Heart Failure Guidelines on Pharmacotherapy.

Heart Failure (HF) is a serious emerging Public Health issue mainly in the high-income countries. In the USA, more than 6 million adults are affected. Despite the latest advances in device and pharmacological therapeutics, it still carries a huge burden, partially reflected in the annual healthcare cost of approximately $30 billion (2012) and the 5 year mortality rate of 50%. In this article, we review the medications, proven to significantly reduce mortality and morbidity in HF patients with structural myocardial disease and past or current symptoms, based on the latest North American HF guidelines. We, finally, perform a brief comparison between the former recommendations and the published 2016 HF guidelines by European Society of Cardiology.

Utility of positron emission tomography for drug development for heart failure.

Only about 1 in 5,000 investigational agents in a preclinical stage acquires Food and Drug Administration approval. Among many reasons for this includes an inefficient transition from preclinical to clinical phases, which exponentially increase the cost and the delays the process of drug development. Positron emission tomography (PET) is a nuclear imaging technique that has been used for the diagnosis, risk stratification, and guidance of therapy. However, lately with the advance of radiochemistry and of molecular imaging technology, it became evident that PET could help novel drug development process. By using a PET radioligand to report on receptor occupancy during novel agent therapy, it may help assess the effectiveness, efficacy, and safety of such a new medication in an early preclinical stage and help design successful clinical trials even at a later phase. In this article, we explore the potential implications of PET in the development of new heart failure therapies and review PET's application in the respective pathophysiologic pathways such as myocardial perfusion, metabolism, innervation, inflammation, apoptosis, and cardiac remodeling.

Echocardiography in Acute Heart Failure: Current Perspectives.

In contrast to chronic heart failure (HF), the use of echocardiography in acute HF (AHF) is less well defined, both in clinical practice and in clinical trials. Current guidelines recommend the utility of echocardiography as an adjunct diagnostic tool in the clinical setting of new-onset or decompensated HF. However, despite its unique advantages as the only practical imaging modality in AHF, echocardiography poses unique challenges in this setting. Data from early-phase clinical studies and trials provide evidence that echocardiographic end points can be clinically meaningful surrogate end points as a means to track response to treatment in AHF; however, the optimal timing and selection of echocardiographic measures is under active investigation. In addition, despite a number of studies indicating that certain echocardiographic measures of cardiac function are predictive of post-discharge prognosis, the role of echocardiography as a tool for patient classification and risk determination in AHF is less well defined. Importantly, it is unclear whether echocardiography can be used to phenotype and select AHF patients for interventions. In this article, we (1) appraise the current evidence for use of echocardiographic measures in AHF, (2) identify knowledge gaps regarding optimal use of echocardiography in AHF, and (3) assess the evidence for echocardiography as a prognosis determination and risk stratification tool in AHF.

Effect of Obesity on Response to Spironolactone in Patients With Heart Failure With Preserved Ejection Fraction.

Obesity is common in heart failure with preserved ejection fraction (HFpEF). Whether obesity modifies the response to spironolactone in patients with HFpEF remains unclear. We aimed to investigate the effect of obesity, defined by body mass index (BMI) and waist circumference (WC), on response to spironolactone in patients with HFpEF enrolled in Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial. This was a post-hoc, exploratory analysis of the Americas cohort of Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial. BMI≥30 kg/m2 was used to define the obese group and WC≥102 cm in men and ≥88 cm in women were defined as high WC. In separate analyses, BMI and WC were treated as continuous variables. The effect of spironolactone versus placebo on outcomes was calculated by BMI and WC using Cox proportional hazard models. Obese patients were younger and had more co-morbidities. In multivariate analysis, spironolactone use was associated with a significant reduction in the primary end point, compared with placebo in obese [hazard ratio (HR = 0.618, 95% CI 0.460 to 0.831, p = 0.001), but not in nonobese subjects (HR = 0.946, 95% CI 0.623 to 1.437, p = 0.796; p for interaction = 0.056). There was a linear association between continuous BMI and the effect of spironolactone, with the effect becoming significant at 33kg/m2. Similar results were obtained for the WC-based analysis. In conclusion, use of spironolactone in obese patients with HFpEF was associated with a decreased risk of the primary end point, cardiovascular death and HF hospitalizations, compared with placebo. Further prospective randomized studies in obese subjects are required.

Torrential Mitral Regurgitation After Transcatheter Edge-to-Edge Mitral Valve Repair.

A patient with severe mitral regurgitation and chronic systolic heart failure taking inotropic support at home presents for transcatheter edge-to-edge mitral valve repair, complicated by torrential mitral regurgitation from damaged mitral leaflets requiring escalating mechanical circulatory support and ultimately expedited orthotopic heart transplantation. (Level of Difficulty: Intermediate.).

Low- Versus Moderate-Sodium Diet in Patients With Recent Hospitalization for Heart Failure: The PROHIBIT (Prevent Adverse Outcomes in Heart Failure by Limiting Sodium) Pilot Study.

BACKGROUND: We conducted a pilot study to assess feasibility, on-study retention, trends in natriuretic peptide levels, quality of life, and safety of a 12-week feeding trial with 1500- versus 3000-mg daily sodium meals in high-risk patients with heart failure. METHODS: Of 196 patients with recent (≤2 weeks) hospitalization for heart failure, ejection fraction ≤40%, on optimal medical therapy, functionally independent, and able to communicate, 83 (47%) consented to participate. Of these, 27 (age, 62±11 years; 22 men; 20 white; ejection fraction, 26±8%) had 24-hour urine sodium ≥3000 mg and agreed to randomly receive either 1500-mg (N=12) or 3000-mg (N=15) sodium meals. RESULTS: On-study retention at 12 weeks was 77% (82% versus 73%; P=0.53); 6 patients (2 in 1500-mg, 4 in 3000-mg arm) withdrew before study completion. Food satisfaction questionnaires indicated that both diets were well tolerated. Quality of life improved in the 1500-mg arm at 12 weeks but did not change in the 3000-mg arm. Average compliance with meals was 52% (based on urinary sodium) and was not significantly different between arms (42% versus 60%; P=0.25). Study meals reduced 24-hour urinary sodium by 137±21 mmol (1500-mg arm) and 82±16 mmol (3000-mg arm), both P<0.001; between-arms difference was 55 mmol (95% CI, 3-107; P=0.037). NT-proBNP (N-terminal pro-B-type natriuretic peptide) was not affected. Hospitalizations and low blood pressure events did not differ significantly between arms. Serum creatinine decreased more (by 0.17 mg/dL [95% CI, 0.06-0.28]; P=0.003) in the 1500-mg arm. Creatinine increases >0.5 mg/dL over baseline only occurred in 1 patient in the 3000-mg arm. CONCLUSIONS: Even with prepared meals, investigating optimal dietary sodium in heart failure comes with challenges, including need for extensive screening, reluctance to participate, and compliance issues. Because both diets reduced urinary sodium without adverse safety or quality of life signals, a larger trial, with modifications to improve participation and compliance, would be ethical and feasible. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02467296.

The Limitations of Symptom-based Heart Failure Management.

Heart failure (HF) has emerged as a global epidemic and it affects about 6 million adults in the US. HF medical treatment, as recommended in guidelines, significantly improves survival and quality of life; however, the mortality burden of HF remains high. For decades, treatment has been guided, mainly by symptoms, leading to undertreatment in a range of settings. Current evidence emphasises the unfavourable outcomes of HF even in early stages or in patients who achieve reverse remodeling and remission or recovery under optimised treatment. This should stimulate efforts towards a more objective, rigorous management, covering the entire spectrum of mild, moderate and severe HF.

Comorbidities, Sociodemographic Factors, and Hospitalizations in Outpatients With Heart Failure and Preserved Ejection Fraction.

Patients with heart failure and preserved ejection fraction (HFpEF) tend to be older and have a high co-morbidity burden. The impact of co-morbid conditions and sociodemographic risk factors on outcomes in these patients has not been quantified. We evaluated 445 consecutive outpatients with HFpEF, defined as established diagnosis of heart failure (HF) with left ventricular ejection fraction at presentation >40% and no previous left ventricular ejection fraction ≤40%. Patients with specific cardiomyopathies, congenital heart disease, primary right-sided disease, valvular disease, or previous advanced HF therapies were excluded. After 2 years, there were 44 deaths and 609 all-cause hospitalizations; of these, 260 (42.7%) were cardiovascular hospitalizations, including HF, and 173 (28.4%) were specifically for HF. The highest attributable risk for hospitalizations was associated with marital status (single, divorced, and widowed had higher hospitalization rates compared with married patients), hypoalbuminemia, diabetes, atrial fibrillation, and renal dysfunction. The proportion of hospitalizations potentially attributable to these factors was 66.6% (95% confidence interval [CI] 56.4 to 74.4) for all-cause hospitalizations, 76.9% (95% CI 65.2 to 84.6) for cardiovascular hospitalizations, and 83.0% (95% CI 70.3 to 90.3) for HF hospitalizations. For composite end points, the proportion was 46.9% (95% CI 34.0% to 57.3%) for death or all-cause hospitalization, 45.7% (95% CI 29.3% to 58.2%) for death or cardiovascular hospitalization, and 43.7% (95% CI 24.2% to 58.2%) for death or HF-related hospitalization. In conclusion, among outpatients with HFpEF, most hospitalizations could be attributed to co-morbidities and sociodemographic factors. Effects of HF therapies on hospitalizations and related end points may be difficult to demonstrate in these patients. Multidisciplinary approaches are more likely to impact hospitalizations in HFpEF.

Mobile health applications in cardiovascular research.

Cardiovascular disease is the leading cause of mortality and morbidity globally. With widespread and growing use of smart phones and mobile devices, the use of mobile health (mHealth) in transmission of physiologic parameters and patient-referred symptoms to healthcare providers and researchers, as well as reminders and care plan applications from providers to patients, has potential to revolutionize both clinical care and the conduct of clinical trials with improved designs, data capture, and potentially lower costs. In randomized early phase proof-of-concept studies, focusing on lifestyle intervention, there is evidence that mHealth technology can improve outcomes. By contrast, results from small randomized controlled trials that tested mHealth interventions in heart failure patients were disappointing with inconsistent findings. These inconclusive results could be partially attributed to a lack of methodological rigor (insufficient sample size, quasi-experimental design, inadequate mHealth equipment). Therefore, there is an urgent need to develop systematic evidence-based guidelines and parameters for mHealth to be effectively utilized in cardiovascular clinical trials.

Heart failure guidelines: What's new?

Heart Failure is a global epidemic, affecting approximately 5 million adults in the U.S.A. The cornerstone of contemporary pharmacological therapy targets the over activated renin-angiotensin-aldosterone and sympathetic autonomic systems. The 2016 focused pharmacologic update on the current Heart Failure Guidelines introduces the use of two newly approved regimens valsartan/sacubitril and ivabradine. Over the last two decades, guideline directed medical therapy has accomplished significant improvement in survival rates among heart failure patients; however these novel compounds were reported to exert additional mortality and morbidity benefits, in heart failure subpopulations with reduced ejection fraction.

Serelaxin for the treatment of heart failure.

Outcomes for patients with acute heart failure remain suboptimal and treatments principally target improvement of symptoms. To date there has been no therapy approved for acute heart failure shown to improve mortality or readmission risk post-discharge. Serelaxin, a recombinant form of the naturally occurring polypeptide hormone relaxin, has demonstrated promise in preclinical and early clinical trials as a potentially novel therapy for acute heart failure. It is postulated through its anti-fibrotic and vasodilatory effects that this agent can improve outcomes in both the short and long term in these patients. Randomized clinical data has suggested that the medication is safe and well tolerated. However, definitive outcomes data is currently being assessed in a large multi-center trial.

Hyperkalemia in Heart Failure.

Disorders of potassium homeostasis can potentiate the already elevated risk of arrhythmia in heart failure. Heart failure patients have a high prevalence of chronic kidney disease, which further heightens the risk of hyperkalemia, especially when renin-angiotensin-aldosterone system inhibitors are used. Acute treatment for hyperkalemia may not be tolerated in the long term. Recent data for patiromer and sodium zirconium cyclosilicate, used to treat and prevent high serum potassium levels on a more chronic basis, have sparked interest in the treatment of hyperkalemia, as well as the potential use of renin-angiotensin-aldosterone system inhibitors in patients who were previously unable to take these drugs or tolerated only low doses. This review discusses the epidemiology, pathophysiology, and outcomes of hyperkalemia in heart failure; provides an overview of traditional and novel ways to approach management of hyperkalemia; and discusses the need for further research to optimally treat heart failure.

Characteristics and Outcomes of Adult Outpatients With Heart Failure and Improved or Recovered Ejection Fraction.

IMPORTANCE: Heart failure (HF) guidelines recognize that a subset of patients with HF and preserved left ventricular ejection fraction (LVEF) previously had reduced LVEF but experienced improvement or recovery in LVEF. However, data on these patients are limited. OBJECTIVE: To investigate the characteristics and outcomes of adult outpatients with HF and improved or recovered ejection fraction (HFrecEF). DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study (inception period, January 1, 2012, to April 30, 2012) with 3-year follow-up at cardiology clinics (including HF subspecialty) in an academic institution. The dates of the analysis were May 21, 2015, to August 10, 2015. Participants were all outpatients 18 years or older who received care for a verified diagnosis of HF not attributed to specific cardiomyopathies or other special causes during the inception period. EXPOSURES: Type of HF at baseline, classified as HF with reduced ejection fraction (HFrEF) (defined as current LVEF ≤40%), HF with preserved ejection fraction (HFpEF) (defined as current and all previous LVEF reports >40%), and HF with recovered ejection fraction (HFrecEF) (defined as current LVEF >40% but any previously documented LVEF ≤40%). MAIN OUTCOMES AND MEASURES: Mortality, hospitalization rates, and composite end points. RESULTS: The study cohort comprised 2166 participants. Their median age was 65 years, 41.4% (896 of 2166) were female, 48.7% (1055 of 2166) were white and 45.2% (1368 of 2166) black, and 63.2% (1368 of 2166) had coronary artery disease. Preserved (>40%) LVEF at inception was present in 816 of 2166 (37.7%) patients. Of these patients, 350 of 2166 (16.2%) had previously reduced (≤40%) LVEF and were classified as having HFrecEF, whereas 466 of 2166 (21.5%) had no previous reduced LVEF and were classified as having HFpEF. The remaining 1350 (62.3%) patients were classified as having HFrEF. After 3 years, age and sex-adjusted mortality was 16.3% in patients with HFrEF, 13.2% in patients with HFpEF, and 4.8% in patients with HFrecEF (P < .001 vs HFrEF or HFpEF). Compared with patients with HFpEF and patients with HFrEF, patients with HFrecEF had fewer all-cause (adjusted rate ratio [RR] vs HFpEF, 0.71; 95% CI, 0.55-0.91; P = .007), cardiovascular (RR, 0.50; 95% CI, 0.35-0.71; P < .001), and HF-related (RR, 0.48; 95% CI, 0.30-0.76; P = .002) hospitalizations and were less likely to experience composite end points commonly used in clinical trials (death or cardiovascular hospitalization and death or HF hospitalization). CONCLUSIONS AND RELEVANCE: Outpatients with HFrecEF have a different clinical course than patients with HFpEF and HFrEF, with lower mortality, less frequent hospitalizations, and fewer composite end points. These patients may need to be investigated separately in outcomes studies and clinical trials.

Inflammatory Biomarkers and Therapeutic Targets in Heart Failure.

Improved outcomes of acute cardiac conditions, population aging, prevalent lifestyle-related risk factors, and advances in heart failure (HF) therapy, all have led to an ever-increasing prevalence of HF, currently considered a public health priority in developed countries and a major noncommunicable syndrome in developing regions. Heart failure is a complex syndrome with a host of pathophysiological mechanisms in action. Inflammation, an integral component of homeostasis, is a complex tissue response to stressors that attempts to mitigate their effect and initiate healing. Inflammation plays a critical role in the development, course, severity and outcomes of HF. The delicate balance of pro- and antiinflammatory processes can lead to beneficial or detrimental effects to the failing heart. In this article, we review the evidence on inflammatory biomarkers and their potential role in prognosis and therapeutic decisions for patients with HF. Although attempts to directly disrupt the inflammatory cascade in HF have been largely abandoned due to lack of efficacy and potential harm, there are still important gaps in our knowledge. Despite the strong association of levels of inflammatory biomarkers with HF severity and comorbidities, the causal association of certain markers and pathways with specific types or aspects of HF remains to be elucidated. When used as treatment response markers in conjunction with other risk factors, inflammatory markers have the potential to improve risk stratification of patients with HF and personalize HF treatment, with the ultimate goal to improve quality of life and prolong survival in these patients.

Mineralocorticoid Receptor Antagonism in Acute Heart Failure.

OPINION STATEMENT: Heart failure (HF) remains a tremendous burden to health care systems and patients worldwide. The cornerstone neurohormonal disruption that leads to the debilitating sequelae in HF patients revolves primarily around aldosterone and the renin-angiotensin-aldosterone system (RAAS). Aldosterone plays a detrimental role in tissue remodeling by inducing inflammation and fibrosis within the cardiovascular and renal systems, leaving mineralocorticoid receptor antagonists (MRAs) as key pharmacological tools to slow pathogenesis and improve patient outcomes. The role of MRA in improving morbidity and mortality in outpatients with chronic HF and low ejection fraction is well established and supported by large randomized controlled trials. However, evidence-based data relating to the use of MRA in acute HF (AHF) remain somewhat limited, and therefore, the use of MRA is not ubiquitously considered in the acute setting. Current studies for the use of MRA in AHF are limited by small sample size as well as safety concerns relating to the dose-dependent effects on electrolyte homeostasis and renal function. Here, we discuss the imperative need for additional trials elucidating the potential benefits of MRA in AHF as an adjunct diuretic therapy. We not only discuss the role of MRA in neurohormonal regulation of aldosterone but also highlight a potential dose-dependent role for MRA in natriuresis. Furthermore, we showcase existing and recent evidence-based data demonstrating the effectiveness of MRA in AHF and on long-term outcomes. Finally, we look at several treatment strategies and safety concerns as they relate to MRA use so as to aid in avoidance of MRA-related complications while facilitating achievement of treatment goals.

Population risk prediction models for incident heart failure: a systematic review.

BACKGROUND: The prevalence of heart failure is expected to significantly rise unless high-risk patients are effectively screened and appropriate, cost-effective prevention interventions are implemented. METHODS AND RESULTS: We performed a systematic review to evaluate the prediction characteristics of the published heart failure risk prediction models as of August 2014 using MEDLINE and EMBASE databases. Eligible studies reported the development, validation, or impact assessment of a model. Two investigators performed independent review to extract data on study design and characteristics, risk predictors, discrimination, calibration, and reclassification ability of models, as well as validation and impact analysis. We included 13 publications reporting on 28 heart failure risk prediction models. Models had acceptable-to-good discriminatory ability (c-statistics, >0.70) in the derivation sample. Calibration was less commonly assessed, but was acceptable when it was. Only 2 models were externally validated more than once, displaying modest-to-acceptable discrimination (c-statistics, 0.61-0.79). When assessed, novel blood and imaging markers modestly improved risk prediction. One model assessed the prediction properties in race-based subgroups, whereas 2 models evaluated sex-based subgroups. Impact analysis found none of the models recommended for use in any clinical practice guideline. CONCLUSIONS: Incident heart failure risk prediction remains at an early stage. The discrimination ability of current models is acceptable in derivation data sets but most models have not been externally validated. It remains unclear which models are cost-effective and best suit population screening needs. The effects of models on clinical and preventative care requires further study.

Adherence to Mediterranean Diet Offers an Additive Protection Over the Use of Statin Therapy: Results from the ATTICA Study (2002-2012).

BACKGROUND AND AIMS: The protective role of Mediterranean diet on cardiovascular disease (CVD) risk has been extensively discussed in the literature, but its incremental effect over the use of CVD risk reducing agents (such as hypolipidemic treatment) has rarely been evaluated. METHODS: The ATTICA study was carried out in the Athens area during 2001-2002 and included 3042 participants free of CVD at baseline (49.8% men, aged 18-89 years). Adherence to Mediterranean diet was assessed using the MedDietScore (range 0-55) and statin use was recorded for all subjects. During 2011-2012, 2583 out of the 3042 baseline participants attended the 10-year follow-up of the ATTICA study (15% lost-to-follow-up) and CVD development was recorded. RESULTS: Adherence to Mediterranean diet (highest tertile) decreased CVD risk by 29.3% (Hazard Ratio (HR): 0.707, 95% Confidence Intervals (CI): 0.537-0.831) as compared with the lowest tertile, independently of statin use. Patients with hyperlipidemia on a statin that adopted unhealthy dietary habits (lowest tertile) had 75% increased CVD risk than normolipidemic subjects with healthy dietary habits (HR=1.75, 95%CI: 1.33-2.29). The addition of Mediterranean diet tertiles in the multivariable model reclassified 46.7% of the participants to CVD risk categories. CONCLUSION: Adherence to Mediterranean diet confers a considerable reduction in CVD risk, independently of gender, age, family history of CVD, diabetes mellitus, smoking status, hypertension and physical activity status. Therefore, CVD prevention strategies should involve the implementation of a Mediterranean diet in both the general population and patients on a statin.

In-hospital worsening heart failure.

Acute worsening heart failure (WHF) is seen in a sizable portion of patients hospitalized for heart failure, and is increasingly being recognized as an entity that is associated with an adverse in-hospital course. WHF is generally defined as worsening heart failure symptoms and signs requiring an intensification of therapy, and is reported to be seen in anywhere from 5% to 42% of heart failure admissions. It is difficult to ascertain the exact epidemiology of WHF due to varying definitions used in the literature. Studies indicate that WHF cannot be precisely predicted on the basis of baseline variables assessed at the time of admission. Recent data suggest that some experimental therapies may reduce the risk of development of WHF among hospitalized heart failure patients, and this is associated with a reduction in risk of subsequent post-discharge cardiovascular mortality. In this respect, WHF holds promise as a endpoint for acute heart failure clinical trials to better elucidate the benefit of targeted novel therapies. Better understanding of the pathophysiology and a consensus on the definition of WHF will further improve our epidemiological and clinical understanding of this entity.