Guidelines for the prevention, detection and management of people with chronic heart failure in Australia 2006

* Chronic heart failure (CHF) is found in 1.5%–2.0% of Australians. Considered rare in people aged less than 45 years, its prevalence increases to over 10% in people aged ≥ 65 years. * CHF is one of the most common reasons for hospital admission and general practitioner consultation in the elderly (≥ 70 years). * Common causes of CHF are ischaemic heart disease (present in > 50% of new cases), hypertension (about two-thirds of cases) and idiopathic dilated cardiomyopathy (around 5%–10% of cases). * Diagnosis is based on clinical features, chest x-ray and objective measurement of ventricular function (eg, echocardiography). Plasma levels of B-type natriuretic peptide (BNP) may have a role in diagnosis, primarily as a test for exclusion. Diagnosis may be strengthened by a beneficial clinical response to treatment(s) directed towards amelioration of symptoms. * Management involves prevention, early detection, amelioration of disease progression, relief of symptoms, minimisation of exacerbations, and prolongation of survival.

The Effect of Selective Heart Rate Slowing in Heart Failure with Preserved Ejection Fraction

Acknowledgments Dr Ashrafian acknowledges support from the BHF Center of Research Excellence, Oxford, UK. The research was also supported by the National Institute for Health Research Oxford Biomedical Research Center Program and by the National Institute for Health Research Rare Diseases Translational Research Collaboration (NIHR RD-TRC)

The Effect of Selective Heart Rate Slowing in Heart Failure with Preserved Ejection Fraction

Acknowledgments Dr Ashrafian acknowledges support from the BHF Center of Research Excellence, Oxford, UK. The research was also supported by the National Institute for Health Research Oxford Biomedical Research Center Program and by the National Institute for Health Research Rare Diseases Translational Research Collaboration (NIHR RD-TRC)

Preservation of myocardial beta-adrenergic receptor signaling delays the development of heart failure after myocardial infarction.

When the heart fails, there is often a constellation of biochemical alterations of the beta-adrenergic receptor (betaAR) signaling system, leading to the loss of cardiac inotropic reserve. betaAR down-regulation and functional uncoupling are mediated through enhanced activity of the betaAR kinase (betaARK1), the expression of which is increased in ischemic and failing myocardium. These changes are widely viewed as representing an adaptive mechanism, which protects the heart against chronic activation. In this study, we demonstrate, using in vivo intracoronary adenoviral-mediated gene delivery of a peptide inhibitor of betaARK1 (betaARKct), that the desensitization and down-regulation of betaARs seen in the failing heart may actually be maladaptive. In a rabbit model of heart failure induced by myocardial infarction, which recapitulates the biochemical betaAR abnormalities seen in human heart failure, delivery of the betaARKct transgene at the time of myocardial infarction prevents the rise in betaARK1 activity and expression and thereby maintains betaAR density and signaling at normal levels. Rather than leading to deleterious effects, cardiac function is improved, and the development of heart failure is delayed. These results appear to challenge the notion that dampening of betaAR signaling in the failing heart is protective, and they may lead to novel therapeutic strategies to treat heart disease via inhibition of betaARK1 and preservation of myocardial betaAR function.

Text-messaging as a Tool for Medication Adherence and Behavior Change in Disease Management among Patients with Coronary Heart Disease

Background: Evidence-based medication and lifestyle modification are important for secondary prevention of cardiovascular disease but are underutilized. Mobile health strategies could address this gap but existing evidence is mixed. Therefore, we piloted a pre-post study to assess the impact of patient-directed text messages as a means of improving medication adherence and modifying major health risk behaviors among coronary heart disease (CHD) patients in Hainan, China.

Methods: 92 CVD patients were surveyed between June and August 2015 (before the intervention) and then between October and December 2015 (after 12 week intervention) about (a) medication use (b) smoking status,(c) fruit and vegetable consumption, and (d) physical activity uptake. Acceptability of text-messaging intervention was assessed at follow-up. Descriptive statistics, along with paired comparisons between the pre and post outcomes were conducted using both parametric (t-test) and non-parametric (Wilcoxon signed rank test) methods.

Results: The number of respondents at follow-up was 82 (89% retention rate). Significant improvements were observed for medication adherence (P<0.001) and for the number of cigarettes smoked per day (P=.022). However there was no change in the number of smokers who quitted smoking at follow-up. There were insignificant changes for physical activity (P=0.91) and fruit and vegetable consumption.

Exercise Training Reduces Liver Fat and Increases Rates of VLDL Clearance, but not VLDL Production in NAFLD

Context Randomised controlled trials in non-alcoholic fatty liver disease (NAFLD) have shown that regular exercise, even without calorie restriction, reduces liver steatosis. A previous study has shown that 16 weeks supervised exercise training in NAFLD did not affect total VLDL kinetics. Objective To determine the effect of exercise training on intrahepatocellular fat (IHCL) and the kinetics of large triglyceride-(TG)-rich VLDL1 and smaller denser VLDL2 which has a lower TG content. Design A 16 week randomised controlled trial. Patients 27 sedentary patients with NAFLD. Intervention Supervised exercise with moderate-intensity aerobic exercise or conventional lifestyle advice (control). Main outcome Very low density lipoprotein1 (VLDL1) and VLDL2-TG and apolipoproteinB (apoB) kinetics investigated using stable isotopes before and after the intervention. Results In the exercise group VO2max increased by 31±6% (mean±SEM) and IHCL decreased from 19.6% (14.8, 30.0) to 8.9% (5.4, 17.3) (median (IQR)) with no significant change in VO2max or IHCL in the control group (change between groups p<0.001 and p=0.02, respectively). Exercise training increased VLDL1-TG and apoB fractional catabolic rates, a measure of clearance, (change between groups p=0.02 and p=0.01, respectively), and VLDL1-apoB production rate (change between groups p=0.006), with no change in VLDL1 -TG production rate. Plasma TG did not change in either group. Conclusion An increased clearance of VLDL1 may contribute to the significant decrease in liver fat following 16 weeks of exercise in NAFLD. A longer duration or higher intensity exercise interventions may be needed to lower plasma TG and VLDL production rate.

A Central Role for Monocyte-Platelet Interactions in Heart Failure

Heart failure (HF) is an increasingly prevalent and costly multifactorial syndrome with high morbidity and mortality rates. The exact pathophysiological mechanisms leading to the development of HF are not completely understood. Several emerging paradigms implicate cardiometabolic risk factors, inflammation, endothelial dysfunction, myocardial fibrosis, and myocyte dysfunction as key factors in the gradual progression from a healthy state to HF. Inflammation is now a recognized factor in disease progression in HF and a therapeutic target. Furthermore, the monocyte-platelet interaction has been highlighted as an important pathophysiological link between inflammation, thrombosis, endothelial activation, and myocardial malfunction. The contribution of monocytes and platelets to acute cardiovascular injury and acute HF is well established. However, their role and interaction in the pathogenesis of chronic HF are not well understood. In particular, the cross talk between monocytes and platelets in the peripheral circulation and in the vicinity of the vascular wall in the form of monocyte-platelet complexes (MPCs) may be a crucial element, which influences the pathophysiology and progression of chronic heart disease and HF. In this review, we discuss the role of monocytes and platelets as key mediators of cardiovascular inflammation in HF, the mechanisms of cell activation, and the importance of monocyte-platelet interaction and complexes in HF pathogenesis. Finally, we summarize recent information on pharmacological inhibition of inflammation and studies of antithrombotic strategies in the setting of HF that can inform opportunities for future work. We discuss recent data on monocyte-platelet interactions and the potential benefits of therapy directed at MPCs, particularly in the setting of HF with preserved ejection fraction.

MicroRNA signatures differentiate preserved from reduced ejection fraction heart failure

AIMS: Differentiation of heart failure with reduced (HFrEF) or preserved (HFpEF) ejection fraction independent of echocardiography is challenging in the community. Diagnostic strategies based on monitoring circulating microRNA (miRNA) levels may prove to be of clinical value in the near future. The aim of this study was to identify a novel miRNA signature that could be a useful HF diagnostic tool and provide valuable clinical information on whether a patient has HFrEF or HFpEF.

METHODS AND RESULTS: MiRNA biomarker discovery was carried out on three patient cohorts, no heart failure (no-HF), HFrEF, and HFpEF, using Taqman miRNA arrays. The top five miRNA candidates were selected based on differential expression in HFpEF and HFrEF (miR-30c, -146a, -221, -328, and -375), and their expression levels were also different between HF and no-HF. These selected miRNAs were further verified and validated in an independent cohort consisting of 225 patients. The discriminative value of BNP as a HF diagnostic could be improved by use in combination with any of the miRNA candidates alone or in a panel. Combinations of two or more miRNA candidates with BNP had the ability to improve significantly predictive models to distinguish HFpEF from HFrEF compared with using BNP alone (area under the receiver operating characteristic curve >0.82).

CONCLUSION: This study has shown for the first time that various miRNA combinations are useful biomarkers for HF, and also in the differentiation of HFpEF from HFrEF. The utility of these biomarker combinations can be altered by inclusion of natriuretic peptide. MiRNA biomarkers may support diagnostic strategies in subpopulations of patients with HF.

Heart failure in sub-Saharan Africa: review of the aetiology of heart failure and the role of point-of-care biomarker diagnostics

Within Africa, the burden of heart failure is significant. This arises from the increase in cardiovascular disease and associated risk factors such as hypertension and diabetes, as well as causes of heart failure which are particular to sub-Saharan Africa, such as endomyocardial fibrosis. The lack of access to echocardiography and other imaging modalities, from a cost and technical perspective, combined with the predominantly rural nature of many countries with poor transport links, means that the vast majority of people never obtain an appropriate diagnosis. Similarly, research has been limited on the causes and treatment of heart failure in Africa and in particular endemic causes such as EMF and rheumatic heart disease. This review outlines the burden of heart failure in Africa and highlights the opportunity to expand diagnosis through the use of biomarkers, in particular natriuretic peptides. This builds on the success of point-of-care testing in human immunodeficiency virus and tuberculosis which have been extensively deployed in community settings in Africa.

Life expectancy for community-based patients with heart failure from time of diagnosis

AIMS: Heart failure has been demonstrated in previous studies to have a dismal prognosis. However, the modern-day prognosis of patients with new onset heart failure diagnosed in the community managed within a disease management programme is not known. The purpose of this study is to report on prognosis of patients presenting with new onset heart failure in the community who are subsequently followed in a disease management program.

METHODS AND RESULTS: A review of patients referred to a rapid access heart failure diagnostic clinic between 2002 and 2012 was undertaken. Details of diagnosis, demographics, medical history, medications, investigations and mortality data were analysed. A total of 733 patients were seen in Rapid Access Clinic for potential new diagnosis of incident of heart failure. 38.9% (n=285) were diagnosed with heart failure, 40.7% (n=116) with HF-REF and 59.3% (n=169) with HF-PEF. There were 84 (29.5%) deaths in the group of patients diagnosed with heart failure; 41 deaths (35.3%) occurred in patients with HF-REF and 43 deaths (25.4%) occurred in patients with HF-PEF. In patients with heart failure, 52.4% (n=44) died from cardiovascular causes. 63.8% of HF patients were alive after 5 years resulting on average in a month per year loss of life expectancy over that period compared with aged matched simulated population.

CONCLUSIONS: In this community-based cohort, the prognosis of heart failure was better than reported in previous studies. This is likely due to the impact of prompt diagnosis, the improvement in therapies and care within a disease management structure.

Importance of risk factor management in diabetic patients and reduction in Stage B heart failure

BACKGROUND: A number of studies have demonstrated the presence of a diabetic cardiomyopathy, increasing the risk of heart failure development in this population. Improvements in present-day risk factor control may have modified the risk of diabetes-associated cardiomyopathy.

AIM: We sought to determine the contemporary impact of diabetes mellitus (DM) on the prevalence of cardiomyopathy in at-risk patients with and without adjustment for risk factor control.

DESIGN: A cross-sectional study in a population at risk for heart failure.

METHODS: Those with diabetes were compared to those with other cardiovascular risk factors, unmatched, matched for age and gender and then matched for age, gender, body mass index, systolic blood pressure and low density lipoprotein cholesterol.

RESULTS: In total, 1399 patients enrolled in the St Vincent's Screening to Prevent Heart Failure (STOP-HF) cohort were included. About 543 participants had an established history of DM. In the whole sample, Stage B heart failure (asymptomatic cardiomyopathy) was not found more frequently among the diabetic cohort compared to those without diabetes [113 (20.8%) vs. 154 (18.0%), P = 0.22], even when matched for age and gender. When controlling for these risk factors and risk factor control Stage B was found to be more prevalent in those with diabetes [88 (22.2%)] compared to those without diabetes [65 (16.4%), P = 0.048].

CONCLUSION: In this cohort of patients with established risk factors for Stage B heart failure superior risk factor management among the diabetic population appears to dilute the independent diabetic insult to left ventricular structure and function, underlining the importance and benefit of effective risk factor control in this population on cardiovascular outcomes.

Natriuretic peptide-based screening and collaborative care for heart failure:the STOP-HF randomized trial

IMPORTANCE: Prevention strategies for heart failure are needed.

OBJECTIVE: To determine the efficacy of a screening program using brain-type natriuretic peptide (BNP) and collaborative care in an at-risk population in reducing newly diagnosed heart failure and prevalence of significant left ventricular (LV) systolic and/or diastolic dysfunction.

DESIGN, SETTING, AND PARTICIPANTS: The St Vincent's Screening to Prevent Heart Failure Study, a parallel-group randomized trial involving 1374 participants with cardiovascular risk factors (mean age, 64.8 [SD, 10.2] years) recruited from 39 primary care practices in Ireland between January 2005 and December 2009 and followed up until December 2011 (mean follow-up, 4.2 [SD, 1.2] years).

INTERVENTION: Patients were randomly assigned to receive usual primary care (control condition; n=677) or screening with BNP testing (n=697). Intervention-group participants with BNP levels of 50 pg/mL or higher underwent echocardiography and collaborative care between their primary care physician and specialist cardiovascular service.

MAIN OUTCOMES AND MEASURES: The primary end point was prevalence of asymptomatic LV dysfunction with or without newly diagnosed heart failure. Secondary end points included emergency hospitalization for arrhythmia, transient ischemic attack, stroke, myocardial infarction, peripheral or pulmonary thrombosis/embolus, or heart failure.

RESULTS: A total of 263 patients (41.6%) in the intervention group had at least 1 BNP reading of 50 pg/mL or higher. The intervention group underwent more cardiovascular investigations (control, 496 per 1000 patient-years vs intervention, 850 per 1000 patient-years; incidence rate ratio, 1.71; 95% CI, 1.61-1.83; P<.001) and received more renin-angiotensin-aldosterone system-based therapy at follow-up (control, 49.6%; intervention, 56.5%; P=.01). The primary end point of LV dysfunction with or without heart failure was met in 59 (8.7%) of 677 in the control group and 37 (5.3%) of 697 in the intervention group (odds ratio [OR], 0.55; 95% CI, 0.37-0.82; P = .003). Asymptomatic LV dysfunction was found in 45 (6.6%) of 677 control-group patients and 30 (4.3%) of 697 intervention-group patients (OR, 0.57; 95% CI, 0.37-0.88; P = .01). Heart failure occurred in 14 (2.1%) of 677 control-group patients and 7 (1.0%) of 697 intervention-group patients (OR, 0.48; 95% CI, 0.20-1.20; P = .12). The incidence rates of emergency hospitalization for major cardiovascular events were 40.4 per 1000 patient-years in the control group vs 22.3 per 1000 patient-years in the intervention group (incidence rate ratio, 0.60; 95% CI, 0.45-0.81; P = .002).

CONCLUSION AND RELEVANCE: Among patients at risk of heart failure, BNP-based screening and collaborative care reduced the combined rates of LV systolic dysfunction, diastolic dysfunction, and heart failure.

TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00921960.

Progression of left atrial volume index in a population at risk for heart failure:a substudy of the STOP-HF (St Vincent's Screening TO Prevent Heart Failure) trial

AIMS: Limited data are available concerning the evolution of the left atrial volume index (LAVI) in pre-heart failure (HF) patients. The aim of this study was to investigate clinical characteristics and serological biomarkers in a cohort with risk factors for HF and evidence of serial atrial dilatation.

METHODS AND RESULTS: This was a prospective substudy within the framework of the STOP-HF cohort (NCT00921960) involving 518 patients with risk factors for HF electively undergoing serial clinical, echocardiographic, and natriuretic peptide assessment. Mean follow-up time between assessments was 15 ± 6 months. 'Progressors' (n = 39) were defined as those with serial LAVI change ≥3.5 mL/m(2) (and baseline LAVI between 20 and 34 mL/m(2)). This cut-off was derived from a calculated reference change value above the biological, analytical, and observer variability of serial LAVI measurement. Multivariate analysis identified significant baseline clinical associates of LAVI progression as increased age, beta-blocker usage, and left ventricular mass index (all P < 0.05). Serological biomarkers were measured in a randomly selected subcohort of 30 'Progressors' matched to 30 'Non-progressors'. For 'Progressors', relative changes in matrix metalloproteinase 9 (MMP9), tissue inhibitor of metalloproteinase 1 (TIMP1), and the TIMP1/MMP9 ratio, markers of interstitial remodelling, tracked with changes in LAVI over time (all P < 0.05).

CONCLUSION: Accelerated LAVI increase was found to occur in up to 14% of all pre-HF patients undergoing serial echocardiograms over a relatively short follow-up period. In a randomly selected subcohort of 'Progressors', changes in LAVI were closely linked with alterations in MMP9, TIMP1, and the ratio of these enzymes, a potential aid in highlighting this at-risk group.

Can emerging biomarkers of myocardial remodelling identify asymptomatic hypertensive patients at risk for diastolic dysfunction and diastolic heart failure?

AIMS: Hypertension is one of the main drivers of the heart failure (HF) epidemic. The aims of this study were to profile fibro-inflammatory biomarkers across stages of the hypertensive heart disease (HHD) spectrum and to examine whether particular biochemical profiles in asymptomatic patients identify a higher risk of evolution to HF.

METHODS AND RESULTS: This was a cross-sectional observational study involving a population of 275 stable hypertensive patients divided into two different cohorts: Group 1, asymptomatic hypertension (AH) (n= 94); Group 2, HF with preserved ejection fraction (n= 181). Asymptomatic hypertension patients were further subdivided according to left atrial volume index ≥34 mL/m(2) (n= 30) and <34 mL/m(2) (n= 64). Study assays involved inflammatory markers [interleukin 6 (IL6), interleukin 8 (IL8), monocyte chemoattractant protein 1 (MCP1), and tumour necrosis factor α], collagen 1 and 3 metabolic markers [carboxy-terminal propeptide of collagen 1, amino-terminal propeptide of collagen 1, amino-terminal propeptide of collagen 3 (PIIINP), and carboxy-terminal telopeptide of collagen 1 (CITP)], extra-cellular matrix turnover markers [matrix metalloproteinase 2 (MMP2), matrix metalloproteinase 9 (MMP9), and tissue inhibitor of metalloproteinase 1 (TIMP1)], and the brain natriuretic peptide. Data were adjusted for age, sex, systolic blood pressure, and creatinine. Heart failure with preserved ejection fraction was associated with an increased inflammatory signal (IL6, IL8, and MCP1), an increased fibrotic signal (PIIINP and CITP), and an increased matrix turnover signal (MMP2 and MMP9). Alterations in MMP and TIMP enzymes were found to be significant indicators of greater degrees of asymptomatic left ventricular diastolic dysfunction.

CONCLUSION: These data define varying fibro-inflammatory profiles throughout different stages of HHD. In particular, the observations on MMP9 and TIMP1 raise the possibility of earlier detection of those at risk of evolution to HF which may help focus effective preventative strategies.

Murine Models of Diastolic Dysfunction and Heart Failure With Preserved Ejection Fraction

Left ventricular diastolic dysfunction leads to heart failure with preserved ejection fraction, an increasingly prevalent condition largely driven by modern day lifestyle risk factors. As heart failure with preserved ejection fraction accounts for almost one-half of all patients with heart failure, appropriate nonhuman animal models are required to improve our understanding of the pathophysiology of this syndrome and to provide a platform for preclinical investigation of potential therapies. Hypertension, obesity, and diabetes are major risk factors for diastolic dysfunction and heart failure with preserved ejection fraction. This review focuses on murine models reflecting this disease continuum driven by the aforementioned common risk factors. We describe various models of diastolic dysfunction and highlight models of heart failure with preserved ejection fraction reported in the literature. Strengths and weaknesses of the different models are discussed to provide an aid to translational scientists when selecting an appropriate model. We also bring attention to the fact that heart failure with preserved ejection fraction is difficult to diagnose in animal models and that, therefore, there is a paucity of well described animal models of this increasingly important condition.