A network analysis to identify pathophysiological pathways distinguishing ischaemic from non-ischaemic heart failure

Aims Heart failure (HF) is frequently caused by an ischaemic event (e.g. myocardial infarction) but might also be caused by a primary disease of the myocardium (cardiomyopathy). In order to identify targeted therapies specific for either ischaemic or non‐ischaemic HF, it is important to better understand differences in underlying molecular mechanisms. Methods and results We performed a biological physical protein–protein interaction network analysis to identify pathophysiological pathways distinguishing ischaemic from non‐ischaemic HF. First, differentially expressed plasma protein biomarkers were identified in 1160 patients enrolled in the BIOSTAT‐CHF study, 715 of whom had ischaemic HF and 445 had non‐ischaemic HF. Second, we constructed an enriched physical protein–protein interaction network, followed by a pathway over‐representation analysis. Finally, we identified key network proteins. Data were validated in an independent HF cohort comprised of 765 ischaemic and 100 non‐ischaemic HF patients. We found 21/92 proteins to be up‐regulated and 2/92 down‐regulated in ischaemic relative to non‐ischaemic HF patients. An enriched network of 18 proteins that were specific for ischaemic heart disease yielded six pathways, which are related to inflammation, endothelial dysfunction superoxide production, coagulation, and atherosclerosis. We identified five key network proteins: acid phosphatase 5, epidermal growth factor receptor, insulin‐like growth factor binding protein‐1, plasminogen activator urokinase receptor, and secreted phosphoprotein 1. Similar results were observed in the independent validation cohort. Conclusions Pathophysiological pathways distinguishing patients with ischaemic HF from those with non‐ischaemic HF were related to inflammation, endothelial dysfunction superoxide production, coagulation, and atherosclerosis. The five key pathway proteins identified are potential treatment targets specifically for patients with ischaemic HF

Genetic Risk and Atrial Fibrillation in Patients with Heart Failure

Aims: To study the association between an atrial fibrillation (AF) genetic risk score with prevalent AF and all-cause mortality in patients with heart failure. Methods and results: An AF genetic risk score was calculated in 3759 European ancestry individuals (1783 with sinus rhythm, 1976 with AF) from the BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) by summing 97 single nucleotide polymorphism (SNP) alleles (ranging from 0–2) weighted by the natural logarithm of the relative SNP risk from the latest AF genome-wide association study. Further, we assessed AF risk variance explained by additive SNP variation, and performance of clinical or genetic risk factors, and the combination in classifying AF prevalence. AF was classified as AF or atrial flutter (AFL) at baseline electrocardiogram and/or a history of AF or AFL. The genetic risk score was associated with AF after multivariable adjustment. Odds ratio for AF prevalence per 1-unit increase genetic risk score was 2.12 (95% confidence interval 1.84–2.45, P = 2.15 × 10−24) in the total cohort, 2.08 (1.72–2.50, P = 1.30 × 10−14) in heart failure with reduced ejection fraction (HFrEF) and 2.02 (1.37–2.99, P = 4.37 × 10−4) in heart failure with preserved ejection fraction (HFpEF). AF-associated loci explained 22.9% of overall AF SNP heritability. Addition of the genetic risk score to clinical risk factors increased the C-index by 2.2% to 0.721. Conclusions: The AF genetic risk score was associated with increased AF prevalence in HFrEF and HFpEF. Genetic variation accounted for 22.9% of overall AF SNP heritability. Addition of genetic risk to clinical risk improved model performance in classifying AF prevalence

Machine learning based on biomarker profiles identifies distinct subgroups of heart failure with preserved ejection fraction

International audienceAims: The lack of effective therapies for patients with heart failure with preserved ejection fraction (HFpEF) is often ascribed to the heterogeneity of patients with HFpEF. We aimed to identify distinct pathophysiologic clusters of HFpEF based on circulating biomarkers.Methods and results: We performed an unsupervised cluster analysis using 363 biomarkers from 429 patient with HFpEF. Relative differences in expression profiles of the biomarkers between clusters were assessed and used for pathway over-representation analyses. We identified four distinct patients subgroups based on their biomarker profiles : cluster 1 with the highest prevalence of diabetes mellitus and renal disease; cluster 2 with oldest age and frequent age-related comorbidities; cluster 3 with youngest age, largest body size, least symptoms and lowest NT-proBNP levels; and cluster 4 with highest prevalence of ischemic aetiology, smoking and chronic lung disease, most symptoms, as well as highest NT-proBNP and troponin levels. Over a median follow-up of 21 months, the occurrence of death or HF hospitalization was highest in clusters 1 and 4 (62.1% and 62.8% respectively) and lowest in cluster 3 (25.6%). Pathway over-representation analyses revealed that the biomarker profile of patients in cluster 1 was associated with activation of inflammatory pathways while the biomarker profile of patients in cluster 4 was specifically associated with pathways implicated in cell proliferation regulation and cell survival.Conclusion: Unsupervised cluster analysis based on biomarker profiles identified mutually exclusive subgroups of patients with HFpEF with distinct biomarker profiles, clinical characteristics and outcomes, suggesting different underlying pathophysiological pathway

Biomarker changes as surrogate endpoints in early-phase trials in heart failure with reduced ejection fraction

Aims: No biomarker has achieved widespread acceptance as a surrogate endpoint for early‐phase heart failure (HF) trials. We assessed whether changes over time in a panel of plasma biomarkers were associated with subsequent morbidity/mortality in HF with reduced ejection fraction (HFrEF). Methods and results: In 1040 patients with HFrEF from the BIOSTAT‐CHF cohort, we investigated the associations between changes in the plasma concentrations of 30 biomarkers, before (baseline) and after (9 months) attempted optimization of guideline‐recommended therapy, on top of the BIOSTAT risk score and the subsequent risk of HF hospitalization/all‐cause mortality using Cox regression models. C‐statistics were calculated to assess discriminatory power of biomarker changes/month‐nine assessment. Changes in N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) and WAP four‐disulphide core domain protein HE4 (WAP‐4C) were the only independent predictors of the outcome after adjusting for their baseline plasma concentration, 28 other biomarkers (both baseline and changes), and BIOSTAT risk score at baseline. When adjusting for month‐nine rather than baseline biomarkers concentrations, only changes in NT‐proBNP were independently associated with the outcome. The C‐statistic of the model including the BIOSTAT risk score and NT‐proBNP increased by 4% when changes were considered on top of baseline concentrations and by 1% when changes in NT‐proBNP were considered on top of its month‐nine concentrations and the BIOSTAT risk score. Conclusions: Among 30 relevant biomarkers, a change over time was significantly and independently associated with HF hospitalization/all‐cause death only for NT‐proBNP. Changes over time were modestly more prognostic than baseline or end‐values alone. Changes in biomarkers should be further explored as potential surrogate endpoints in early phase HF trials

Integrated Omics Reveals the Orchestrating Role of Calycosin in Danggui Buxue Tang, a Herbal Formula Containing Angelicae Sinensis Radix and Astragali Radix, in Inducing Osteoblastic Differentiation and Proliferation

Systems biology unravels the black box of signaling pathway of cells; but which has not been extensively applied to reveal the mechanistic synergy of a herbal formula. The therapeutic efficacies of a herbal formula having multi-target, multi-function and multi-pathway are the niches of traditional Chinese medicine (TCM). Here, we reported an integrated omics approach, coupled with the knockout of an active compound, to measure the regulation of cellular signaling, as to reveal the landscape in cultured rat osteoblasts having synergistic pharmacological efficacy of Danggui Buxue Tang (DBT), a Chinese herbal formula containing Angelicae Sinensis Radix and Astragali Radix. The changes in signaling pathways responsible for energy metabolism, RNA metabolism and protein metabolism showed distinct features between DBT and calycosin-depleted DBT. Here, our results show that calycosin within DBT can orchestrate the osteoblastic functions and signaling pathways of the entire herbal formula. This finding reveals the harmony of herbal medicine in pharmacological functions, as well as the design of drug/herbal medicine formulation. The integration of systems biology can provide novel and essential insights into the synergistic property of a herbal formula, which is a key in modernizing TCM

Distinct pathophysiological pathways in women and men with heart failure

Aims: Clinical differences between women and men have been described in heart failure (HF). However, less is known about the underlying pathophysiological mechanisms. In this study, we compared multiple circulating biomarkers to gain better insights into differential HF pathophysiology between women and men. Methods and Results: In 537 women and 1485 men with HF, we compared differential expression of a panel of 363 biomarkers. Then, we performed a pathway over-representation analysis to identify differential biological pathways in women and men. Findings were validated in an independent HF cohort (575 women, 1123 men). In both cohorts, women were older and had higher ejection fraction (LVEF). In the index and validation cohorts respectively, we found 14/363 and 12/363 biomarkers that were relatively up-regulated in women, while 21/363 and 14/363 were up-regulated in men. In both cohorts, the strongest up-regulated biomarkers in women were leptin and fatty acid binding protein-4, compared to matrix metalloproteinase-3 in men. Similar findings were replicated in a subset of patients from both cohorts matched by age and LVEF. Pathway over-representation analysis revealed increased activity of pathways associated with lipid metabolism in women, and neuroinflammatory response in men (all p < 0.0001). Conclusion: In two independent cohorts of HF patients, biomarkers associated with lipid metabolic pathways were observed in women, while biomarkers associated with neuro-inflammatory response were more active in men. Differences in inflammatory and metabolic pathways may contribute to sex differences in clinical phenotype observed in HF, and provide useful insights towards development of tailored HF therapies

Development of Drugs for Nontuberculous Mycobacterial Disease:Clinicians’ Interpretation of a US Food and Drug Administration Workshop

The US Food and Drug Administration convened a workshop to discuss clinical trial design challenges and considerations related to the treatment of nontuberculous mycobacterial pulmonary disease, to include topics such as clinical trial end points, duration, and populations. The clinicians participating in the meeting provide here their interpretation of the discussion, which included US Food and Drug Administration and industry representatives. The treatment of nontuberculous mycobacterial pulmonary disease typically includes multiple antibiotics for a prolonged period and can be difficult to tolerate; there is a great need for new treatment options. Most individuals have a microbiologic response to therapy, but data correlating decreasing bacillary load with patient-reported outcomes or measured functional improvement are lacking. Accordingly, trial designs for new therapeutic agents should incorporate both microbiologic and clinical outcome measures and select appropriate study candidates with capacity for measurable change of such outcome measures. The need for shorter study designs, early primary end points, and placebo control arms was highlighted during the workshop

Distinct pathophysiological pathways in women and men with heart failure

Aims Clinical differences between women and men have been described in heart failure (HF). However, less is known about the underlying pathophysiological mechanisms. In this study, we compared multiple circulating biomarkers to gain better insights into differential HF pathophysiology between women and men. Methods and results In 537 women and 1485 men with HF, we compared differential expression of a panel of 363 biomarkers. Then, we performed a pathway over-representation analysis to identify differential biological pathways in women and men. Findings were validated in an independent HF cohort (575 women, 1123 men). In both cohorts, women were older and had higher left ventricular ejection fraction (LVEF). In the index and validation cohorts respectively, we found 14/363 and 12/363 biomarkers that were relatively up-regulated in women, while 21/363 and 14/363 were up-regulated in men. In both cohorts, the strongest up-regulated biomarkers in women were leptin and fatty acid binding protein-4, compared to matrix metalloproteinase-3 in men. Similar findings were replicated in a subset of patients from both cohorts matched by age and LVEF. Pathway over-representation analysis revealed increased activity of pathways associated with lipid metabolism in women, and neuro-inflammatory response in men (all p &lt; 0.0001). Conclusion In two independent cohorts of HF patients, biomarkers associated with lipid metabolic pathways were observed in women, while biomarkers associated with neuro-inflammatory response were more active in men. Differences in inflammatory and metabolic pathways may contribute to sex differences in clinical phenotype observed in HF, and provide useful insights towards development of tailored HF therapies.</p

Concentric vs. eccentric remodelling in heart failure with reduced ejection fraction:clinical characteristics, pathophysiology and response to treatment

Aims: Heart failure is traditionally classified by left ventricular ejection fraction (LVEF), rather than by left ventricular (LV) geometry, with guideline-recommended therapies in heart failure with reduced ejection fraction (HFrEF) but not heart failure with preserved ejection fraction (HFpEF). Most patients with HFrEF have eccentric LV hypertrophy, but some have concentric LV hypertrophy. We aimed to compare clinical characteristics, biomarker patterns, and response to treatment of patients with HFrEF and eccentric vs. concentric LV hypertrophy. Methods and results: We performed a retrospective post-hoc analysis including 1015 patients with HFrEF (LVEF <40%) from the multinational observational BIOSTAT-CHF study. LV geometry was classified using two-dimensional echocardiography. Network analysis of 92 biomarkers was used to investigate pathophysiologic pathways. Concentric LV hypertrophy was present in 142 (14%) patients, who were on average older and more likely hypertensive compared to those with eccentric LV hypertrophy. Network analysis revealed that N-terminal pro-B-type natriuretic peptide was an important hub in eccentric hypertrophy, whereas in concentric hypertrophy, tumour necrosis factor receptor 1, urokinase plasminogen activator surface receptor, paraoxonase and P-selectin were central hubs. Up-titration of beta-blockers was associated with a mortality benefit in HFrEF with eccentric but not concentric LV hypertrophy (P-value for interaction ≤0.001). For angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, the hazard ratio for mortality was higher in concentric hypertrophy, but the interaction was not significant. Conclusion: Patients with HFrEF with concentric hypertrophy have a clinical and biomarker phenotype that is distinctly different from those with eccentric hypertrophy. Patients with concentric hypertrophy may not experience similar benefit from up.-titration of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and beta-blockers compared to patients with eccentric hypertrophy