Metabolic profiling of aortic stenosis and hypertrophic cardiomyopathy identifies mechanistic contrasts in substrate utilization.

Aortic stenosis (AS) and hypertrophic cardiomyopathy (HCM) are distinct disorders leading to left ventricular hypertrophy (LVH), but whether cardiac metabolism substantially differs between these in humans remains to be elucidated. We undertook an invasive (aortic root, coronary sinus) metabolic profiling in patients with severe AS and HCM in comparison with non-LVH controls to investigate cardiac fuel selection and metabolic remodeling. These patients were assessed under different physiological states (at rest, during stress induced by pacing). The identified changes in the metabolome were further validated by metabolomic and orthogonal transcriptomic analysis, in separately recruited patient cohorts. We identified a highly discriminant metabolomic signature in severe AS in all samples, regardless of sampling site, characterized by striking accumulation of long-chain acylcarnitines, intermediates of fatty acid transport across the inner mitochondrial membrane, and validated this in a separate cohort. Mechanistically, we identify a downregulation in the PPAR-α transcriptional network, including expression of genes regulating fatty acid oxidation (FAO). In silico modeling of ß-oxidation demonstrated that flux could be inhibited by both the accumulation of fatty acids as a substrate for mitochondria and the accumulation of medium-chain carnitines which induce competitive inhibition of the acyl-CoA dehydrogenases. We present a comprehensive analysis of changes in the metabolic pathways (transcriptome to metabolome) in severe AS, and its comparison to HCM. Our results demonstrate a progressive impairment of ß-oxidation from HCM to AS, particularly for FAO of long-chain fatty acids, and that the PPAR-α signaling network may be a specific metabolic therapeutic target in AS.

Quality indicators for the care and outcomes of adults with atrial fibrillation.

AIMS: To develop quality indicators (QIs) that may be used to evaluate the quality of care and outcomes for adults with atrial fibrillation (AF). METHODS AND RESULTS: We followed the ESC methodology for QI development. This methodology involved (i) the identification of the domains of AF care for the diagnosis and management of AF (by a group of experts including members of the ESC Clinical Practice Guidelines Task Force for AF); (ii) the construction of candidate QIs (including a systematic review of the literature); and (iii) the selection of the final set of QIs (using a modified Delphi method). Six domains of care for the diagnosis and management of AF were identified: (i) Patient assessment (baseline and follow-up), (ii) Anticoagulation therapy, (iii) Rate control strategy, (iv) Rhythm control strategy, (v) Risk factor management, and (vi) Outcomes measures, including patient-reported outcome measures (PROMs). In total, 17 main and 17 secondary QIs, which covered all six domains of care for the diagnosis and management of AF, were selected. The outcome domain included measures on the consequences and treatment of AF, as well as PROMs. CONCLUSION: This document defines six domains of AF care (patient assessment, anticoagulation, rate control, rhythm control, risk factor management, and outcomes), and provides 17 main and 17 secondary QIs for the diagnosis and management of AF. It is anticipated that implementation of these QIs will improve the quality of AF care.

Effect of Selective Heart Rate Slowing in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is associated with significant morbidity and mortality but is currently refractory to therapy. Despite limited evidence, heart rate reduction has been advocated, on the basis of physiological considerations, as a therapeutic strategy in HFpEF. We tested the hypothesis that heart rate reduction improves exercise capacity in HFpEF. METHODS AND RESULTS: We conducted a randomized, crossover study comparing selective heart rate reduction with the If blocker ivabradine at 7.5 mg twice daily versus placebo for 2 weeks each in 22 symptomatic patients with HFpEF who had objective evidence of exercise limitation (peak oxygen consumption at maximal exercise [o2 peak] <80% predicted for age and sex). The result was compared with 22 similarly treated matched asymptomatic hypertensive volunteers. The primary end point was the change in o2 peak. Secondary outcomes included tissue Doppler-derived E/e' at echocardiography, plasma brain natriuretic peptide, and quality-of-life scores. Ivabradine significantly reduced peak heart rate compared with placebo in the HFpEF (107 versus 129 bpm; P<0.0001) and hypertensive (127 versus 145 bpm; P=0.003) cohorts. Ivabradine compared with placebo significantly worsened the change in o2 peak in the HFpEF cohort (-2.1 versus 0.9 mL·kg(-1)·min(-1); P=0.003) and significantly reduced submaximal exercise capacity, as determined by the oxygen uptake efficiency slope. No significant effects on the secondary end points were discernable. CONCLUSION: Our observations bring into question the value of heart rate reduction with ivabradine for improving symptoms in a HFpEF population characterized by exercise limitation. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02354573.

Risk prediction in patients with heart failure: a systematic review and analysis.

OBJECTIVES: This study sought to review the literature for risk prediction models in patients with heart failure and to identify the most consistently reported independent predictors of risk across models. BACKGROUND: Risk assessment provides information about patient prognosis, guides decision making about the type and intensity of care, and enables better understanding of provider performance. METHODS: MEDLINE and EMBASE were searched from January 1995 to March 2013, followed by hand searches of the retrieved reference lists. Studies were eligible if they reported at least 1 multivariable model for risk prediction of death, hospitalization, or both in patients with heart failure and reported model performance. We ranked reported individual risk predictors by their strength of association with the outcome and assessed the association of model performance with study characteristics. RESULTS: Sixty-four main models and 50 modifications from 48 studies met the inclusion criteria. Of the 64 main models, 43 models predicted death, 10 hospitalization, and 11 death or hospitalization. The discriminatory ability of the models for prediction of death appeared to be higher than that for prediction of death or hospitalization or prediction of hospitalization alone (p = 0.0003). A wide variation between studies in clinical settings, population characteristics, sample size, and variables used for model development was observed, but these features were not significantly associated with the discriminatory performance of the models. A few strong predictors emerged for prediction of death; the most consistently reported predictors were age, renal function, blood pressure, blood sodium level, left ventricular ejection fraction, sex, brain natriuretic peptide level, New York Heart Association functional class, diabetes, weight or body mass index, and exercise capacity. CONCLUSIONS: There are several clinically useful and well-validated death prediction models in patients with heart failure. Although the studies differed in many respects, the models largely included a few common markers of risk.

An unusual cause of a recurrent painful rash.

Churg-Strauss syndrome is an uncommon multisystem disease involving small and medium-sized arteries, capillaries, veins, and venules. It is characterised by the presence of asthma, hypereosinophilia, and evidence of vasculitis affecting a number of organs. It is important for acute medical physicians to recognise this condition as delayed diagnosis results in a higher morbidity and mortality. Here we describe a case of Churg-Strauss syndrome in a 41 year old woman presenting with a recurrent painful rash. The clinical manifestations and management of this condition are discussed.

Elevated plasma vascular endothelial growth factor levels in non-diabetic predialysis uraemia.

Chronic renal impairment is associated with increased vascular morbidity and mortality. The pathogenesis of this aggressive vascular pathology is unknown but believed to be multi-factorial in origin. There is accumulating in vivo and in vitro evidence to suggest that the vascular endothelium is dysfunctional in uraemia, including the propensity of endothelial cells to produce VEGF in response to acidosis. There is also preliminary data to suggest abnormally increased endothelial permeability in uraemia. To investigate the potential abnormal circulating levels of VEGF in uraemia, EDTA plasma samples were collected from 20 non-diabetic predialysis patients and matched controls. Free plasma VEGF levels were detected using a commercially available ELISA kit. There were significantly higher plasma levels of VEGF predialysis group (median 351 pg/ml, range 70-636 pg/ml) compared to matched controls (median 125.5 pg/ml, range 22-450 pg/ml), p < 0.002. In conclusion, free plasma VEGF levels are high in chronic renal impairment. We hypothesise that this potent growth and permeability factor may contribute to the endothelial dysfunction of uraemia.