The DZHK research platform: maximisation of scientific value by enabling access to health data and biological samples collected in cardiovascular clinical studies

The German Centre for Cardiovascular Research (DZHK) is one of the German Centres for Health Research and aims to conduct early and guideline-relevant studies to develop new therapies and diagnostics that impact the lives of people with cardiovascular disease. Therefore, DZHK members designed a collaboratively organised and integrated research platform connecting all sites and partners. The overarching objectives of the research platform are the standardisation of prospective data and biological sample collections among all studies and the development of a sustainable centrally standardised storage in compliance with general legal regulations and the FAIR principles. The main elements of the DZHK infrastructure are web-based and central units for data management, LIMS, IDMS, and transfer office, embedded in a framework consisting of the DZHK Use and Access Policy, and the Ethics and Data Protection Concept. This framework is characterised by a modular design allowing a high standardisation across all studies. For studies that require even tighter criteria additional quality levels are defined. In addition, the Public Open Data strategy is an important focus of DZHK. The DZHK operates as one legal entity holding all rights of data and biological sample usage, according to the DZHK Use and Access Policy. All DZHK studies collect a basic set of data and biosamples, accompanied by specific clinical and imaging data and biobanking. The DZHK infrastructure was constructed by scientists with the focus on the needs of scientists conducting clinical studies. Through this, the DZHK enables the interdisciplinary and multiple use of data and biological samples by scientists inside and outside the DZHK. So far, 27 DZHK studies recruited well over 11,200 participants suffering from major cardiovascular disorders such as myocardial infarction or heart failure. Currently, data and samples of five DZHK studies of the DZHK Heart Bank can be applied for

Splicing factor YBX1 mediates persistence of JAK2-mutated neoplasms

Janus kinases (JAKs) mediate responses to cytokines, hormones and growth factors in haematopoietic cells. The JAK gene JAK2 is frequently mutated in the ageing haematopoietic system and in haematopoietic cancers. JAK2 mutations constitutively activate downstream signalling and are drivers of myeloproliferative neoplasm (MPN). In clinical use, JAK inhibitors have mixed effects on the overall disease burden of JAK2-mutated clones, prompting us to investigate the mechanism underlying disease persistence. Here, by in-depth phosphoproteome profiling, we identify proteins involved in mRNA processing as targets of mutant JAK2. We found that inactivation of YBX1, a post-translationally modified target of JAK2, sensitizes cells that persist despite treatment with JAK inhibitors to apoptosis and results in RNA mis-splicing, enrichment for retained introns and disruption of the transcriptional control of extracellular signal-regulated kinase (ERK) signalling. In combination with pharmacological JAK inhibition, YBX1 inactivation induces apoptosis in JAK2-dependent mouse and primary human cells, causing regression of the malignant clones in vivo, and inducing molecular remission. This identifies and validates a cell-intrinsic mechanism whereby differential protein phosphorylation causes splicing-dependent alterations of JAK2-ERK signalling and the maintenance of JAK2(V617F) malignant clones. Therapeutic targeting of YBX1-dependent ERK signalling in combination with JAK2 inhibition could thus eradicate cells harbouring mutations in JAK2

Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function

BACKGROUND: Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function. METHODS: A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function. RESULTS: The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue. CONCLUSION: The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies. FUNDING: For detailed information per study, see Acknowledgments.This work was supported by a grant from the US National Heart, Lung, and Blood Institute (N01-HL-25195; R01HL 093328 to RSV), a MAIFOR grant from the University Medical Center Mainz, Germany (to PSW), the Center for Translational Vascular Biology (CTVB) of the Johannes Gutenberg-University of Mainz, and the Federal Ministry of Research and Education, Germany (BMBF 01EO1003 to PSW). This work was also supported by the research project Greifswald Approach to Individualized Medicine (GANI_MED). GANI_MED was funded by the Federal Ministry of Education and Research and the Ministry of Cultural Affairs of the Federal State of Mecklenburg, West Pomerania (contract 03IS2061A). We thank all study participants, and the colleagues and coworkers from all cohorts and sites who were involved in the generation of data or in the analysis. We especially thank Andrew Johnson (FHS) for generation of the gene annotation database used for analysis. We thank the German Center for Cardiovascular Research (DZHK e.V.) for supporting the analysis and publication of this project. RSV is a member of the Scientific Advisory Board of the DZHK. Data on CAD and MI were contributed by CARDIoGRAMplusC4D investigators. See Supplemental Acknowledgments for consortium details. PSW, JFF, AS, AT, TZ, RSV, and MD had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis

Heterogeneous Metabolic Response to Exercise Training in Heart Failure with Preserved Ejection Fraction

The prevalence of heart failure with preserved ejection fraction (HFpEF) is constantly increasing and no evidence-based pharmacological treatment option is available. While exercise training (ET) improves diastolic function, its metabolic mechanisms in HFpEF are unclear. We assessed the metabolic response to 12 weeks of ET in patients with HFpEF by performing a post hoc analysis of the EX-DHF-P trial (ISRCTN86879094). Plasma concentrations of 188 endogenous metabolites were measured in 44 ET and 20 usual care (UC) patients at baseline and 3-months follow-up. Metabolic differences between ET and UC from baseline to follow-up were compared and differential responses to ET were examined by random forest feature selection. ET prevented the increase of acetylornithine and carnitine as well as the decrease of three glycerophospholipids. After ET, two opposite metabolic response clusters were identified. Cluster belonging was associated with perceived well-being at baseline and changes in low-density lipoprotein but not with cardiorespiratory, ventilatory or echocardiographic parameters. These two ET-induced metabolic response patterns illustrate the heterogeneity of the HFpEF patient population. Our results suggest that other biological parameters might be helpful besides clinical variables to improve HFpEF patient stratification. Whether this approach improves response prediction regarding ET and other treatments should be explored

Effects of beta-blocker therapy on hs-CRP levels in elderly patients with ischemic and non-ischemic heart failure: Results from the CIBIS-ELD trail

C reactive protein (CRP) is a biomarker indicating systemic inflammation. Elevated levels of this biomarker are associated with increased rates of cardiovascular disease, including chronic heart failure (HF). High‐sensitivity CRP assays were developed in order to measure lower levels of CRP, down to 0.3mg/l (hs‐CRP). Up to now, very little is known about the effects of beta‐blocker titration on hs‐CRP levels in ischemic and non‐ischemic HF patients. Also, little is known if this effect differs between selective and unselective blockers. Purpose: This research explored the trajectories of hs‐CRP before and after beta‐blocker (carvedilol vs bisoprolol) titration in elderly HF patients depending on the type of beta‐blocker used and the etiology of the disease (ischemic vs non‐ischemic). Methods: We measured plasma levels of hs‐CRP and NT‐proBNP in 520 HF patients ≥ 65 years (72.06±5.24 years, 38%f, LVEF 41.8±13.8%; ischemic n=243; nonischemic n=277) of the Cardiac Insufficiency Bisoprolol Study in ELDerly (CIBIS‐ELD). In this trial, patients were randomized to bisoprolol vs. carvedilol and doses were uptitrated to the target or maximally tolerated dose. hs‐CRP and NT‐proBNP levels were assessed at baseline (BL) and at follow‐up (FU), after 12 weeks. Results: In patients with ischemic HF, hs‐CRP levels decreased in the bisoprolol group (BL=0.60±0.94 mg/ dl, n=166; FU=0.43±0.694mg/dl, n=131; p=0.010), and were without a change in the carvedilol group (BL=0.60±1.69mg/dl, n=181; FU=0.57±0.982mg/ dl, n=136; p=0.731). There was also no change of hs‐CRP levels in non‐ischemic HF patients in both groups (bisoprolol: BL=0.64±1.175 mg/dl, n=197; FU=0.470±0.81mg/dl, n=152, p=0.069; carvedilol: BL=0.45±0.78mg/dl, n=198; FU=0.41±0.701 mg/ dl, n=152, p=0.420). Plasma levels of NT‐proBNP decreased in ischemic patients treated with bisoprolol, (BL=1594±2146 pg/ml, n=169; FU=1468±2110pg/ ml, n=133, p=0.04), while changes in the carvedilol group were not significant (BL=1648±1991 pg/ml, n=188; FU=1567±2119pg/ml, n=135, p=0.556). In the non‐ischemic group NT‐pro levels did not change significantly in the carvedilol group, while there was an increase in non‐ischemic patients in the bisoprolol group (BL=1427±3113 pg/ml, n=208; FU=1533±5385 pg/ml, n=166, p=0.017). Conclusion: Results indicate that bisoprolol might be associated with a decrease of hs‐CRP and NT‐proBNP levels only in ischemic HF patients, while in nonischemic HF patients there was no change of hs‐CRP and an increase of NT‐proBNP levels. In carvedilol treated patients no significant changes were shown in neither group

Iron deficiency impacts diastolic function, aerobic exercise capacity, and patient phenotyping in heart failure with preserved ejection fraction : a subanalysis of the OptimEx-Clin Study

AIMS: Iron deficiency (ID) is linked to reduced aerobic exercise capacity and poor prognosis in patients with heart failure (HF) with reduced ejection fraction (HFrEF); however, data for HF with preserved ejection fraction (HFpEF) is scarce. We assessed the relationship between iron status and diastolic dysfunction as well as aerobic exercise capacity in HFpEF, and the contribution of iron status to patient phenotyping. METHODS AND RESULTS: Among 180 patients with HFpEF (66% women; median age, 71 years) recruited for the Optimizing Exercise Training in Prevention and Treatment of Diastolic HF (OptimEx-Clin) trial, baseline iron status, including iron, ferritin, and transferrin saturation, was analyzed (n = 169) in addition to exercise capacity (peak oxygen uptake [peak V̇O(2)]) and diastolic function (E/e′). ID was present in 60% of patients and was more common in women. In multivariable linear regression models, we found that diastolic function and peak V̇O(2) were independently related to iron parameters; however, these relationships were present only in patients with HFpEF and ID [E/e′ and iron: β−0.19 (95% confidence interval −0.32, −0.07), p = 0.003; E/e′ and transferrin saturation: β−0.16 (−0.28, −0.04), p = 0.011; peak V̇O(2) and iron: β 3.76 (1.08, 6.44), p = 0.007; peak V̇O(2) and transferrin saturation: β 3.58 (0.99, 6.16), p = 0.007]. Applying machine learning, patients were classified into three phenogroups. One phenogroup was predominantly characterized by the female sex and few HFpEF risk factors but a high prevalence of ID (86%, p < 0.001 vs. other phenogroups). When excluding ID from the phenotyping analysis, results were negatively influenced. CONCLUSION: Iron parameters are independently associated with impaired diastolic function and low aerobic capacity in patients with HFpEF and ID. Patient phenotyping in HFpEF is influenced by including ID. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier NCT02078947

Peak O2‐pulse predicts exercise training‐induced changes in peak V̇O2 in heart failure with preserved ejection fraction

Abstract Aims Exercise training (ET) has been consistently shown to increase peak oxygen consumption (V̇O2) in patients with heart failure with preserved ejection fraction (HFpEF); however, inter‐individual responses vary significantly. Because it is unlikely that ET‐induced improvements in peak V̇O2 are significantly mediated by an increase in peak heart rate (HR), we aimed to investigate whether baseline peak O2‐pulse (V̇O2 × HR−1, reflecting the product of stroke volume and arteriovenous oxygen difference), not baseline peak V̇O2, is inversely associated with the change in peak V̇O2 (adjusted by body weight) following ET versus guideline control (CON) in patients with HFpEF. Methods and results This was a secondary analysis of the OptimEx‐Clin (Optimizing Exercise Training in Prevention and Treatment of Diastolic Heart Failure, NCT02078947) trial, including all 158 patients with complete baseline and 3 month cardiopulmonary exercise testing measurements (106 ET, 52 CON). Change in peak V̇O2 (%) was analysed as a function of baseline peak V̇O2 and its determinants (absolute peak V̇O2, peak O2‐pulse, peak HR, weight, haemoglobin) using robust linear regression analyses. Mediating effects on change in peak V̇O2 through changes in peak O2‐pulse, peak HR and weight were analysed by a causal mediation analysis with multiple correlated mediators. Change in submaximal exercise tolerance (V̇O2 at the ventilatory threshold, VT1) was analysed as a secondary endpoint. Among 158 patients with HFpEF (66% female; mean age, 70 ± 8 years), changes in peak O2‐pulse explained approximately 72% of the difference in changes in peak V̇O2 between ET and CON [10.0% (95% CI, 4.1 to 15.9), P = 0.001]. There was a significant interaction between the groups for the influence of baseline peak O2‐pulse on change in peak V̇O2 (interaction P = 0.04). In the ET group, every 1 mL/beat higher baseline peak O2‐pulse was associated with a decreased mean change in peak V̇O2 of −1.45% (95% CI, −2.30 to −0.60, P = 0.001) compared with a mean change of −0.08% (95% CI, −1.11 to 0.96, P = 0.88) following CON. None of the other factors showed significant interactions with study groups for the change in peak V̇O2 (P > 0.05). Change in V̇O2 at VT1 was not associated with any of the investigated factors (P > 0.05). Conclusions In patients with HFpEF, the easily measurable peak O2‐pulse seems to be a good indicator of the potential for improving peak V̇O2 through exercise training. While changes in submaximal exercise tolerance were independent of baseline peak O2‐pulse, patients with high O2‐pulse may need to use additional therapies to significantly increase peak V̇O2