinued in 4 patients because of diarrhea (n = 1) or gastrointestinal discomfort (n = 3) leaving 50 evaluable patients. Overall nonadherence at baseline for any of the 4 items was 74% versus 38% after 4 months (P = .0001). Thereafter, adherence improved in 28 patients (56.0%), was unchanged in 18 (36.0%), and decreased in 4 subjects (8.0%). The VAS score improved from 82.3% ± 2.6% to 97.5% ± 4.8% (P.0001). No significant changes were observed after 4 months regarding hematologic, renal, or liver function parameters (all P = NS).Therapeutic regimens for transplant recipients are often complex, contributing to a high incidence of medication nonadherence. This study in chronic, stable, heart transplantation patients demonstrated a significant improvement in patient adherence after a switch to modified release TAC, which was generally well tolerated.

The objectives of the present study were to evaluate the incidence of malignancies and to describe the effects of immunosuppression on survival and recurrence of malignancies after heart transplantation (HTX). Data were analyzed in 211 cardiac allograft recipients, in whom HTX was performed between 1989 and 2005. All of these patients survived for more than 2 years after HTX and received induction therapy with antithymocyte globulin (RATG) guided by T-cell monitoring since 1994. An immunosuppressive regimen consisting of cyclosporine A (CsA) combined with azathioprine was followed by CsA and mycophenolate mofetil (MMF) in 2001; mammalian target of rapamycin (mTOR) inhibitors (everolimus/sirolimus) were used since 2003. Mean patient age at HTX was 51.4 ± 10.5 years; mean follow-up time after HTX 9.2 ± 4.7 years. Overall incidence of neoplasias was 30.8%. Individual risk factors associated with a higher risk of malignancy after HTX were higher age at transplantation (P = .003), male gender (P = .005) and ischemic cardiomyopathy before HTX (P = .04). Administration of azathioprine (P < .0001) or a calcineurin inhibitor (CNI) (P = .02) for more than 1 year was associated with development of malignancy, whereas significantly fewer malignancies were noticed in patients receiving an mTOR-inhibitor (P < .0001). Kaplan-Meier analysis demonstrated a strong statistical trend toward an improved survival in patients with a noncutaneous neoplasia switched to a CNI-free protocol (P = .05). This study demonstrated the impact of a variety of individual risk factors and immunosuppressive drugs on development of malignancy after HTX. Markedly fewer patients with noncutaneous malignancies died after switch to a CNI-free regimen, not quite reaching statistical significance by Kaplan-Meier analysis, however.

Z-disks, the mechanical integration sites of heart and skeletal muscle cells, link anchorage of myofilaments to force reception and processing. The key molecules that enable the Z-disk to persistently withstand the extreme mechanical forces during muscle contraction have not yet been identified. Here we isolated nexilin (encoded by NEXN) as a novel Z-disk protein. Loss of nexilin in zebrafish led to perturbed Z-disk stability and heart failure. To evaluate the role of nexilin in human heart failure, we performed a genetic association study on individuals with dilated cardiomyopathy and found several mutations in NEXN associated with the disease. Nexilin mutation carriers showed the same cardiac Z-disk pathology as observed in nexilin-deficient zebrafish. Expression in zebrafish of nexilin proteins encoded by NEXN mutant alleles induced Z-disk damage and heart failure, demonstrating a dominant-negative effect and confirming the disease-causing nature of these mutations. Increasing mechanical strain aggravated Z-disk damage in nexilin-deficient skeletal muscle, implying a unique role of nexilin in protecting Z-disks from mechanical trauma.

Peripartum cardiomyopathy (PPCM) is a major cause of pregnancy-related maternal heart failure that develops towards the end of pregnancy or in the months following delivery. In small retrospective case series, autoimmune responses in the pathogenesis of PPCM have been proposed upon identification of autoantibodies (AABs) to cardiac antigens. However, their clinical and prognostic relevance still remain unclear. In this study, we evaluated the presence of circulating AABs against cardiac sarcomeric myosin (MHC) and troponin I (TnI) in the sera of PPCM patients and in relation to clinical presentation. In this case-control study, 70 patients diagnosed with PPCM and 50 pregnancy-matched healthy women with normal cardiac function were enrolled. Clinical assessment, echocardiography and blood tests were performed at baseline and at 6 ± 2 months follow-up. The presence of serum AABs against MHC (anti-MHC) and TnI (anti-TnI) was determined with a custom-made enzyme-linked immunosorbent assay (ELISA). The seropositivity for these AABs was correlated with the severity of LV dysfunction and the occurrence of pericardial effusion indicative of perimyocardial inflammation at baseline. Potential impact of these AABs on disease progression was evaluated with regard to functional (left ventricular ejection fraction) and clinical improvement at follow-up. Either anti-MHC or anti-TnI or both AABs were detected in the serum of 46 % of PPCM patients and in 8 % of healthy controls. In PPCM the presence of either one of these AABs was associated with significantly lower baseline LVEF and lower rate of full cardiac recovery at follow-up. Patients who were seropositive for anti-TnI AABs showed more frequently pericardial effusion indicative of a more pronounced immune response of the peri-/myocardium in these patients. Further studies are required to clarify cellular and molecular circuits leading to elevated levels of AABs and their pathophysiological relevance for disease initiation and progression in PPCM.

Aims Peripartum cardiomyopathy (PPCM) is a major cause of acute heart failure in the peripartum period and considered potentially life threatening. While many aspects of its clinical profiles have been frequently reported, functional analysis, in particular of the right ventricle, and tissue characterization by cardiovascular magnetic resonance (CMR) imaging have been only sporadically described. The aim of the present study was to analyse pathological alterations and their prognostic relevance found in CMR imaging of patients newly diagnosed with PPCM. Methods and results In this multicenter study 34 patients with confirmed PPCM underwent CMR imaging at the time of diagnosis and at 5 ± 1 months follow-up. Cine imaging of PPCM patients showed moderate to severe reduction of systolic left ventricular (LV) function (mean LVEF: 29.7 ± 12.8%). In 35% of the patients right ventricular (RV) systolic function was also reduced with a mean RVEF of 42.9 ± 13.9%. Dilatation of the LV was observed in 91% (mean LV-EDV/BSA 128.5 ± 32.1 mL/m2), and dilatation of the RV was present in 24% (mean RV-EDV/BSA 87.4 ± 18.5 mL/m2) of the patients. Focal non-ischemic late gadolinium enhancement (LGE) was visible in 71%, and regional wall motion abnormalities were evident in 88% of the patients. LGE and wall motion abnormalities were predominantly located in the anteroseptal and basal to midventricular segments. RV dysfunction at baseline was associated with reduced probability of full cardiac recovery at 5 ± 1 months follow-up. Conclusions Besides LV systolic dysfunction, RV dysfunction and dilatation are observed in about one third of PPCM patients at the time of diagnosis. RV dysfunction is associated with unfavourable outcome. A distinct pattern of LV wall motion abnormalities and myocardial scar is evident in most PPCM patients. The present study may help to establish a set of CMR criteria suitable for diagnosis in patients with suspected PPCM and may add further knowledge to the pathology of the disease.

We would like to thank the authors for their insightful review of Clostridium difficile infection (CDI) (1) and to add the following information to complement the section about stool transplantation: At the SRH Kurpfalz Hospital, 22 stool transplantations (allogenic intestinal recolonizations) have been performed to treat CDI to date. In all of these cases, donor feces was infused exclusively into the duodenum using an endoscope, in line with the method described by van Nood (2). The clinical response rate was comparable with published data; 16 of 17 patients were relapse-free during the 3-month follow-up period. Due to the pooling of the data on gastric and duodenal administration, no inferiority of the antegrade versus the retrograde route of administration can be derived from Table 3. In contrast to the information provided in the table, the 18 patients of Aas et al. (3) received the fecal suspension by gastric delivery. Thus, in 3 of 6 studies (45 of 101 patients) gastric application of the fecal suspension was performed, involving the risk of aspiration pneumonia by fecal bacteria, besides the inactivation of the donor microbiota by gastric acid. Another significant difference in the methods used is the preceding bowel lavage which, among the studies with antegrade application, was only used in the study by van Nood which was also the only randomized controlled trial (2). Colonoscopic application is more taxing for the patient and associated with the risk of perforation of the inflamed colon. Provided the patients receive sedation with propofol, the acceptance is excellent. The passage of the donor microbiota through the small intestine does not represent an undesirable contamination but is rather seen as favorable, as it accelerates the reconstitution of the resident microbiota. Thus, we consider duodenal application after peroral bowl lavage as described by van Nood as the reference method until other data from randomized trials have become available.

Rasmus Rivinius,1 Matthias Helmschrott,1 Arjang Ruhparwar,2 Bastian Schmack,2 Berthold Klein,2 Christian Erbel,1 Christian A Gleissner,1 Mohammadreza Akhavanpoor,1 Lutz Frankenstein,1 Fabrice F Darche,1 Dierk Thomas,1 Philipp Ehlermann,1 Tom Bruckner,3 Hugo A Katus,1 Andreas O Doesch11Department of Cardiology, Angiology and Pneumology, 2Department of Cardiac Surgery, 3Institute for Medical Biometry and Informatics, University of Heidelberg, Heidelberg, GermanyObjective: The aim of this study was to analyze the distribution of malignancies in patients after heart transplantation (HTX) and to evaluate the risk factors including immunosuppressive therapy with regard to the development of malignancies and survival. Special emphasis was placed on the effects of a mammalian target of rapamycin (mTOR) containing immunosuppressive regimen.Methods: A total of 381 patients (age ≥18 years) receiving HTX were included in the present analysis. All patients were followed-up at the University of Heidelberg Heart Center, Heidelberg, Germany. Data were retrieved from the Heidelberg Registry for Heart Transplantation being collected between 1989 and 2014. According to center standard, all patients received induction therapy with anti-thymocyte globulin guided by T-cell monitoring since 1994. The initial immunosuppressive regimen consisting of cyclosporine A (CsA) and azathioprine (AZA) was replaced by CsA and mycophenolate mofetil (MMF) in 2001 and by tacrolimus (TAC) and MMF in 2006. Additionally, mTOR inhibitors (everolimus/sirolimus) were applied since 2003.Results: Mean recipient age at HTX was 51.2±10.5years and the mean follow-up period after HTX was 9.7±5.9years. During follow-up, 130 patients developed a neoplasm (34.1% of total). Subgroup analysis revealed 58 patients with cutaneous malignancy only (15.2%), 56 patients with noncutaneous malignancy only (14.7%), and 16 patients with both cutaneous and noncutaneous malignancy (4.2%). Statistically significant risk factors associated with an increased risk of malignancy after HTX were older age (P1 treated rejection episode (TRE) in the first year after HTX (P=0.0091). Administration of CsA (P=0.0195), AZA (P=0.0008), or steroids (P=0.0018) for >1 year after HTX was associated with increased development of malignancy, whereas administration of MMF (P

Anemia after heart transplantation is common; however, there are scant data on etiology and treatment. This study evaluates type of anemia and the effects of erythropoietin therapy.In 37 anemic heart transplant recipients (31 male/59.1+/-10.3 years/hemoglobin12.0 g/dl), complete anemia work-up was performed including erythropoietin determination. For three months, 12 anemic patients with renal failure (9 male/64.1+/-13.6 years) were treated with 1-3x4000 IU of epoietin beta/week; treatment endpoints were hemoglobin levels and quality of life as determined by questionnaire.In 31 patients no other cause of anemia than renal insufficiency (mean creatinine 1.9+/-0.9 mg/dl, mean calculated GFR 50.8+/-21.5 ml/min, no hemodialysis) was found; in 93.5% of these patients with renal insufficiency, measured erythropoietin levels were markedly lower than predicted [Beguin Y, Clemons GK, Pootrakul P, Fillet G. Quantitative assessment of erythropoiesis and functional classification of anemia based on measurements of serum transferrin receptor and erythropoietin. Blood 1993; 81(4):1067-1076.]. There was an inverse correlation of hemoglobin levels with serum creatinine/creatinine clearance and a strong trend for inverse correlation of erythropoietin levels. All 12 patients treated with erythropoietin showed a significant increase in hemoglobin levels after three months returning to pre-treatment values within 3 months of cessation of therapy (before study 10.8+/-1.1 g/dl, end of study 14.1+/-1.7 g/dl, three months after end of study 11.6+/-2.1 g/dl; p0.005). Quality of life was significantly improved in eight patients (75%).Anemia after heart transplantation is associated with moderate renal failure and low erythropoietin levels in most patients. Erythropoietin therapy resulted in increased hemoglobin levels in all and improved quality of life in 75% of patients. Erythropoietin may be a superior marker of functional renal impairment after heart transplantation; its therapeutic substitution allows effective anemia management and improves quality of life.

Systemic embolism is a frequent cause of stroke. At the beginning of the last decade by introduction of transesophageal echocardiography and other imaging techniques atheromatosis of the aortic arch has been recognized as an important source of embolism. Formerly in the pre-TEE era, this entity was included into cryptogenic strokes. Aortic atheromas are found in about one quarter of patients presenting with embolic events. The severity of atherosclerosis graded by TEE correlates with the risk for future embolism, especially if mobile lesions or superimposed thrombi are present. Independent of plaque extension, patients with unstable plaques characterized by echo-lucency, inhomogenity, lacking of calcifications, ulceration, mobile parts and concomitant spontaneous echo contrast within the aorta have a higher risk for embolic events. However, the diagnosis of aortic atheromatosis is mostly established if an embolic event has already occurred. Therefore, it is important to identify patients at risk, especially before they undergo interventions with manipulation at the aorta like coronary bypass surgery. Risk factors are age above 70, diabetes mellitus, hyperlipidemia, arterial hypertension, aortic calcifications on standard chest X-ray, elevated serum levels of C-reactive protein, other inflammatory markers, and an activated coagulation. Randomized studies for treatment of patients with severe aortic atheromatosis are not yet existing. Warfarin has been shown to prevent stroke in patients with mobile atheromas and superimposed thrombi, but there are case reports about aggravation of cholesterol embolism under warfarin treatment. It is concluded from other atherosclerotic manifestations that plaque stabilizing treatment with statins and ACE inhibitors is also beneficial.

S100A1, a Ca2+-sensing protein of the EF-hand family, is most highly expressed in myocardial tissue, and cardiac S100A1 overexpression in vitro has been shown to enhance myocyte contractile properties. To study the physiological consequences of S100A1 in vivo, transgenic mice were developed with cardiac-restricted overexpression of S100A1. Characterization of two independent transgenic mouse lines with approximately 4-fold overexpression of S100A1 in the myocardium revealed a marked augmentation of in vivo basal cardiac function that remained elevated after beta-adrenergic receptor stimulation. Contractile function and Ca2+ handling properties were increased in ventricular cardiomyocytes isolated from S100A1 transgenic mice. Enhanced cellular Ca2+ cycling by S100A1 was associated both with increased sarcoplasmic reticulum Ca2+ content and enhanced sarcoplasmic reticulum Ca2+-induced Ca2+ release, and S100A1 was shown to associate with the cardiac ryanodine receptor. No alterations in beta-adrenergic signal transduction or major cardiac Ca2+-cycling proteins occurred, and there were no signs of hypertrophy with chronic cardiac S100A1 overexpression. Our findings suggest that S100A1 plays an important in vivo role in the regulation of cardiac function perhaps through interacting with the ryanodine receptor. Because S100A1 protein expression is down-regulated in heart failure, increasing S100A1 expression in the heart may represent a novel means to augment contractility.

Aims To investigate the prognostic impact of left-ventricular (LV) cardiac magnetic resonance (CMR) deformation imaging in patients with non-ischaemic dilated cardiomyopathy (DCM) compared with late-gadolinium enhancement (LGE) quantification and LV ejection fraction (EF). Methods and results A total of 210 subjects with DCM were examined prospectively with standard CMR including measurement of LGE for quantification of myocardial fibrosis and feature tracking strain imaging for assessment of LV deformation. The predefined primary endpoint, a combination of cardiac death, heart transplantation, and aborted sudden cardiac death, occurred in 26 subjects during the median follow-up period of 5.3 years. LV radial, circumferential, and longitudinal strains were significantly associated with outcome. Using separate multivariate analysis models, global longitudinal strain (average of peak negative strain values) and mean longitudinal strain (negative peak of the mean curve of all segments) were independent prognostic parameters surpassing the value of global and mean LV radial and circumferential strain, as well as NT-proBNP, EF, and LGE mass. A global longitudinal strain greater than −12.5% predicted outcome even in patients with EF < 35% ( P < 0.01) and in those with presence of LGE ( P < 0.001). Mean longitudinal strain was further investigated using a clinical model with predefined cut-offs (EF < 35%, presence of LGE, NYHA class, mean longitudinal strain greater than −10%). Mean longitudinal strain exhibited an independent prognostic value surpassing that provided by NYHA, EF, and LGE (HR = 5.4, P < 0.01). Conclusion LV longitudinal strain assessed with CMR is an independent predictor of survival in DCM and offers incremental information for risk stratification beyond clinical parameters, biomarker, and standard CMR.

We performed a prospective multi-center study to assess gender-specific differences in the predictive value of the measured level of NT-proBNP and the calculated Heart Failure Survival Score (HFSS). Baseline characteristics and follow-up data up to 5 years from 2,019 men and 530 women diagnosed with chronic heart failure (CHF) due to ischemic heart disease or dilated cardiomyopathy were prospectively compared. Death from any cause constituted the endpoint of the study. NT-proBNP was measured and HFSS calculated according to standard methods. Survival of men and women according to level of NT-proBNP and HFSS was analyzed in logistic regression models. Median NT-proBNP level in men was 1,394 ng/l (IQR 516–3,406 ng/l) and 1,168 ng/l (IQR 444–2,830 ng/l) in women (p = n.s.). Median HFSS value was 8.4 (IQR 7.7–9.1) and 8.5 (8.0–9.1) in men and women, respectively. NT-proBNP levels and HFSS score correlated well with survival rates in both genders (p for interaction = 0.22 for NT-proBNP and 0.93 for HFSS). The all-cause death rates were similar in men and women. Despite a number of gender-specific differences in CHF and the general predominance of men measured levels of NT-proBNP and HFSS score can be utilized for risk stratification with similar informative value in men and women.

S100A1, a Ca 2+ binding protein of the EF-hand type, is preferentially expressed in myocardial tissue and has been found to colocalize with the sarcoplasmic reticulum (SR) and the contractile filaments in cardiac tissue. Because S100A1 is known to modulate SR Ca 2+ handling in skeletal muscle, we sought to investigate the specific role of S100A1 in the regulation of myocardial contractility. To address this issue, we investigated contractile properties of adult cardiomyocytes as well as of engineered heart tissue after S100A1 adenoviral gene transfer. S100A1 gene transfer resulted in a significant increase of unloaded shortening and isometric contraction in isolated cardiomyocytes and engineered heart tissues, respectively. Analysis of intracellular Ca 2+ cycling in S100A1-overexpressing cardiomyocytes revealed a significant increase in cytosolic Ca 2+ transients, whereas in functional studies on saponin-permeabilized adult cardiomyocytes, the addition of S100A1 protein significantly enhanced SR Ca 2+ uptake. Moreover, in Triton-skinned ventricular trabeculae, S100A1 protein significantly decreased myofibrillar Ca 2+ sensitivity ([EC 50% ]) and Ca 2+ cooperativity, whereas maximal isometric force remained unchanged. Our data suggest that S100A1 effects are cAMP independent because cellular cAMP levels and protein kinase A-dependent phosphorylation of phospholamban were not altered, and carbachol failed to suppress S100A1 actions. These results show that S100A1 overexpression enhances cardiac contractile performance and establish the concept of S100A1 as a regulator of myocardial contractility. S100A1 thus improves cardiac contractile performance both by regulating SR Ca 2+ handling and myofibrillar Ca 2+ responsiveness.

We determined the utility of single-point measurements of circulating cardiac troponin T (cTnT) for the noninvasive estimation of infarct size in 16 beagle dogs after left anterior descending artery (LAD) ligation. Pathoanatomical infarct sizes were determined by the triphenyltetrazolium chloride method and correlated with serum concentration changes of cTnT. Peak cTnT levels (14.10 ± 4.71 μg/l) were reached after 110 ± 21 h. A significant correlation was found between peak cTnT levels (p = 0.0001, r = 0.83) or cumulative cTnT levels and relative infarct size (p = 0.0010, r = 0.72). A single cTnT measurement 96 h after LAD ligation was equally predictive of infarct size (p = 0.0010, r = 0.74) as peak or cumulative cTnT levels derived from serial sampling. cTnT levels at 96 h may thus be useful for practical and cost-effective estimation of infarct size.

Ibrahim Gueler,1 Susanne Mueller,1 Matthias Helmschrott,1 Christian U Oeing,1 Christian Erbel,1 Lutz Frankenstein,1 Christian Gleißner,1 Arjang Ruhparwar,2 Philipp Ehlermann,1 Thomas J Dengler,3 Hugo A Katus,1 Andreas O Doesch1 1Department of Cardiology, University of Heidelberg, Heidelberg, 2Department of Cardiac Surgery, University of Heidelberg, Heidelberg, 3Department of Cardiology, SLK-Kliniken Heilbronn, Bad Friedrichshall, Germany Background: Type 2 Diabetes mellitus (T2DM) is a common comorbidity in patients after heart transplantation (HTx) and is associated with adverse long-term outcomes. Methods: The retrospective study reported here analyzed the effects of vildagliptin therapy in stable patients post-HTx with T2DM and compared these with control patients for matched-pairs analysis. A total of 30 stable patients post-HTx with T2DM were included in the study. Fifteen patients (mean age 58.6 ± 6.0 years, mean time post-HTx 4.9 ± 5.3 years, twelve male and three female) were included in the vildagliptin group (VG) and 15 patients were included in the control group (CG) (mean age 61.2 ± 8.3 years, mean time post-HTx 7.2 ± 6.6 years, all male). Results: Mean glycated hemoglobin (HbA1c) in the VG was 7.4% ± 0.7% before versus 6.8% ± 0.8% after 8 months of vildagliptin therapy (P = 0.002 vs baseline). In the CG, HbA1c was 7.0% ± 0.7% versus 7.3% ± 1.2% at follow-up (P = 0.21). Additionally, there was a significant reduction in mean blood glucose in the VG, from 165.0 ± 18.8 mg/dL to 147.9 ± 22.7 mg/dL (P = 0.002 vs baseline), whereas mean blood glucose increased slightly in the CG from 154.7 ± 19.7 mg/dL to 162.6 ± 35.0 mg/dL (P = 0.21). No statistically significant changes in body weight (from 83.3 ± 10.8 kg to 82.0 ± 10.9 kg, P = 0.20), total cholesterol (1.5%, P = 0.68), or triglyceride levels (8.0%, P = 0.65) were seen in the VG. No significant changes in immunosuppressive drug levels or dosages were observed in either group. Conclusion: Vildagliptin therapy significantly reduced HbA1c and mean blood glucose levels in post-HTx patients in this study with T2DM and did not have any negative effects on lipid profile or body weight. Thus, vildagliptin therapy presented an interesting therapeutic approach for this selected patient cohort. Keywords: immunosuppression, glycated hemoglobin, mean blood glucose

Background Treatment options in patients with amyloidotic transthyretin (ATTR) cardiomyopathy are limited. Epigallocatechin-3-gallate (EGCG), the most abundant catechin in green tea (GT), inhibits fibril formation from several amyloidogenic proteins in vitro. Thus, it might also halt progression of TTR amyloidosis. This is a single-center observational report on the effects of GT consumption in patients with ATTR cardiomopathy. Methods 19 patients with ATTR cardiomyopathy were evaluated by standard blood tests, echocardiography, and cardiac MRI (n = 9) before and after consumption of GT and/or green tea extracts (GTE) for 12 months. Results Five patients were not followed up for reasons of death (n = 2), discontinuation of GT/GTE consumption (n = 2), and heart transplantation (n = 1). After 12 months no increase of left ventricular (LV) wall thickness and LV myocardial mass was observed by echocardiography. In the subgroup of patients evaluated by cardiac MRI a mean decrease of LV myocardial mass (−12.5 %) was detected in all patients. This was accompanied by an increase of mean mitral annular systolic velocity of 9 % in all 14 patients. Total cholesterol (191.9 ± 8.9 vs. 172.7 ± 9.4 mg/dL; p

The purpose of our study was to investigate whether the quantification of myocardial blush grade (MBG) during surveillance coronary angiography can predict long-term outcome after heart transplantation (HT). In 105 HT recipients who underwent cardiac catheterization, cardiac allograft vasculopathy (CAV) was assessed visually using the ISHLT grading scale (prospective cohort study). MBG was quantified by dividing the plateau of contrast agent gray-level intensity (G(max)) by the time-to-peak intensity (T(max)). In a subgroup (n = 72), myocardial perfusion index by cardiac magnetic resonance imaging (CMR) was assessed. During a mean follow-up duration of 2.7 (standard deviation [SD] 1.0) years, 26 patients experienced cardiac events, including 7 with cardiac death and 19 who underwent coronary revascularization. G(max)/T(max) was related to CAV by ISHLT criteria and to subsequent cardiac events. By univariate analysis, patient age, organ age, CAV, MBG and myocardial perfusion index by CMR were all predictive for cardiac events. Multivariable analysis demonstrated that G(max)/T(max) provided the most robust prediction of cardiac death (hazard ratio [HR] = 0.2, 95% confidence interval [CI] = 0.06-0.64, p < 0.01) and cardiac events (HR = 0.52, 95% CI = 0.32-0.84, p < 0.01), beyond clinical parameters and the presence of CAV. G(max)/T(max) is a valuable surrogate parameter of microvascular integrity, which is associated with cardiac death and revascularization procedures after HT.

Dilated cardiomyopathies (DCM) show remarkable variability in their age of onset, phenotypic presentation, and clinical course. Hence, disease mechanisms must exist that modify the occurrence and progression of DCM, either by genetic or epigenetic factors that may interact with environmental stimuli. In the present study, we examined genome-wide cardiac DNA methylation in patients with idiopathic DCM and controls. We detected methylation differences in pathways related to heart disease, but also in genes with yet unknown function in DCM or heart failure, namely Lymphocyte antigen 75 (LY75), Tyrosine kinase-type cell surface receptor HER3 (ERBB3), Homeobox B13 (HOXB13) and Adenosine receptor A2A (ADORA2A). Mass-spectrometric analysis and bisulphite-sequencing enabled confirmation of the observed DNA methylation changes in independent cohorts. Aberrant DNA methylation in DCM patients was associated with significant changes in LY75 and ADORA2A mRNA expression, but not in ERBB3 and HOXB13. In vivo studies of orthologous ly75 and adora2a in zebrafish demonstrate a functional role of these genes in adaptive or maladaptive pathways in heart failure.

To investigate determinants and temporal developments of treatment strategies, 5-year survival and heart transplantation rates between patients treated at secondary and tertiary hospitals. Baseline characteristics, treatment and follow-up data from 2,023 patients with chronic systolic heart failure due to ischaemic or dilated cardiomyopathy enrolled between 1995 and 2005 (996 patients treated at a secondary hospital vs. 1,027 patients treated at a tertiary hospital) were prospectively compared. Patients treated at the secondary hospital setting were twice as likely to have ischaemic cardiomyopathy compared to the tertiary hospital setting as the underlying cause of heart failure (59.7% vs. 33.0%, respectively) and were almost a decade older (mean age 65.2 vs. 56.7 years, respectively). The use of guideline-recommended therapy increased in both centres over time. In direct temporal comparison, both guideline-adherent pharmacological therapy and device therapy were implemented earlier at the tertiary hospital. Survival rates were significantly lower among patients treated at the secondary hospital (log-rank test P

We report two cases of young men in whom acute heart failure due to myocarditis was diagnosed. The patients had been transferred to the intensive care unit (ICU) with commencing symptoms of acute heart failure and consecutive multiorgan failure for further treatment and to evaluate the indication for implantation of a ventricular assist device or for high urgent orthotopic heart transplantation. In both patients, theIf-channel inhibitor ivabradine was administered off-label to provide selective heart rate reduction, and thus support hemodynamic stabilization. Though currently considered off-label use in patients suffering from severe hypotension and acute heart failure, the use of ivabradine may beneficially influence outcome by allowing optimization of the patient's heart rate concomitant to initial measures of clinical stabilization.

The role of serial NT-proBNP measurements in patients suffering from chronic systolic heart failure (CHF) who already receive individually optimized pharmacotherapy is still unresolved.NT-proBNP was assessed at baseline and at 6 months follow-up in 504 stable CHF patients treated with individually optimized pharmacotherapy. After assessment of clinical stability at 6 months, patients were followed up for at least 1 year. The combined primary endpoint was defined as death, hospitalization due to cardiac reasons or heart transplantation in 1-year follow-up. We stratified our patients according to two principles: first, a percent change of value (CV) between the first and second measurement of NT-proBNP and secondly, the transformed logarithm of NT-proBNP measured at 6 months.During the follow-up period of 1 year, 50 patients (9.9%) reached the combined primary endpoint. Stratification according to percentage CV was less accurate in predicting endpoint-free survival compared to a classification in categories of lnNT-proBNP measured at 6 months (ROC AUC = 0.615; 95% CI 0.525-0.70 vs. ROC AUC = 0.790; 95% CI 0.721-0.856, respectively). When entered into proportional hazard regression analysis, lnNT-proBNP measured at 6 months remained an independent predictor of the combined primary endpoint with an associated HR of 2.53 (95% CI 1.385-4.280).To date, this is the largest analysis of serial NT-proBNP measurements in patients with CHF receiving individually optimized medical therapy. These data suggest that a single NT-proBNP measurement after 6 months in stable clinical conditions may have higher predictive value than stratification of change in serial measurements.