Urinary peptides in heart failure: a link to molecular pathophysiology.

AIMS: Heart failure (HF) is a major public health concern worldwide. The diversity of HF makes it challenging to decipher the underlying complex pathological processes using single biomarkers. We examined the association between urinary peptides and HF with reduced (HFrEF), mid-range (HFmrEF) and preserved (HFpEF) ejection fraction, defined based on the European Society of Cardiology guidelines, and the links between these peptide biomarkers and molecular pathophysiology. METHODS AND RESULTS: Analysable data from 5608 participants were available in the Human Urinary Proteome database. The urinary peptide profiles from participants diagnosed with HFrEF, HFmrEF, HFpEF and controls matched for sex, age, estimated glomerular filtration rate, systolic and diastolic blood pressure, diabetes and hypertension were compared applying the Mann-Whitney test, followed by correction for multiple testing. Unsupervised learning algorithms were applied to investigate groups of similar urinary profiles. A total of 577 urinary peptides significantly associated with HF were sequenced, 447 of which (77%) were collagen fragments. In silico analysis suggested that urinary biomarker abnormalities in HF principally reflect changes in collagen turnover and immune response, both associated with fibrosis. Unsupervised clustering separated study participants into two clusters, with 83% of non-HF controls allocated to cluster 1, while 65% of patients with HF were allocated to cluster 2 (P < 0.0001). No separation based on HF subtype was detectable. CONCLUSIONS: Heart failure, irrespective of ejection fraction subtype, was associated with differences in abundance of urinary peptides reflecting collagen turnover and inflammation. These peptides should be studied as tools in early detection, prognostication, and prediction of therapeutic response.

Cognitive Impairment and Heart Failure: Systematic Review and Meta-Analysis.

BACKGROUND: Cognitive impairment and dementia are associated with a range of cardiovascular conditions, including hypertension, coronary artery disease, and atrial fibrillation. We aimed to describe the association with heart failure, summarizing published data to give estimates of prevalence, incidence, and relative risk of cognitive impairment/dementia in heart failure. METHODS: We searched multidisciplinary databases including MEDLINE (OVID), EMBASE (OVID), CINAHL (EBSCO), PsychINFO (EBSCO), Web of Science (Thomson Reuters), and CENTRAL (Cochrane Library) from inception until May 31, 2015. All relevant studies looking at cognitive impairment/dementia in heart failure were included. Studies were selected by 2 independent reviewers using prespecified inclusion/exclusion criteria. Where data allowed, we performed meta-analysis and pooled results using random effects models. RESULTS: From 18,000 titles, 37 studies were eligible (n = 8411 participants). Data from 4 prospective cohorts (n = 2513 participants) suggest greater cognitive decline in heart failure compared with non-heart failure over the longer term. These data were not suitable for meta-analysis. In case control studies describing those with and without heart failure (n = 4 papers, 1414 participants) the odds ratio for cognitive impairment in the heart failure population was 1.67 (95% confidence interval 1.15-2.42). Prevalence of cognitive impairment in heart failure cohorts (n = 26 studies, 4176 participants) was 43% (95% confidence interval 30-55). CONCLUSIONS: This review suggests a substantial proportion of patients with heart failure have concomitant cognitive problems. This has implications for planning treatment and services. These data do not allow us to comment on causation, and further work is needed to describe the underlying pathophysiology.

Dementia-related adverse events in PARADIGM-HF and other trials in heart failure with reduced ejection fraction.

AIMS: Inhibition of neprilysin, an enzyme degrading natriuretic and other vasoactive peptides, is beneficial in heart failure with reduced ejection fraction (HFrEF), as shown in PARADIGM-HF which compared the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan with enalapril. As neprilysin is also one of many enzymes clearing amyloid-ß peptides from the brain, there is a theoretical concern about the long-term effects of sacubitril/valsartan on cognition. Therefore, we have examined dementia-related adverse effects (AEs) in PARADIGM-HF and placed these findings in the context of other recently conducted HFrEF trials. METHODS AND RESULTS: In PARADIGM-HF, patients with symptomatic HFrEF were randomized to sacubitril/valsartan 97/103 mg b.i.d. or enalapril 10 mg b.i.d. in a 1:1 ratio. We systematically searched AE reports, coded using the Medical Dictionary for Regulatory Activities (MedDRA), using Standardized MedDRA Queries (SMQs) with 'broad' and 'narrow' preferred terms related to dementia. In PARADIGM-HF, 8399 patients aged 18-96 years were randomized and followed for a median of 2.25 years (up to 4.3 years). The narrow SMQ search identified 27 dementia-related AEs: 15 (0.36%) on enalapril and 12 (0.29%) on sacubitril/valsartan [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.33-1.59]. The broad search identified 97 (2.30%) and 104 (2.48%) AEs (HR 1.01, 95% CI 0.75-1.37), respectively. The rates of dementia-related AEs in both treatment groups in PARADIGM-HF were similar to those in three other recent trials in HFrEF. CONCLUSION: We found no evidence that sacubitril/valsartan, compared with enalapril, increased dementia-related AEs, although longer follow-up may be necessary to detect such a signal and more sensitive tools are needed to detect lesser degrees of cognitive impairment. Further studies to address this question are warranted.

Clinical outcomes according to QRS duration and morphology in the irbesartan in patients with heart failure and preserved systolic function (I-PRESERVE) trial.

BACKGROUND: The aims of this study were to describe the prevalence of QRS prolongation and abnormal QRS morphology in patients with heart failure and preserved ejection fraction (HF-PEF) and to examine the relationship between these QRS abnormalities and clinical outcomes. METHODS AND RESULTS: We categorized patients in the Irbesartan in Heart Failure with Preserved Ejection Fraction trial (I-PRESERVE) according to QRS duration <120 vs. ≥120 ms and QRS morphology: normal, left bundle branch block (LBBB), and right bundle branch block (RBBB) or other non-specific intra-ventricular conduction defect (IVCD). The outcomes examined were the composite of cardiovascular death or heart failure hospitalization (and its components) and all-cause mortality. Of the 4128 patients enrolled in I-PRESERVE, 3754 were included in the present analyses. A total of 606 patients had a QRS duration ≥120 ms, 302 had LBBB and 742 had RBBB/IVCD. Patients with an abnormal QRS had evidence of more severe heart failure [lower left ventricular ejection fraction, lower estimated glomerular filtration rate, higher N-terminal pro-B-type natriuretic peptide (NT-proBNP)] and worse clinical status (higher New York Heart Association functional class and greater use of diuretics). Both abnormalities of QRS duration and QRS morphology were associated with worse outcomes. The rates of the composite outcome were: 6.0 and 9.3 per 100 patient years in the <120 ms and ≥120 ms groups, respectively [adjusted hazard ratio (HR) 1.32, 95% confidence interval (CI) 1.11-1.57; P = 0.002) and 6.0, 7.7 and 8.7 per 100 patient years in the normal, non-LBBB and LBBB groups, respectively (adjusted HR 1.19, 95% CI 1.00-1.42, P = 0.046; and HR 1.31, 95% CI 1.03-1.66, P = 0.026, respectively, compared with normal). The heightened risk related to QRS abnormalities persisted after adjustment for other prognostic variables, including NT-proBNP. CONCLUSION: We found that both prolongation of QRS duration and abnormal QRS morphology were associated with a high risk of fatal and non-fatal adverse outcomes in heart failure with preserved ejection fraction.

Clinical outcomes according to QRS duration and morphology in the Eplerenone in Mild Patients: Hospitalization and SurvIval Study in Heart Failure (EMPHASIS-HF).

AIMS: We examined the relationship between different degrees of QRS prolongation and different QRS morphologies and clinical outcomes in patients with heart failure, reduced ejection fraction (HF-REF), and mild symptoms in the Eplerenone in Mild Patients Hospitalization and SurvIval Study in Heart Failure trial (EMPHASIS-HF). We also evaluated the effect of eplerenone in these patients according to QRS duration/morphology. METHODS AND RESULTS: Patients were categorized as: QRS duration (ms) (i) <120 (n = 1375); (ii) 120-149 (n = 517); and (iii) ≥150 (n = 383), and QRS morphology (i) normal (n = 1252); (ii) left bundle branch block (BBB) (n = 608); and (iii) right BBB/intraventricular conduction defect (IVCD) (n = 415). The outcomes examined were the composite of cardiovascular death or heart failure hospitalization and all-cause mortality. Both abnormal QRS duration and QRS morphology were associated with higher risk, e.g. the rates of the composite outcome were: 10.2, 17.6, and 15.5 per 100 patient-years in the <120, 120-149, and ≥150 ms groups, respectively. Eplerenone reduced the risk of the primary outcome and mortality, compared with placebo, consistently across the QRS duration/morphology subgroups. CONCLUSION: We found that even moderate prolongation of QRS duration and right BBB/IVCD were associated with a high risk of adverse outcomes in HF-REF. Eplerenone was similarly effective, irrespective of QRS duration/morphology.

Highlights from the British Society for Heart Failure 17th annual autumn meeting: "yesterday's problems, today's solutions".

The 17th Annual Autumn meeting of the British Society of Heart Failure entitled "Yesterday's problems, today's solutions" took place on the 27-28 November 2014 at the Queen Elizabeth II Conference Centre in London. Over 700 delegates joined together from across the UK, Europe and as far away as Australia to attend this year's meeting. Professionals from a range of backgrounds including physicians, surgeons, nurses, psychologists, pharmacists and trainees highlighted the multidisciplinary nature of heart failure care. The symposium, which is accredited by the Royal College of Physicians and the Royal College of Nursing, delivered the key message this year of the importance of a holistic approach to patients with heart failure.

Improving outcomes in peripartum cardiomyopathy.

Peripartum cardiomyopathy (PPCM) is a rare condition with a diverse spectrum of potential outcomes, ranging from frequent complete recovery to fulminant heart failure and death. The pathogenesis of PPCM is not well understood, and relatively little is known about its incidence and prevalence. PPCM is often under-recognised in the clinical setting. Early investigation and diagnosis with subsequent expert management may improve outcomes. The development of registries will allow this condition to be better characterised and may help answer crucial questions regarding its optimal medical and surgical management. This paper reviews the potential approaches to improve outcomes in patients with PPCM.

'Hearts and minds': association, causation and implication of cognitive impairment in heart failure.

The clinical syndrome of heart failure is one of the leading causes of hospitalisation and mortality in older adults. An association between cognitive impairment and heart failure is well described but our understanding of the relationship between the two conditions remains limited. In this review we provide a synthesis of available evidence, focussing on epidemiology, the potential pathogenesis, and treatment implications of cognitive decline in heart failure. Most evidence available relates to heart failure with reduced ejection fraction and the syndromes of chronic cognitive decline or dementia. These conditions are only part of a complex heart failure-cognition paradigm. Associations between cognition and heart failure with preserved ejection fraction and between acute delirium and heart failure also seem evident and where data are available we will discuss these syndromes. Many questions remain unanswered regarding heart failure and cognition. Much of the observational evidence on the association is confounded by study design, comorbidity and insensitive cognitive assessment tools. If a causal link exists, there are several potential pathophysiological explanations. Plausible underlying mechanisms relating to cerebral hypoperfusion or occult cerebrovascular disease have been described and it seems likely that these may coexist and exert synergistic effects. Despite the prevalence of the two conditions, when cognitive impairment coexists with heart failure there is no specific guidance on treatment. Institution of evidence-based heart failure therapies that reduce mortality and hospitalisations seems intuitive and there is no signal that these interventions have an adverse effect on cognition. However, cognitive impairment will present a further barrier to the often complex medication self-management that is required in contemporary heart failure treatment.

What can we learn from RELAX-AHF compared to previous AHF trials and what does the future hold?

Each year in the USA there are over 1 million hospital admissions directly related to heart failure (HF). With similar rates across Europe, this places a huge economic burden on healthcare systems globally. Hospitalisation for HF is associated with poor clinical outcomes with 25% of patients being readmitted with signs and symptoms of HF within 1 month of discharge and 10-20% dying in the 6 months after discharge. Although hospital admission could be a sign of disease progression, it is also possible that some of the treatments given acutely for example, inotropic therapy, may result in neurohormonal, haemodynamic and other effects accelerating end-organ damage and contributing to these poor outcomes after discharge. In contrast to the treatment of chronic heart failure (CHF), clinical trials conducted over the past decade in patients with acute HF (AHF) have failed to show significant reductions in morbidity or mortality despite some agents causing beneficial changes in symptoms. As such, the current treatment of patients hospitalised with HF is mainly based on consensus rather than clinical evidence and has changed little over time. We review RELAX-AHF in the context of the other key, large-scale AHF trials conducted over the past 15 years and compare and contrast study design and outcomes in an attempt to determine which factors might be associated with a successful trial in the future.

Emerging biomarkers for heart failure: an update.

A growing array of biological pathways underpins the syndrome we recognize as heart failure. These include both deleterious pathways promoting its development and progression, as well as compensatory cardioprotective pathways. Components of these pathways can be utilized as biomarkers of this condition to aid diagnosis, prognostication and potentially guide management. As our understanding of the pathophysiology of heart failure deepens further candidate biomarkers are being identified. We provide an overview of the more recently emerging biomarkers displaying potential promise for future clinical use.

Highlights from the British Society for Heart Failure 16(th) Annual Autumn Meeting: 'Making sense of acute heart failure'.

16th Annual Autumn Meeting of the British Society of Heart Failure: 'Making sense of acute heart failure', London, UK, 28-29 November 2013 The 16th Annual Autumn Meeting of the British Society of Heart Failure entitled 'Making sense of acute heart failure' took place on the 28-29 November 2013 at the Queen Elizabeth II Conference Centre in London. This year saw the 1000th member join the British Society of Heart Failure and over 700 delegates from the UK, Europe and North America attended this year's meeting. Professionals from a range of backgrounds were present including physicians, nurses, scientists, trainees and representatives from industry. The symposium, which is accredited by the Royal College of Physicians and the Royal College of Nursing, highlighted that although we have recently seen substantial progress in the management and outcomes of patients with chronic heart failure, acute heart failure management and outcomes have not changed significantly over almost a generation.