Effect of mineralocorticoid receptor antagonists on cardiac function in patients with heart failure and preserved ejection fraction: a systematic review and meta-analysis of randomized controlled trials

Heart failure with preserved ejection fraction (HFpEF) is a disease with limited evidence-based treatment options. Mineralocorticoid receptor antagonists (MRA) offer benefit in heart failure with reduced ejection fraction (HFrEF), but their impact in HFpEF remains unclear. We therefore evaluated the effect of MRA on echocardiographic, functional, and systemic parameters in patients with HFpEF by a systematic review and meta-analysis. We searched MEDLINE, EMBASE, clinicaltrials.gov, and Cochrane Clinical Trial Collection to identify randomized controlled trials that (a) compared MRA versus placebo/control in patients with HFpEF and (b) reported echocardiographic, functional, and/or systemic parameters relevant to HFpEF. Studies were excluded if: they enrolled asymptomatic patients; patients with HFrEF; patients after an acute coronary event; compared MRA to another active comparator; or reported a follow-up of less than 6 months. Primary outcomes were changes in echocardiographic parameters. Secondary end-points were changes in functional capacity, quality of life measures, and systemic parameters. Quantitative analysis was performed by generating forest plots and calculating effect sizes by random-effect models. Between-study heterogeneity was assessed through Q and I2 statistics. Nine trials with 1164 patients were included. MRA significantly decreased E/e′ (mean difference − 1.37, 95% confidence interval − 1.72 to − 1.02), E/A (− 0.04, − 0.08 to 0.00), left ventricular end-diastolic diameter (− 0.78 mm, − 1.34 to − 0.22), left atrial volume index (− 1.12 ml/m2, − 1.91 to − 0.33), 6-min walk test distance (− 11.56 m, − 21 to − 2.13), systolic (− 4.75 mmHg, − 8.94 to − 0.56) and diastolic blood pressure (− 2.91 mmHg, − 4.15 to − 1.67), and increased levels of serum potassium (0.23 mmol/L, 0.19 to 0.28) when compared with placebo/control. In patients with HFpEF, MRA treatment significantly improves indices of cardiac structure and function, suggesting a decrease in left ventricular filling pressure and reverse cardiac remodeling. MRA increase serum potassium and decrease blood pressure; however, a small decrease in 6-min-walk distance is also noted. Larger prospective studies are warranted to provide definitive answers on the effect of MRA in patients with HFpEF

Study design, result posting, and publication of late-stage cardiovascular trials

AIMS: Pre-registration of study protocols in accessible databases is required for publication of study results in high-impact medical journals. Nonetheless, data on characteristics of clinical trials registered in these databases and their outcome, in terms of result reporting and publication are limited. METHODS AND RESULTS: We searched for interventional, late-phase cardiovascular disease (CVD) studies in adults registered in Clinicaltrials.gov. first posted after 1 January 2013 and completed up to 31 December 2018. Data on study design, result reporting, and publication were collected, and potential associations with a pre-defined set of explanatory factors were examined. In total, 250 CVD trials were included in the analysis. Of these, 193 (77.2%) were randomized studies, 99 (39.6%) open label designs, and 126 (50.4%) had industry as main sponsor. One hundred and seventy-nine trials (71.6%) evaluated the effect of drugs and 27 (10.8%) evaluated devices. The most common primary outcomes were non-clinical endpoints (76.0%), with only 17% of studies evaluating clinical endpoints. Industry-funded trials focused on patent-protected drugs and devices more often than non-industry-funded trials (72.0% vs. 30.6%, P < 0.001 and 55.0% vs. 26.3%, P = 0.033, respectively). Sixty-three studies (25.2%) had results posted on clinicaltrials.gov, and 116 (46.4%) had results published in the scientific literature. In multivariate analysis, industry sponsorship was statistically significantly associated with results posting [odds ratio (OR): 3.38; 95% confidence interval (CI): 1.56-7.30, P = 0.002] and publication (OR: 0.41; 95% CI: 0.23-0.75, P = 0.004). CONCLUSION: Among late-stage cardiovascular trials only one-fourth had results posted on clinicaltrials.gov and <50% had results published. Industry sponsors were more likely to invest in research on patent-protected drugs and devices than were non-industry sponsors. Industry-sponsored studies were more likely to have their results posted, but less likely to have their results published in the scientific literature

Use of loop diuretics in chronic heart failure: do we adhere to the Hippocratian principle "do no harm"?

Although approaches to optimize volume status, such as modifying fluid and salt intake, are important,1 use of loop diuretics remains the mainstay of treatment for congestion in patients with both acute (AHF) and chronic heart failure (CHF), regardless of the underlying left ventricular ejection fraction.2 Characteristically, more than 80% of patients with CHF receive regular treatment with some kind of oral loop diuretic.3,4 The 2016 European guidelines on heart failure (HF) recommend the use of diuretics for patients with signs and symptoms of congestion (recommendation class I, level of evidence B).5 However, loop diuretics may exert a range of adverse effects including electrolyte depletion, which predispose to life-threatening ventricular arrhythmias, hyperglycaemia, hyperuricaemia, orthostatic hypotension, vestibular symptoms and renal function deterioration.2 Furthermore, they seem to activate the neurohormonal system and hamper the up-titration of guideline-recommended HF treatment.6,7 Thus, current guidelines recommend use of diuretics at the lowest dose needed to achieve and maintain euvolaemia, meaning that reduced loop diuretic dose may often be indicated in stable CHF patients.5 Recently, the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) put together a comprehensive consensus document on the use of diuretics in HF,1 providing, among others, guidance on the challenging task of assessing HF patients\u2019 fluid status. Herein we summarize the existing literature on loop diuretic dose changes in CHF and call for randomized trials. Loop diuretic strategies in AHF are not addressed

Innate heart regeneration: endogenous cellular sources and exogenous therapeutic amplification

Introduction: The -once viewed as heretical- concept of the adult mammalian heart as a dynamic organ capable of endogenous regeneration has recently gained traction. However, estimated rates of myocyte turnover vary wildly and the underlying mechanisms of cardiac plasticity remain controversial. It is still unclear whether the adult mammalian heart gives birth to new myocytes through proliferation of resident myocytes, through cardiomyogenic differentiation of endogenous progenitors or through both mechanisms.Areas covered: In this review, the authors discuss the cellular origins of postnatal mammalian cardiomyogenesis and touch upon therapeutic strategies that could potentially amplify innate cardiac regeneration.Expert opinion: The adult mammalian heart harbors a limited but detectable capacity for spontaneous endogenous regeneration. During normal aging, proliferation of pre-existing cardiomyocytes is the dominant mechanism for generation of new cardiomyocytes. Following myocardial injury, myocyte proliferation increases modestly, but differentiation of endogenous progenitor cells appears to also contribute to cardiomyogenesis (although agreement on the latter point is not universal). Since cardiomyocyte deficiency underlies almost all types of heart disease, development of therapeutic strategies that amplify endogenous regeneration to a clinically-meaningful degree is of utmost importance

Multichamber Involvement of Metastatic Cardiac Melanoma

A 30-year-old man with a history of an in-situ melanoma of the forehead was referred for cardiac evaluation because of tachycardia and elevated levels of serum troponin. The transthoracic echocardiogram revealed multiple masses attached to the walls of both ventricles and the right atrium (RA). A large mass was occupying almost one third of the right ventricle (RV), resulting in reduction of the end-diastolic RV volume and tachycardia. A cardiac magnetic resonance imaging confirmed multifocal myocardial infiltration and intracavitary masses and excluded the presence of thrombus in any of the cardiac chambers. Diffuse metastatic involvement in the liver, the spleen, and the brain by computed tomography precluded surgical management. Being BRAF-unmutated, the patient was initially treated with a combination of nivolumab and ipilimumab. One month later, the cardiac metastases in RA and left ventricle were unchanged on echocardiogram, while the tumor in RV was enlarged occupying the majority of the chamber, resulting in further reduction of the cardiac output and tachycardia. The treatment was changed to a combination of dacarbazine and carboplatin, but the patient eventually died two months later. Heart is not a common metastatic site of melanoma and cardiac involvement is usually clinically silent making ante mortem diagnosis difficult. Multimodalidy imaging plays a pivotal role in the diagnostic work up. Cardiac melanoma metastases indicate an advance stage disease with poor prognosis

Cardiac Autonomic Neuropathy Predicts All-Cause and Cardiovascular Mortality in Patients With End-Stage Renal Failure: A 5-Year Prospective Study

Chronic renal disease is associated with increased cardiovascular (CV) mortality. Cardiac autonomic neuropathy (CAN) is predictive of mortality for diseases that affect the autonomic nervous system. We prospectively evaluated the prognostic value of indexes of left ventricular (LV) function and CAN in all-cause and CV mortality of patients with end-stage renal failure (ESRF). Methods: A total of 133 patients with ESRF were recruited. LV function was evaluated by echocardiography, whereas cardiac autonomic function was assessed using the battery of the 4 standardized tests proposed by Ewing. Results: A total of 123 of 133 (92.5%) patients completed the study and were followed for a mean of 4.9 ± 2.6 years. Mean LV ejection fraction (LVEF) was 50.9 ± 6.9%, whereas 70 (57.9%) patients had CAN. Sixty-nine all-cause and 36 CV deaths were recorded. The survival rates at 3, 5, and 7 years were 77.2%, 57.4%, and 33.7%, respectively. Multivariate analysis after adjustment for waist circumference, current smoking, history of diabetes, and coronary artery disease demonstrated that the only independent predictors of all-cause mortality during follow-up were age, serum triglycerides, LVEF, and presence of CAN. Competing risk regression analysis, after adjusting for waist circumference, coronary heart disease, serum glucose, and triglycerides, indicated that age and presence of CAN were independent risk factors for CV mortality. Discussion: Age and presence of CAN are independent predictors of all-cause and CV mortality in patients with ESRF. The functionality of the cardiac autonomic nervous system activity can be used for the risk stratification in patients with ESRF

Diet, life-style and cardiovascular morbidity in the rural, free living population of Elafonisos island

Abstract Background There are about 70 small islands in the Aegean and Ionian Sea, of less than 300 Km2 and 5000 inhabitants each, comprising a total population of more than 75,000 individuals with geographical and socioeconomic characteristics of special interest. The objective of the present study was to assess lifestyle characteristics and the state of cardiovascular risk of the population of a small Eastern Mediterranean island, Elafonisos. Methods PERSEAS (Prospective Evaluation of cardiovascular Risk Surrogates in Elafonisos Area Study) is an ongoing, population-based, longitudinal survey of cardiovascular risk factors, life-style characteristics and related morbidity/mortality performed in a small and relatively isolated island of the Aegean Sea, named Elafonisos. Validated, closed-ended questionnaires for demographic, socio-economic, clinical and lifestyle characteristics were distributed and analyzed. The MedDietScore, a validated Mediterranean diet score was also calculated. In addition, all participants underwent measurement of anthropometric parameters, blood pressure and a full blood panel for glucose and lipids. Results The analysis included 596 individuals who represented 74.5% of the target population. The mean age of the population was 49.5 ± 19.6 years and 48.2% were males. Fifty participants (8.4%) had a history of cardiovascular disease (CVD). The rates of reported diabetes, hypertension, and hypercholesterolemia were 7.7%, 30.9% and 30.9% respectively, with screen-detection of each condition accounting for an additional 4.0%, 12.9%, and 23.3% of cases, respectively. Four hundred and seven individuals (68.3%) were overweight or obese, 25% reported being physically inactive and 36.6% were active smokers. The median MedDietScore was 25 [interquartile range: 6, range 12–47] with higher values significantly associated with older age, better education, increased physical activity, absence of history of diabetes and known history of hypercholesterolemia. Conclusions Obesity and traditional risk factors for CVD are highly prevalent among the inhabitants of a small Mediterranean island. Adherence to the traditional Mediterranean diet in this population is moderate, while physical activity is low. There seems to be a need for lifestyle modification programs in order to reverse the increasing cardiovascular risk trends in rural isolated areas of the Mediterranean basin

Counterpulsation: A concept with a remarkable past, an established present and a challenging future

The intra-aortic balloon pump (IABP), which is the main representative of the counterpulsation technique, has been an invaluable tool in cardiologists’ and cardiac surgeons’ armamentarium for approximately half a century. The IABP confers awide variety of vaguely understood effects on cardiac physiology andmechano-energetics. Although, the recommendations for its use are multiple, most are not substantially evidence-based. Indicatively, the results of recently performed prospective studies have put IABP’s utility in the setting of post-infarction cardiogenic shock into question. However, the particular issue remains open to further research. IABP support in high-risk patients undergoing PCI is associated with favorable long-term clinical outcome. In cardiac surgery, the use of IABP in cases of peri-operative low-output syndrome, refractory angina or ischemia-related mechanical complications is a usual, but poorly justified strategy. Anecdotal cases of treatment of incessant ventricular arrhythmias, reversal of right ventricular dysfunction and partial myocardial recovery have also been reported with its use. Converging data demonstrate the potential of safe long-term IABP support as a bridge to decision making or a bridge to transplantation modality in patients with heart failure. The feasibility of IABP insertion via other than the femoral artery sites enhances this potential. Despite the fact that several other counterpulsation devices have been developed and tested overtime none has managed to substitute the IABP, which continues to be most frequently used mechanical assist device. (C) 2014 Elsevier Ireland Ltd. All rights reserved