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Aims: Insulin like growth factor binding protein 7 (IGFBP7) is a marker of senescence secretome and a novel biomarker in patients with heart failure (HF). We evaluated the prognostic value of IGFBP7 in patients with heart failure and examined associations to uncover potential new pathophysiological pathways related to increased plasma IGFBP7 concentrations. Methods and results: We have measured plasma IGFBP7 concentrations in 2250 subjects with new‐onset or worsening heart failure (BIOSTAT‐CHF cohort). Higher IGFBP7 plasma concentrations were found in older subjects, those with worse kidney function, history of atrial fibrillation, and diabetes mellitus type 2, and in subjects with higher number of HF hospitalizations. Higher IGFBP7 levels also correlate with the levels of several circulating biomarkers, including higher NT‐proBNP, hsTnT, and urea levels. Cox regression analyses showed that higher plasma IGFBP7 concentrations were strongly associated with increased risk of all three main endpoints (hospitalization, all‐cause mortality, and combined hospitalization and mortality) (HR 1.75, 95% CI 1.25–2.46; HR 1.71, 95% CI 1.39–2.11; and HR 1.44, 95% CI 1.23–1.70, respectively). IGFBP7 remained a significant predictor of these endpoints in patients with both reduced and preserved ejection fraction. Likelihood ratio test showed significant improvement of all three risk prediction models, after adding IGFBP7 (P < 0.001). A biomarker network analysis showed that IGFBP7 levels activate different pathways involved in the regulation of the immune system. Results were externally validated in BIOSTAT‐CHF validation cohort. Conclusions: IGFPB7 presents as an independent and robust prognostic biomarker in patients with HF, with both reduced and preserved ejection fraction. We validate the previously published data showing IGFBP7 has correlations with a number of echocardiographic markers. Lastly, IGFBP7 pathways are involved in different stages of immune system regulation, linking heart failure to senescence pathways. [ABSTRACT FROM AUTHOR]

Aims: Limited data exist regarding the prognostic relevance of changes in left atrial (LA) dimensions in patients with heart failure (HF). We assessed changes in LA dimension and their relation with outcomes after optimization of guideline‐directed medical therapy (GDMT) in patients with new‐onset or worsening HF. Methods and results: Left atrial diameter was assessed at baseline and 9 months after GDMT optimization in 632 patients (mean age 65.8 ± 12.1 years, 22.3% female) enrolled in BIOSTAT‐CHF. LA adverse remodelling (LAAR) was defined as an increase in LA diameter on transthoracic echocardiography between baseline and 9 months. After the 9‐month visit, patients were followed for a median of 13 further months. LAAR was observed in 247 patients (39%). Larger baseline LA diameter (odds ratio [OR] 0.90; 95% confidence interval [CI] 0.87–0.93; p < 0.001) and up‐titration to higher doses of angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers (ACEi/ARBs) (OR 0.56; 95% CI 0.34–0.92; p = 0.022) were independently associated with lower likelihood of LAAR. LAAR was associated with an increased risk of the composite of all‐cause mortality or HF hospitalization (log‐rank p = 0.007 and adjusted hazard ratio 1.73, 95% CI 1.22–2.45, p = 0.002). The association was more pronounced in patients without a history of atrial fibrillation (p for interaction = 0.009). Conclusion: Among patients enrolled in BIOSTAT‐CHF, LAAR was associated with an unfavourable outcome and was prevented by ACEi/ARB up‐titration. Changes in LA dimension may be a useful marker of response to treatment and improve risk stratification in patients with HF. [ABSTRACT FROM AUTHOR]

Background and Purpose: Vascular tone is regulated by the relative contractile state of vascular smooth muscle cells (VSMCs). Several integrins directly modulate VSMC contraction by regulating calcium influx through L-type voltage-gated Ca2+ channels (VGCCs). Genetic variants in ITGA9, which encodes the α9 subunit of integrin α9β1, and SVEP1, a ligand for integrin α9β1, associate with elevated blood pressure; however, neither SVEP1 nor integrin α9β1 has reported roles in vasoregulation. We determined whether SVEP1 and integrin α9β1 can regulate VSMC contraction.Experimental Approach: SVEP1 and integrin binding were confirmed by immunoprecipitation and cell binding assays. Human induced pluripotent stem cell-derived VSMCs were used in in vitro [Ca2+ ]i studies, and aortas from a Svep1+/- knockout mouse model were used in wire myography to measure vessel contraction.Key Results: We confirmed the ligation of SVEP1 to integrin α9β1 and additionally found SVEP1 to directly bind to integrin α4β1. Inhibition of SVEP1, integrin α4β1 or α9β1 significantly enhanced [Ca2+ ]i levels in isolated VSMCs to Gαq/11 -vasoconstrictors. This response was confirmed in whole vessels where a greater contraction to U46619 was seen in vessels from Svep1+/- mice compared to littermate controls or when integrin α4β1 or α9β1 was inhibited. Inhibition studies suggested that this effect was mediated via VGCCs, PKC and Rho A/Rho kinase dependent mechanisms.Conclusions and Implications: Our studies reveal a novel role for SVEP1 and the integrins α4β1 and α9β1 in reducing VSMC contractility. This could provide an explanation for the genetic associations with blood pressure risk at the SVEP1 and ITGA9 loci. [ABSTRACT FROM AUTHOR]

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 < 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims: Few data regarding the prevalence and prognostic impact of mitral regurgitation (MR) in patients with worsening chronic or new‐onset acute heart failure (HF) are available. We investigated the role of MR in the BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT‐CHF). Methods and results: We performed a retrospective post‐hoc analysis including patients from both the index and validation BIOSTAT‐CHF cohorts with data regarding MR status. The primary endpoint was a composite of all‐cause death or HF hospitalization. Among 4023 patients included, 1653 patients (41.1%) had moderate–severe MR. Compared to others, patients with moderate–severe MR were more likely to have atrial fibrillation and chronic kidney disease and had larger left ventricular (LV) dimensions, lower LV ejection fraction (LVEF), worse quality of life, and higher plasma concentrations of N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP). A primary outcome event occurred in 697 patients with, compared to 836 patients without, moderate–severe MR [Kaplan–Meier 2‐year estimate: 42.2% vs. 35.3%; hazard ratio (HR) 1.28; 95% confidence interval (CI) 1.16–1.41; log‐rank P < 0.0001]. The association between MR and the primary endpoint remained significant after adjusting for baseline variables and the previously validated BIOSTAT‐CHF risk score (adjusted HR 1.11; 95% CI 1.00–1.23; P = 0.041). Subgroup analyses showed a numerically larger impact of MR on the primary endpoint in patients with lower LVEF, larger LV end‐diastolic diameter, and higher plasma NT‐proBNP. Conclusions: Moderate–severe MR is common in patients with worsening chronic or new‐onset acute HF and is strongly associated with outcome, independently of other features related to HF severity. [ABSTRACT FROM AUTHOR]

Aims: Inflammation is thought to play a role in heart failure (HF) pathophysiology. Neutrophil‐to‐lymphocyte ratio (NLR) is a simple, routinely available measure of inflammation. Its relationship with other inflammatory biomarkers and its association with clinical outcomes in addition to other risk markers have not been comprehensively evaluated in HF patients. Methods: We evaluated patients with worsening or new‐onset HF from the BIOlogy Study to Tailored Treatment in Chronic Heart Failure (BIOSTAT‐CHF) study who had available NLR at baseline. The primary outcome was time to all‐cause mortality or HF hospitalization. Outcomes were validated in a separate HF population. Results: 1622 patients were evaluated (including 523 ventricular ejection fraction [LVEF] < 40% and 662 LVEF ≥ 40%). NLR was significantly correlated with biomarkers related to inflammation as well as NT‐proBNP. NLR was significantly associated with the primary outcome in patients irrespective of LVEF (hazard ratio [HR] 1.18 per standard deviation increase; 95% confidence interval [CI] 1.11–1.26, P < 0.001). Patients with NLR in the highest tertile had significantly worse outcome than those in the lowest independent of LVEF (<40%: HR 2.75; 95% CI 1.84–4.09, P < 0.001; LVEF ≥ 40%: HR 1.51; 95% CI 1.05–2.16, P = 0.026). When NLR was added to the BIOSTAT‐CHF risk score, there were improvements in integrated discrimination index (IDI) and net reclassification index (NRI) for occurrence of the primary outcome (IDI + 0.009; 95% CI 0.00–0.019, P = 0.030; continuous NRI + 0.112, 95% CI 0.012–0.176, P = 0.040). Elevated NLR was similarly associated with adverse outcome in the validation cohort. Decrease in NLR at 6 months was associated with reduced incidence of the primary outcome (HR 0.75; 95% CI 0.57–0.98, P = 0.036). Conclusions: Elevated NLR is significantly associated with elevated markers of inflammation in HF patients and is associated with worse outcome. Elevated NLR might potentially be useful in identifying high‐risk HF patients and may represent a treatment target. [ABSTRACT FROM AUTHOR]

Background: The role of neurohormonal inhibition in chronic heart failure (HF) is well established. There are limited data on the effect of up‐titration of renin–angiotensin inhibitors (RASi) and beta‐blockers (BBs) on clinical outcomes of patients with worsening HF across the left ventricular ejection fraction (LVEF) spectrum. Methods and results: We analysed data from 2345 patients from BIOSTAT‐CHF (80.9% LVEF <40%), who completed a 3‐month up‐titration period after recent worsening of HF. Patients were classified by achieved dose (% of recommended): ≥100%, 50–99%, 1–49%, and none. Recurrent event analysis using joint and shared frailty models was used to examine the association between RASi/BB dose and all‐cause and HF hospitalizations. In the 21 months following up‐titration, 512 patients died and 879 (37.5%) had ≥1 hospitalization. RASi up‐titration was associated, incrementally, with reduced risk of all‐cause hospitalization at all achieved dose levels compared to no treatment [hazard ratio (95% confidence interval): ≥100%: 0.60 (0.49–0.74), P < 0.001; 50–99%: 0.56 (0.46–0.68), P < 0.001; 1–49%: 0.71 (0.59–0.86), P < 0.001]. This association was consistent up to an LVEF of 49% (P < 0.001), and when considering only HF hospitalizations. Up‐titration of BBs was associated with fewer all‐cause hospitalizations only when LVEF was <40% (overall P < 0.001), but with more HF hospitalizations when LVEF was ≥50%. Up‐titration of both RASi/BBs was associated with lower mortality in LVEF up to 49%. Conclusion: After recent worsening of HF, up‐titration of RASi and BBs was associated with a better prognosis in patients with LVEF ≤49%. Up‐titration of BBs was associated with a greater risk of HF hospitalization when LVEF was ≥50%. [ABSTRACT FROM AUTHOR]

Aims: Liquid chromatography‐mass spectrometry (LC‐MS/MS) is an objective new technique to assess non‐adherence to medications. We used this method to study the prevalence, predictors and outcomes of non‐adherence in patients with heart failure with reduced left ventricular ejection fraction (HFrEF). Methods and results: This study included 1296 patients with HFrEF from BIOSTAT‐CHF, a study that aimed to optimise guideline‐recommended therapies. Angiotensin‐converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists, β‐blockers and loop diuretics were measured in a single spot urine sample at 9 months using LC‐MS/MS. The relationship between medication non‐adherence and the composite endpoint of all‐cause death or heart failure hospitalisation, over a median follow‐up of 21 months, was evaluated. Non‐adherence to at least one prescribed medication was observed in 45.9% of patients. The strongest predictor of non‐adherence was non‐adherence to any of the other medication classes (P < 0.0005). Regional differences within Europe were observed. On multivariable analyses, non‐adherence to ACEi/ARBs and β‐blockers was associated with an increased risk of the composite endpoint [hazard ratio (HR) 1.38, 95% confidence interval (CI) 1.09–1.95, P = 0.008 and HR 1.48, 95% CI 1.12–1.96, P = 0.006, respectively). Non‐adherence to β‐blockers was also associated with an increased risk of death (HR 2.48, 95% CI 1.67–3.68, P < 0.0005). Patients who were non‐adherent to loop diuretics were healthier and had a decreased risk of the composite endpoint (HR 0.69, 95% CI 0.51–0.93, P = 0.014). Non‐adherence to mineralocorticoid receptor antagonists was not related to any clinical outcome. Conclusion: Non‐adherence to medications, assessed by a single urine test, is common and predicts clinical outcomes in patients with HFrEF. [ABSTRACT FROM AUTHOR]

Aims/Introduction: The aim of this study was to examine ethnicity‐specific associations between type 2 diabetes mellitus and the risk of a cardiovascular disease (CVD) event as well as risk of specific CVD phenotypes in England. Methods: We obtained data from the Clinical Practice Research Datalink for adults with and without type 2 diabetes mellitus diagnosed 2000–2006. The outcome was the first CVD event during 2007–2017 and the following components: aortic aneurysm, cerebrovascular accidents, heart failure, myocardial infarction, peripheral vascular disease and other CVD‐related conditions. Flexible parametric survival models were used to estimate ethnicity‐specific adjusted hazard ratios. Results: A total of 734,543 people with and without type 2 diabetes mellitus (29,847; 4.1%) were included; most were of white ethnicity (93.0% with and 92.3% without type 2 diabetes mellitus) followed by South Asian (3.2 and 4.6%). During a median follow‐up period of 11.0 years, 67,218 events occurred (6,156 in individuals with type 2 diabetes mellitus). Type 2 diabetes mellitus was associated with a small increase in CVD events (adjusted hazard ratio 1.06, 95% confidence interval 1.02–1.09) in individuals of white ethnicity; whereas the adjusted hazard ratios were considerably higher in individuals of South Asian ethnicity (1.28, 95% confidence interval 1.09–1.51), primarily due to an increased risk of myocardial infarction (1.53, 95% confidence interval 1.08–2.18). Conclusions: Despite universal access to healthcare, there are large disparities in CVD outcomes in people with and without type 2 diabetes mellitus. Other non‐traditional risk factors might play a role in the higher CVD risk associated with type 2 diabetes mellitus in individuals of South Asian ethnicity. [ABSTRACT FROM AUTHOR]

Aims: 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 patients 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 patient 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 N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) levels; and cluster 4 with highest prevalence of ischaemic 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 heart failure 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 pathways. [ABSTRACT FROM AUTHOR]

Background: Muscle wasting and unintentional weight loss (cachexia) have been associated with worse outcomes in heart failure (HF), but timely identification of these adverse phenomena is difficult. Spot urinary creatinine may be an easily accessible marker to assess muscle loss and cachexia. This study investigated the association of urinary creatinine with body composition changes and outcomes in patients with new‐onset or worsening HF (WHF). Methods: In BIOSTAT‐CHF, baseline spot urinary creatinine measurements were available in 2315 patients with new‐onset or WHF in an international cohort (index cohort) and a validation cohort of 1431 similar patients from Scotland. Results: Median spot urinary creatinine concentrations were 5.2 [2.7–9.6] mmol/L in the index cohort. Median age was 69 ± 12 years and 73% were men. Lower spot urinary creatinine was associated with older age, lower height and weight, worse renal function, more severe HF, and a higher risk of >5% weight loss from baseline to 9 months (odds ratio = 1.23, 95% CI = 1.09–1.39 per log decrease; P = 0.001). Spot urinary creatinine was associated with Evans criteria of cachexia (OR = 1.26 per log decrease, 95% CI = 1.04–1.49; P = 0.016) and clustered with markers of heart failure severity in hierarchical cluster analyses. Lower urinary creatinine was associated with poorer exercise capacity and quality of life (both P < 0.001) and predicted a higher rate for all‐cause mortality [hazard ratio (HR) = 1.27, 95% CI = 1.17–1.38 per log decrease; P < 0.001] and the combined endpoints HF hospitalization or all‐cause mortality (HR = 1.23, 95% CI = 1.15–1.31 per log decrease; P < 0.001). Significance was lost after addition of the BIOSTAT risk model. Analyses of the validation cohort yielded similar findings. Conclusions: Lower spot urinary creatinine is associated with smaller body dimensions, renal dysfunction, and more severe HF in patients with new‐onset/WHF. Additionally, lower spot urinary creatinine is associated with an increased risk of weight loss and a poorer exercise capacity/quality of life. Urinary creatinine could therefore be a novel, easily obtainable marker to assess (risk of) muscle wasting in HF patients. [ABSTRACT FROM AUTHOR]

Aims: We sought to analyse quality of life (QoL) measures derived from two questionnaires widely used in clinical trials, the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the EuroQoL 5 dimensions (EQ‐5D), and to compare their prognostic value in men and women with heart failure and reduced ejection fraction (HFrEF). Methods and results: From the BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT‐CHF) we compared KCCQ and EQ‐5D at baseline and after 9 months in 1276 men and 373 women with new‐onset or worsening symptoms of HFrEF, who were sub‐optimally treated and in whom there was an anticipated up‐titration of guideline‐derived medical therapies. Women had significantly worse baseline QoL (median) as compared with men, both when assessed with KCCQ overall score (KCCQ‐OS, 44 vs. 53, P < 0.001) and EQ‐5D utility score (0.62 vs. 0.73, P < 0.001). QoL improved equally in women and men at follow‐up. All summary measures of QoL were independently associated with all‐cause mortality, with KCCQ‐OS showing the most remarkable association with mortality up to 1 year compared to the EQ‐5D scores (C‐statistic 0.650 for KCCQ‐OS vs. 0.633 and 0.599 for EQ‐5D utility score and EQ‐5D visual analogue scale, respectively). QoL was associated with all outcomes analysed, both in men and women (all P for interaction with sex >0.2). Conclusion: Amongst patients with HFrEF, women reported significantly worse QoL than men. QoL was independently associated with subsequent outcome, similarly in men and women. The KCCQ in general, and the KCCQ‐OS in particular, showed the strongest independent association with outcome. [ABSTRACT FROM AUTHOR]

Aims: Several studies have shown that older patients with heart failure with reduced ejection fraction (HFrEF) are undertreated. The aim of this study was to evaluate the association of up‐titration of angiotensin‐converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB) and beta‐blockers on outcome across the age spectrum in HFrEF patients. Methods and results: We analysed HFrEF patients on sub‐optimal doses of ACEI/ARB and/or beta‐blockers from the BIOSTAT‐CHF study stratified by age. Patients underwent a 3‐month up‐titration period. We used inverse probability weighting to adjust for the likelihood of successful up‐titration to determine the association of achieved dose with mortality and/or heart failure hospitalisation, testing for an interaction with age. Over a median follow‐up of 21 months in 1720 HFrEF patients (76.5% male, mean age 67 years), the primary outcome occurred in 558 patients. Increased percentage of target dose of ACEI/ARB and beta‐blocker achieved at 3 months were both significantly associated with reduced incidence of the primary outcome, [ACEI‐ARB: hazard ratio (HR) per 12.5% increase in dose: 0.92, 95% confidence interval (CI) 0.91–0.94, P < 0.001; beta‐blocker: HR 0.98, 95% CI 0.95–1.00, P = 0.046], with a significant interaction with age seen for beta‐blockers but not ACEI/ARB (P = 0.034 and P = 0.22, respectively). Conclusions: Achieving higher doses of ACEI/ARB was associated with improved outcome regardless of age. However, achieving higher doses of beta‐blockers was only associated with improved outcome in younger, but not in older patients. [ABSTRACT FROM AUTHOR]

Introduction: Sudden cardiac death (SCD) risk assessment is limited, particularly in patients with nonischemic cardiomyopathies. This is the first application, in patients with cardiomyopathies, of two novel risk markers, regional restitution instability index (R2I2) and peak electrocardiogram restitution slope (PERS), which have been shown to be predictive of ventricular arrhythmias (VA) or death in ischemic heart disease patients. Methods: Blinded retrospective study of 50 patients: 33 dilated cardiomyopathy and 17 other; undergoing electrophysiological study (EPS) for SCD risk stratification, and 29 controls with structurally normal hearts undergoing EPS. R2I2 was calculated from an EPS using electrocardiogram surrogates for action potential duration and diastolic interval. Cut‐offs for high and low R2I2/PERS were predefined. Results: R2I2 was significantly higher in study than control patients (0.99 ± 0.05 vs. 0.63 ± 0.04, p <.001). PERS showed a trend to higher values in the study group (1.18[0.63] vs. 1.09[0.54], p =.07). During median follow up of 5.6 years [interquartile range 1.9 years], nine study patients reached the endpoint of VA/death. Patients who experienced VA/death showed trends to higher mean R2I2 (1.14 ± 0.07 vs.0.95 ± 0.05, p =.12) and PERS (1.46[0.49] vs. 1.13[0.62], p =.22). A Cox proportional hazards model using grouped markers: R2I2 < 1.03 + PERS < 1.21/either R2I2 ≥ 1.03 or PERS ≥ 1.21/R2I2 ≥ 1.03 + PERS ≥ 1.21; significantly predicted VA/death (p =.02) with a hazard ratio per positive component of 3.2 (95% confidence interval 1.2–8.8). Conclusion: R2I2≥ 1.03 + PERS ≥ 1.21 may predict VA/death in patients with cardiomyopathies. R2I2 ≥ 1.03 + PERS ≥ 1.21 have the potential to play an important role in SCD risk stratification in cardiomyopathies but their validity should be confirmed in a larger study. [ABSTRACT FROM AUTHOR]

Aims: This retrospective analysis sought to identify markers that might distinguish between acute heart failure (HF) and worsening HF in chronic outpatients. Methods and results: The BIOSTAT‐CHF index cohort included 2516 patients with new or worsening HF symptoms: 1694 enrolled as inpatients (acute HF) and 822 as outpatients (worsening HF in chronic outpatients). A validation cohort included 935 inpatients and 803 outpatients. Multivariable models were developed in the index cohort using clinical characteristics, routine laboratory values, and proteomics data to examine which factors predict adverse outcomes in both conditions and to determine which factors differ between acute HF and worsening HF in chronic outpatients, validated in the validation cohort. Patients with acute HF had substantially higher morbidity and mortality (6‐month mortality was 12.3% for acute HF and 4.7% for worsening HF in chronic outpatients). Multivariable models predicting 180‐day mortality and 180‐day HF readmission differed substantially between acute HF and worsening HF in chronic outpatients. Carbohydrate antigen 125 was the strongest single biomarker to distinguish acute HF from worsening HF in chronic outpatients, but only yielded a C‐index of 0.71. A model including multiple biomarkers and clinical variables achieved a high degree of discrimination with a C‐index of 0.913 in the index cohort and 0.901 in the validation cohort. Conclusions: This study identifies different characteristics and predictors of outcome in acute HF patients as compared to outpatients with chronic HF developing worsening HF. The markers identified may be useful in better diagnosing acute HF and may become targets for treatment development. [ABSTRACT FROM AUTHOR]

Aims: Cathepsin D is a ubiquitous lysosomal protease that is primarily secreted due to oxidative stress. The role of circulating cathepsin D in heart failure (HF) is unknown. The aim of this study is to determine the association between circulating cathepsin D levels and clinical outcomes in patients with HF and to investigate the biological settings that induce the release of cathepsin D in HF. Methods and results: Cathepsin D levels were studied in 2174 patients with HF from the BIOSTAT‐CHF index study. Results were validated in 1700 HF patients from the BIOSTAT‐CHF validation cohort. The primary combined outcome was all‐cause mortality and/or HF hospitalizations. Human pluripotent stem cell‐derived cardiomyocytes were subjected to hypoxic, pro‐inflammatory signalling and stretch conditions. Additionally, cathepsin D expression was inhibited by targeted short hairpin RNAs (shRNA). Higher levels of cathepsin D were independently associated with diabetes mellitus, renal failure and higher levels of interleukin‐6 and N‐terminal pro‐B‐type natriuretic peptide (P < 0.001 for all). Cathepsin D levels were independently associated with the primary combined outcome [hazard ratio (HR) per standard deviation (SD): 1.12; 95% confidence interval (CI) 1.02–1.23], which was validated in an independent cohort (HR per SD: 1.23, 95% CI 1.09–1.40). In vitro experiments demonstrated that human stem cell‐derived cardiomyocytes released cathepsin D and troponin T in response to mechanical stretch. ShRNA‐mediated silencing of cathepsin D resulted in increased necrosis, abrogated autophagy, increased stress‐induced metabolism, and increased release of troponin T from human stem cell‐derived cardiomyocytes under stress. Conclusions: Circulating cathepsin D levels are associated with HF severity and poorer outcome, and reduced levels of cathepsin D may have detrimental effects with therapeutic potential in HF. [ABSTRACT FROM AUTHOR]

Background: Bicuspid aortic valve is the most common congenital valvular heart defect in the general population. BAV is associated with significant morbidity due to valve failure, formation of thoracic aortic aneurysm, and increased risk of infective endocarditis and aortic dissection. Loss of function mutations in NOTCH1 (OMIM 190198) has previously been associated with congenital heart disease involving the aortic valve, left ventricle outflow tract, and mitral valve that segregates in affected pedigrees as an autosomal dominant trait with variable expressivity. Methods: We performed whole‐exome sequencing in four members of a three‐generational family (three affected and one unaffected subject) with clinical phenotypes including aortic valve stenosis, thoracic aortic aneurysm, and ventricular septal defect. Results: We identified 16 potentially damaging genetic variants (one stop variant, one splice variant, and 14 missense variants) cosegregating with the phenotype. Of these variants, the nonsense mutation (p.Tyr291*) in NOTCH1 was the most deleterious variant identified and the most likely variant causing the disease. Conclusion: Inactivating NOTCH1 mutations are a rare cause of familial heart disease involving predominantly left ventricular outflow tract lesions and characterized by the heterogeneity of clinical phenotype. [ABSTRACT FROM AUTHOR]

Aims: Severe deficiency of the essential trace element selenium can cause myocardial dysfunction although the mechanism at cellular level is uncertain. Whether, in clinical practice, moderate selenium deficiency is associated with worse symptoms and outcome in patients with heart failure is unknown.Methods and Results: BIOSTAT-CHF is a multinational, prospective, observational cohort study that enrolled patients with worsening heart failure. Serum concentrations of selenium were measured by inductively coupled plasma mass spectrometry. Primary endpoint was a composite of all-cause mortality and hospitalization for heart failure; secondary endpoint was all-cause mortality. To investigate potential mechanisms by which selenium deficiency might affect prognosis, human cardiomyocytes were cultured in absence of selenium, and mitochondrial function and oxidative stress were assessed. Serum selenium concentration (deficiency) was <70 μg/L in 485 (20.4%) patients, who were older, more often women, had worse New York Heart Association class, more severe signs and symptoms of heart failure and poorer exercise capacity (6-min walking test) and quality of life (Kansas City Cardiomyopathy Questionnaire). Selenium deficiency was associated with higher rates of the primary endpoint [hazard ratio (HR) 1.23; 95% confidence interval (CI) 1.06-1.42] and all-cause mortality (HR 1.52; 95% CI 1.26-1.86). In cultured human cardiomyocytes, selenium deprivation impaired mitochondrial function and oxidative phosphorylation, and increased intracellular reactive oxygen species levels.Conclusions: Selenium deficiency in heart failure patients is independently associated with impaired exercise tolerance and a 50% higher mortality rate, and impaired mitochondrial function in vitro, in human cardiomyocytes. Clinical trials are needed to investigate the effect of selenium supplements in patients with heart failure, especially if they have low plasma concentrations of selenium. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims: Activation of the renin–angiotensin–aldosterone system plays an important role in the pathophysiology of heart failure (HF) and has been associated with poor prognosis. There are limited data on the associations of renin and aldosterone levels with clinical profiles, treatment response, and study outcomes in patients with HF. Methods and results: We analysed 2,039 patients with available baseline renin and aldosterone levels in BIOSTAT‐CHF (a systems BIOlogy study to Tailored Treatment in Chronic Heart Failure). The primary outcome was the composite of all‐cause mortality or HF hospitalization. We also investigated changes in renin and aldosterone levels after administration of mineralocorticoid receptor antagonists (MRAs) in a subset of the EPHESUS trial and in an acute HF cohort (PORTO). In BIOSTAT‐CHF study, median renin and aldosterone levels were 85.3 (percentile25–75 = 28–247) μIU/mL and 9.4 (percentile25–75 = 4.4–19.8) ng/dL, respectively. Prior HF admission, lower blood pressure, sodium, poorer renal function, and MRA treatment were associated with higher renin and aldosterone. Higher renin was associated with an increased rate of the primary outcome [highest vs. lowest renin tertile: adjusted‐HR (95% CI) = 1.47 (1.16–1.86), P = 0.002], whereas higher aldosterone was not [highest vs. lowest aldosterone tertile: adjusted‐HR (95% CI) = 1.16 (0.93–1.44), P = 0.19]. Renin and/or aldosterone did not improve the BIOSTAT‐CHF prognostic models. The rise in aldosterone with the use of MRAs was observed in EPHESUS and PORTO studies. Conclusions: Circulating levels of renin and aldosterone were associated with both the disease severity and use of MRAs. By reflecting both the disease and its treatments, the prognostic discrimination of these biomarkers was poor. Our data suggest that the "point" measurement of renin and aldosterone in HF is of limited clinical utility. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims: To provide insights into pathogenesis of disease progression and potential novel treatment targets for patients with heart failure by investigation of the plasma proteome using network analysis.Methods and Results: The plasma proteome of 50 patients with heart failure who died or were rehospitalised were compared with 50 patients with heart failure, matched for age and sex, who did not have an event. Peptides were analysed on two-dimensional liquid chromatography coupled to tandem mass spectrometry (2D LC ESI-MS/MS) in high definition mode (HDMSE). We identified and quantified 3001 proteins, of which 51 were significantly up-regulated and 46 down-regulated with more than two-fold expression changes in those who experienced death or rehospitalisation. Gene ontology enrichment analysis and protein-protein interaction networks of significant differentially expressed proteins discovered the central role of metabolic processes in clinical outcomes of patients with heart failure. The findings revealed that a cluster of proteins related to glutathione metabolism, arginine and proline metabolism, and pyruvate metabolism in the pathogenesis of poor outcome in patients with heart failure who died or were rehospitalised.Conclusions: Our findings show that in patients with heart failure who died or were rehospitalised, the glutathione, arginine and proline, and pyruvate pathways were activated. These pathways might be potential targets for therapies to improve poor outcomes in patients with heart failure. [ABSTRACT FROM AUTHOR]

Aims: Inflammation is a central process in the pathophysiology of heart failure (HF), but trials targeting tumour necrosis factor (TNF)-α were largely unsuccessful. Interleukin (IL)-6 is an important inflammatory mediator and might constitute a potential pharmacologic target in HF. However, little is known regarding the association between IL-6 and clinical characteristics, outcomes and other inflammatory biomarkers in HF. We thus aimed to identify and characterize these associations.Methods and Results: Interleukin-6 was measured in 2329 patients [89.4% with a left ventricular ejection fraction (LVEF) ≤ 40%] of the BIOSTAT-CHF cohort. The primary outcome was all-cause mortality and HF hospitalization during 2 years, with all-cause, cardiovascular (CV), and non-CV death as secondary outcomes. Approximately half (56%) of all included patients had plasma IL-6 values greater than the previously determined 95th percentile of normal values at baseline. Elevated N-terminal pro-brain natriuretic peptide, procalcitonin and hepcidin, younger age, TNF-α/IL-1-related biomarkers, or having iron deficiency, atrial fibrillation and LVEF > 40% independently predicted elevated IL-6 levels. IL-6 independently predicted the primary outcome [HR (95% confidence interval) per doubling: 1.16 (1.11-1.21), P < 0.001], all-cause mortality [1.22 (1.16-1.29), P < 0.001] and CV as well as non-CV mortality [1.16 (1.09-1.24), P < 0.001; 1.31 (1.18-1.45), P < 0.001], but did not improve discrimination in previously published risk models.Conclusions: In a large, heterogeneous cohort of HF patients, elevated IL-6 levels were found in more than 50% of patients and were associated with iron deficiency, reduced LVEF, atrial fibrillation and poorer clinical outcomes. These findings warrant further investigation of IL-6 as a potential therapeutic target in specific HF subpopulations. [ABSTRACT FROM AUTHOR]

Aims: Association of elevated circulating levels of trimethylamine N-oxide (TMAO) with adverse outcomes in patients with heart failure (HF) has been described. However, response of TMAO levels to treatment and medications has not been investigated. Therefore, we investigated whether TMAO levels are responsive to guideline-recommended treatment and medications, and further reflect changes in outcomes.Methods and Results: TMAO levels were investigated in the systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF), which addressed response to guideline-recommended pharmacological treatment. TMAO levels in 2234 patients with new-onset or progressively worsening HF showed strong associations with adverse events (mortality and/or rehospitalisation) at 1, 2 and 3 years [hazard ratio (HR) 1.37-1.51, P ≤ 0.019). Analysis of 972 patients with plasma available at both enrolment and follow-up visit showed reductions of B-type natriuretic peptide (BNP) levels with guideline-based treatment (P < 0.001), but not for TMAO levels. Moreover, patients with higher TMAO levels than median before and after treatment showed increased association with adverse outcomes [HR 2.21, 95% confidence interval (CI) 1.43-3.43, P < 0.001] compared to patients with lower than median levels either before or after treatment (HR 1.13, 95% CI 0.63-2.04, P = 0.684 and HR 1.14, 95% CI 0.64-2.03, P = 0.662, respectively).Conclusion: TMAO levels were associated with adverse outcomes (mortality and/or rehospitalisation) in BIOSTAT-CHF, and did not respond to guideline-based pharmacological treatment in contrast to BNP levels which did as expected. Lower TMAO levels were associated with favourable outcome regardless of treatment. [ABSTRACT FROM AUTHOR]

Background: Secretion of adrenomedullin (ADM) is stimulated by volume overload to maintain endothelial barrier function, and higher levels of biologically active (bio-) ADM in heart failure (HF) are a counteracting response to vascular leakage and tissue oedema. This study aimed to establish the value of plasma bio-ADM as a marker of congestion in patients with worsening HF.Methods and Results: The association of plasma bio-ADM with clinical markers of congestion, as well as its prognostic value was studied in 2179 patients with new-onset or worsening HF enrolled in BIOSTAT-CHF. Data were validated in a separate cohort of 1703 patients. Patients with higher plasma bio-ADM levels were older, had more severe HF and more signs and symptoms of congestion (all P < 0.001). Amongst 20 biomarkers, bio-ADM was the strongest predictor of a clinical congestion score (r2  = 0.198). In multivariable regression analysis, higher bio-ADM was associated with higher body mass index, more oedema, and higher fibroblast growth factor 23. In hierarchical cluster analysis, bio-ADM clustered with oedema, orthopnoea, rales, hepatomegaly and jugular venous pressure. Higher bio-ADM was independently associated with impaired up-titration of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers after 3 months, but not of beta-blockers. Higher bio-ADM levels were independently associated with an increased risk of all-cause mortality and HF hospitalization (hazard ratio 1.16, 95% confidence interval 1.06-1.27, P = 0.002, per log increase). Analyses in the validation cohort yielded comparable findings.Conclusions: Plasma bio-ADM in patients with new-onset and worsening HF is associated with more severe HF and more oedema, orthopnoea, hepatomegaly and jugular venous pressure. We therefore postulate bio-ADM as a congestion marker, which might become useful to guide decongestive therapy. [ABSTRACT FROM AUTHOR]

Background: The 6-minute walk test (6MWT) is a simple and inexpensive way of measuring exercise capacity in patients with heart failure (HF) that predicts morbidity and mortality. However, there are few reports from large multicentre cohorts assessing the predictive value of baseline and changing walk distance.Methods and Results: In BIOSTAT-CHF, a 6MWT was performed at baseline (n = 1714) and 9 months (n = 1520). Cox proportional hazards models were used to assess the associations between 6MWT distance and the composite of HF hospitalization and/or death. Median follow-up was 21 months. The median (pct25-75 ) of the 6MWT distance at baseline was 300 m (200-388 m). Independent predictors of a shorter 6MWT distance included older age, female sex, higher heart rate, New York Heart Association class III/IV, orthopnoea, ischaemic heart disease, a previous stroke, current malignancy, and higher N-terminal pro-B-type natriuretic peptide (all P < 0.05). Patients in the lowest baseline 6MWT tertile (≤ 240 m) were less likely to receive guideline-recommended doses of disease-modifying therapies (P < 0.05). Compared to patients in the highest baseline 6MWT tertile (> 360 m), those in the lowest and middle tertiles had a worse prognosis [adjusted hazard ratio (HR) 1.73, 95% confidence interval (CI) 1.38-2.18]. Patients with a decrease in the distance walked had a worse prognosis (adjusted HR for each 50 m decrease 1.09, 95% CI 1.06-1.12). 6MWT distance was not modified by treatment up-titration nor the 6MWT improved the BIOSTAT-CHF prognostic models.Conclusions: The 6-minute walk test distance at baseline and a decline in walking distance were both associated with worse prognosis but did not improve the prognostic models. 6MWT distance was not modified by treatment up-titration and its use for assessing the benefits of pharmacologic treatment up-titration may be limited. [ABSTRACT FROM AUTHOR]

Aims: A higher body mass index (BMI) is associated with better survival in heart failure (HF) patients, also known as the obesity paradox. However, BMI does not account for body composition. We therefore analysed the association between abdominal fat, measured via waist-to-hip ratio (WHR), BMI and all-cause mortality in patients with HF.Methods and Results: For this analysis, 1738 patients from the Scottish BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) validation study were included. Patients without waist and hip measurements were excluded. WHR was defined as waist circumference/hip circumference, divided into tertiles and split for sex. A linear regression of principal components from an extensive panel of biomarkers was performed to provide insight in the pathophysiology behind a higher WHR. In total, 1479 patients were included, of which 33% were female and mean age was 75 ±11 years. A higher WHR was independently associated with a higher BMI, a higher prevalence of diabetes and higher New York Heart Association functional class. There was a significant interaction between sex and WHR on its association with mortality (P <0.001). In women, a higher WHR was associated with a higher mortality risk [hazard ratio (HR) 2.23, 95% confidence interval (CI) 1.37-3.63; P =0.001], whereas no significant association was found in men (HR 0.87, 95% CI 0.63-1.20; P = 0.409). We found a strong association between a higher WHR and elevated markers of inflammation and MAPK cascade in women, while these associations were less profound in men.Conclusions: A higher WHR was associated with a higher risk of death in female but not in male HF patients. These findings challenge the obesity paradox, and suggest that fat deposition is pathophysiologically harmful and may be a target for therapy in female patients with HF. [ABSTRACT FROM AUTHOR]

Background: Hyperkalaemia is a common co-morbidity in patients with heart failure with reduced ejection fraction (HFrEF). Whether it affects the use of renin-angiotensin-aldosterone system inhibitors and thereby negatively impacts outcome is unknown. Therefore, we investigated the association between potassium and uptitration of angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB) and its association with outcome.Methods and Results: Out of 2516 patients from the BIOSTAT-CHF study, potassium levels were available in 1666 patients with HFrEF. These patients were sub-optimally treated with ACEi/ARB or beta-blockers and were anticipated and encouraged to be uptitrated. Potassium levels were available at inclusion and at 9 months. Outcome was a composite of all-cause mortality and heart failure hospitalization at 2 years. Patients' mean age was 67 ± 12 years and 77% were male. At baseline, median serum potassium was 4.3 (interquartile range 3.9-4.6) mEq/L. After 9 months, 401 (24.1%) patients were successfully uptitrated with ACEi/ARB. During this period, mean serum potassium increased by 0.16 ± 0.66 mEq/L (P < 0.001). Baseline potassium was an independent predictor of lower ACEi/ARB dosage achieved [odds ratio 0.70; 95% confidence interval (CI) 0.51-0.98]. An increase in potassium was not associated with adverse outcomes (hazard ratio 1.15; 95% CI 0.86-1.53). No interaction on outcome was found between baseline potassium, potassium increase during uptitration, or potassium at 9 months and increased dosage of ACEi/ARB (Pinteraction  > 0.5 for all).Conclusion: Higher potassium levels are an independent predictor of enduring lower dosages of ACEi/ARB. Higher potassium levels do not attenuate the beneficial effects of ACEi/ARB uptitration. [ABSTRACT FROM AUTHOR]

Aims: Previously, low high-density lipoprotein (HDL) cholesterol was found to be one of the strongest predictors of mortality and/or heart failure (HF) hospitalisation in patients with HF. We therefore performed in-depth investigation of the multifunctional HDL proteome to reveal underlying pathophysiological mechanisms explaining the association between HDL and clinical outcome.Methods and Results: We selected a cohort of 90 HF patients with 1:1 cardiovascular death/survivor ratio from BIOSTAT-CHF. A novel optimised protocol for selective enrichment of lipoproteins was used to prepare plasma. Enriched lipoprotein content of samples was analysed using high resolution nanoscale liquid chromatography-mass spectrometry-based proteomics, utilising a label free approach. Within the HDL proteome, 49 proteins significantly differed between deaths and survivors. An optimised model of 12 proteins predicted death with 76% accuracy (Nagelkerke R2 =0.37, P < 0.001). The strongest contributors to this model were filamin-A (related to crosslinking of actin filaments) [odds ratio (OR) 0.31, 95% confidence interval (CI) 0.15-0.61, P = 0.001] and pulmonary surfactant-associated protein B (related to alveolar capillary membrane function) (OR 2.50, 95% CI 1.57-3.98, P < 0.001). The model predicted mortality with an area under the curve of 0.82 (95% CI 0.77-0.87, P < 0.001). Internal cross validation resulted in 73.3 ± 7.2% accuracy.Conclusion: This study shows marked differences in composition of the HDL proteome between HF survivors and deaths. The strongest differences were seen in proteins reflecting crosslinking of actin filaments and alveolar capillary membrane function, posing potential pathophysiological mechanisms underlying the association between HDL and clinical outcome in HF. [ABSTRACT FROM AUTHOR]

Aims: Mineralocorticoid receptor antagonists (MRAs) are recommended (unless contraindicated) to all patients with heart failure with reduced ejection fraction (HFrEF). However, MRAs are still largely underused in routine clinical practice. This study aims to describe the determinants and pattern of use of MRAs in HFrEF.Methods and Results: BIOSTAT-CHF is a European multicentre, prospective study which enrolled patients suboptimally treated with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARBs) and/or beta-blockers, with the aim of optimizing guideline-based use of these agents. From the original 2516 subjects, this retrospective post hoc analysis included the 1325 patients with an indication for MRA therapy (i.e. left ventricular ejection fraction ≤35%, estimated glomerular filtration rate ≥30 mL/min/1.73 m2 , K+ ≤5.0 mmol/L). The mean age was 66.1 ± 12.2 years. At baseline an MRA was prescribed to 741 (56%) patients. Patients who were prescribed MRAs at baseline were younger, more often male, had higher body mass index, lower sodium, higher proportion of hypertension history and ACEi/ARB prescription (all P < 0.05). Of the 1049 patients who completed the baseline plus the 9 month visit, 585 (56%) had an MRA prescribed at baseline and 662 (63%) had an MRA prescribed at 9 months. Among the 585 patients with MRA at baseline, 91 (16%) had discontinued therapy and among the 461 (44%) patients without MRA at baseline 168 (36%) had initiated therapy subsequently. MRA discontinuation was more likely in subjects with higher left ventricular ejection fraction and NYHA class III/IV (P < 0.05 for both). MRA prescription both at baseline and 9 months was not associated with the outcome of death or heart failure hospitalization (adjusted hazard ratio 1.02, 95% confidence interval 0.66-1.58; P = 0.93).Conclusions: In this prospective observational study across Europe, MRAs were largely under-prescribed and frequently discontinued. Owing to these dynamic changes, outcome inferences are inconclusive. [ABSTRACT FROM AUTHOR]

Introduction From a prospective multicentre multicountry clinical trial, we developed and validated risk models to predict prospective all-cause mortality and hospitalizations because of heart failure ( HF) in patients with HF. Methods and results BIOSTAT-CHF is a research programme designed to develop and externally validate risk models to predict all-cause mortality and HF hospitalizations. The index cohort consisted of 2516 patients with HF from 69 centres in 11 European countries. The external validation cohort consisted of 1738 comparable patients from six centres in Scotland, UK. Patients from the index cohort had a mean age of 69 years, 27% were female, 83% were in New York Heart Association ( NYHA) class II-III and the mean left ventricular ejection fraction ( LVEF) was 31%. The full prediction models for mortality, hospitalization owing to HF, and the combined outcome, yielded c-statistic values of 0.73, 0.69, and 0.71, respectively. Predictors of mortality and hospitalization owing to HF were remarkably different. The five strongest predictors of mortality were more advanced age, higher blood urea nitrogen and N-terminal pro-B-type natriuretic peptide, lower haemoglobin, and failure to prescribe a beta-blocker. The five strongest predictors of hospitalization owing to HF were more advanced age, previous hospitalization owing to HF, presence of oedema, lower systolic blood pressure and lower estimated glomerular filtration rate. Patients from the validation cohort were aged 74 years, 34% were female, 85% were in NYHA class II-III, and mean LVEF was 41%; c-statistic values for the full and compact model were comparable to the index cohort. Conclusion A small number of variables, which are usually readily available in the routine clinical setting, provide useful prognostic information for patients with HF. Predictors of mortality were remarkably different from predictors of hospitalization owing to HF. [ABSTRACT FROM AUTHOR]

Aims: Despite major improvements in pharmacological and device treatments, heart failure remains a syndrome with high morbidity and mortality, poor quality of life, and high health-care costs. Given the extensive heterogeneity among patients with heart failure, substantial differences in the response to therapy can be expected. We hypothesize that individualized therapy is an essential next step to improve outcomes in patients with heart failure.Methods: The BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) included 2516 patients with worsening signs and/or symptoms of heart failure from 11 European countries, who were considered to be on suboptimal medical treatment. Another 1738 patients from Scotland were included in a validation cohort. Overall, both patient cohorts were well matched. The majority of patients were hospitalized for acute heart failure, and the remainder presented with worsening signs and/or symptoms of heart failure at outpatient clinics. Approximately half of the patients were in New York Heart Association class III, and 7% vs 34% of patients of the index vs validation cohort had heart failure with preserved ejection fraction. According to study design, all patients used diuretics, but owing to the inclusion criteria of both cohorts, patients were not on optimal, evidence-based medical therapy. In the follow-up phase, uptitration to guideline-recommended doses was encouraged.Conclusion: By using a novel systems biology approach, incorporating demographics, biomarkers, genome-wide analysis, and proteomics, a model that predicts response to therapy will be developed, which should be instrumental in developing alternative therapies for patients with suboptimal response to currently recommended therapies and thus further improve care for patients with heart failure. [ABSTRACT FROM AUTHOR]

The Impact of Power Output During Percutaneous Catheter Radiofrequency Ablation Introduction Percutaneous catheter radiofrequency ablation (RFA) has been widely used to treat patients with atrial fibrillation (AF). Success rates are, however, variable and optimal levels of power used and duration of power delivery have not been fully established. Different ablation centers continue to use various power protocols. We undertook a comprehensive systematic review to evaluate the impact of power output during RFA for AF on efficacy and safety. Methods and results We systematically searched MEDLINE and Cochrane Central Register of Controlled Trials databases for studies on power output during percutaneous RFA for AF. The marked heterogeneous nature of the studies prohibited a meta-analysis. The main findings were (1) power output of ≤30 watts (W) has good safety profiles but low efficacy rates; (2) power output of >30 W-<45 W is safe with good efficacy; (3) power output of ≥ 45 W has a better efficacy profile but associated with a high risk of complications; (4) delivery of higher power of ≥ 45 W at shorter duration (15-20 seconds) is safe and efficacious; and (5) energy titration with visualization of microbubbles by intracardiac echocardiography (ICE) has better efficacy and safety profiles compared to RFA without ICE. Conclusions Despite the overall reduced quality data relating power to outcomes of RFA for AF, the optimal power output showing good efficacy and safety profiles appears generically to be >30 W-<45 W, with significant variation in the literature. [ABSTRACT FROM AUTHOR]

Complement is an important part of the immune system. It is initiated through three different pathways known as the classical, lectin, and alternative pathway. The multimolecular C1 complex of the classical pathway consists of a subcomponent, C1q, which binds to a tetramer comprising two C1r and two C1s proteases. A detailed description of the structure of the C1 complex is essential to fully understand how the complex acts on pathogens. A variety of different models have been proposed, which differ mainly in the way the proteases interact with C1q. In this study, we have used a combination of homology-based structure prediction and molecular dynamics to predict a partial structure of the C1s/C1r/C1r/C1s tetramer. For computational expediency the study was restricted to the CUB1-EGF-CUB2 domains which are directly involved in the formation of the tetramer and its interaction with C1q; the catalytic fragments (CCP1-CCP2-SP), which mediate C1 activation and subsequent cleavage of substrates, were omitted. A systematic molecular dynamics (MD) study of several possible dimeric combinations suggest that the tetramer is formed when a pair of C1r/C1s dimers form a 'doughnut' via a C1s/C1s head-to-tail interaction, which is stabilized by several putative salt bridges at the dimer interface. This result is consistent with biochemical data which have shown that self assembly requires the formation of C1r-C1s contacts and that electrostatic interactions play a key role. Furthermore, it identifies a number of putative binding residues that can be tested using site-directed mutagenesis. Proteins 2012. © 2012 Wiley Periodicals, Inc [ABSTRACT FROM AUTHOR]

MS1 is a protein predominantly expressed in cardiac and skeletal muscle that is upregulated in response to stress and contributes to development of hypertrophy. In the aortic banding model of left ventricular hypertrophy, its cardiac expression was significantly upregulated within 1 h. Its function is postulated to depend on its F-actin binding ability, located to the C-terminal half of the protein, which promotes stabilization of F-actin in the cell thus releasing myocardin-related transcription factors to the nucleus where they stimulate transcription in cooperation with serum response factor. Initial attempts to purify the protein only resulted in heavily degraded samples that showed distinct bands on SDS gels, suggesting the presence of stable domains. Using a combination of combinatorial domain hunting and sequence analysis, a set of potential domains was identified. The C-terminal half of the protein actually contains two independent F-actin binding domains. The most C-terminal fragment (294-375), named actin binding domain 2 (ABD2), is independently folded while a proximal fragment called ABD1 (193-296) binds to F-actin with higher affinity than ABD2 ( KD 2.21 ± 0.47 μ M vs. 10.61 ± 0.7 μ M), but is not structured by itself in solution. NMR interaction experiments show that it binds and folds in a cooperative manner to F-actin, justifying the label of domain. The architecture of the MS1 C-terminus suggests that ABD1 alone could completely fulfill the F-actin binding function opening up the intriguing possibility that ABD2, despite its high level of conservation, could have developed other functions. Proteins 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Aims: Anaemia is highly prevalent and associated with poor prognosis in patients with chronic heart failure (CHF). Reduced erythroid proliferation capacity of haematopoietic progenitor cells is associated with reduced telomere length, a marker of cellular ageing. We hypothesize that short telomere length contributes to the susceptibility to develop anaemia in patients with CHF. [ABSTRACT FROM PUBLISHER]

Abstract: Myocyte stress 1 (MS1) is a recently described striated muscle actin-binding protein that is up-regulated in the early stages of pressure overload left ventricular hypertrophy. The aim of this study was to determine whether MS1 induces cellular hypertrophy and protects against apoptosis. Over-expressed MS1 co-localized with actin in H9c2 cells and altered expression of genes of the myocardin-related transcription factor (MRTF)/serum response factor (SRF) transcriptional pathways and in addition the apoptosis repressor with caspase recruitment domain (Nol3) gene. The size of cells over-expressing MS1 was significantly increased by 55% and over-expression of MS1 dramatically inhibited staurosporine-induced apoptosis by 89%. These findings suggest the involvement of MS1 in cellular hypertrophy and protection against apoptosis. [Copyright &y& Elsevier]

Abstract: The incidence and prevalence of cardiovascular disease increases progressively with advancing age. Cardiovascular disease is a major cause of morbidity and mortality in Western Countries. In the near future, as the population ages, it is expected that the population prevalence of cardiovascular disease will increase dramatically, imposing a major social and economical burden on society. Not only is age closely related to the development and progression of cardiovascular disease, but genetic and environmental factors also play an important role. Recently, a chromosomal mechanism, telomere shortening, has been considered a driving force by which genetic and environmental factors jointly affect biological aging, and possibly the risk for developing age-associated diseases. Telomeres are the extreme ends of chromosomes and shorten progressively during every cell cycle and therefore can be considered an indicator of biological age. In heart failure, telomere length is severely reduced. In the current review, we will discuss the emerging role of telomere biology in the pathophysiology of heart failure. [Copyright &y& Elsevier]

Cardiac baroreceptor sensitivity, a prognostic indicator for a range of diseases, such as myocardial infarction and stroke, may be estimated from spontaneous fluctuations of arterial blood pressure (BP) and heart rate using sequence analysis. We tested the hypothesis that BP values recorded with the non-invasive Finapres device do not always produce sequences coincident with sequences detected from central BP measurements. Finapres recordings of resting BP in the finger, ascending aorta (Millar catheter-tip transducer) and ECG were obtained from 34 patients undergoing coronary angioplasty, including 24 patients treated with betablockers. Coincidence of baroreflex sensitivity (BRS) sequences was expressed by the sensitivity of the Finapres to detect a simultaneously occurring sequence in aortic pressure. The influence of different criteria to detect and accept sequences from beat-to-beat values of systolic BP (SBP) and cardiac interval (RRi) on the Finapres sensitivity was also assessed. The Finapres was able to detect 70·7% of all three beat intra-arterial sequences when the selection criteria was based on the correlation coefficient between SBP and RRi (>0·85), but decreased to 27·5% when the P-value of the linear regression was limited to 0·05. Changing the thresholds for minimum changes in SBP and RRi also had significant effects on sensitivity, as well as in the corresponding values of BRS. Significant differences in BRS were obtained between invasive and non-invasive estimates, but there was no difference between non-invasive estimates calculated from coincident and non-coincident sequences. Non-invasive, compared with intra-arterial estimates of BRS by sequence analysis are not influenced by coincidence of sequences if acceptance of sequences is based on the correlation coefficient criteria (>0·85). [ABSTRACT FROM AUTHOR]

Abstract: Increased plasminogen activator inhibitor-1 (PAI-1) activity is associated with greater risk of myocardial infarction. PAI-1 expression is regulated by a 4G/5G promoter polymorphism. The 4G allele is associated with higher PAI-levels and greater circadian variation. Here we show that clock protein heterodimers BMAL/CLOCK cause greater activation (≈2-fold, P <0.05) of the 4G allele. Site-directed mutagenesis studies suggest that clock genes act on two canonical E-boxes to regulate PAI-1 promoter activity. These results identify a potential novel mechanism whereby allele-specific clock genes – mediated modulation of PAI-1 expression may contribute to circadian variation in cardiac risk. [Copyright &y& Elsevier]

We have identified and characterised a cDNA encoding a novel gene, designated myocyte stress 1 (ms1), that is up-regulated within 1 h in the left ventricle following the application of pressure overload by aortic banding in the rat. The deduced ms1 protein of 317 amino acids contains several putative functional motifs, including a region that is evolutionarily conserved. Distribution analysis indicates that rat ms1 mRNA expression is predominantly expressed in striated muscle and progressively increases in the left ventricle from embryo to adulthood. These findings suggest that ms1 may be important in striated muscle biology and the development of pressure-induced left ventricular hypertrophy. [Copyright &y& Elsevier]