Current Management and Future Directions of Heart Failure With Preserved Ejection Fraction: a Contemporary Review.

Heart failure with preserved ejection fraction (HFpEF), a complex and debilitating syndrome, is commonly seen in elderly populations. Exacerbation of HFpEF is among the most common reasons for hospital admission in the USA. The high rate of morbidity and mortality from this condition underscores the fact that HFpEF is heterogeneous, complex, and poorly characterized. Randomized, controlled trials have been very successful at identifying treatments for HF with reduced ejection fraction (HFrEF), but effective treatment options for HFpEF are lacking. Here, we discuss (1) the pathophysiology of HFpEF, (2) a standardized diagnostic and therapeutic approach, (3) a comparison of the management of recent guidelines, and (4) challenges and future directions for HFpEF management. The authors believe that it is important to identify new subtypes of HFpEF to better classify genotypes and phenotypes of HFpEF and to develop novel targeted therapies. It is our hypothesis that big data analytics will shine new light on unique HFpEF phenotypes that better respond to treatment modalities.

DPP-4 inhibitors and heart failure: a potential role for pharmacogenomics.

There remains an ongoing controversy regarding the safety of dipeptidyl peptidase-4 (DPP-4) inhibitors and the risk of developing heart failure (HF). In addition, none of the animal studies suggested a mechanism for the DPP-4 inhibitors and HF risk. To date, advances in pharmacogenomics have enabled the identification of genetic variants in DPP-4 gene. Studies have shown that genetic polymorphisms in the gene encoding DPP-4 may be associated with potential pathways involved in HF risk. This review discusses the contradictory findings of DPP-4 inhibitors and HF and a potential role for pharmacogenomics. Pharmacogenomics of DPP-4 inhibitors is promising, and genetic information from randomized control trials is urgently needed to gain a full understanding of the safety of DPP-4 inhibitors and the risk of HF.

Prognosis and response to therapy of first inpatient and outpatient heart failure event in a heart failure clinical trial: MADIT-CRT.

AIMS: Hospitalization for worsening heart failure (HF) is known to increase mortality and morbidity risk and has been frequently used as an endpoint in randomized clinical trials. Whether outpatient management of HF exacerbation carries similar prognostic and therapeutic information is less well known, but could be important for the design of trials that use HF hospitalization as an endpoint. METHODS AND RESULTS: MADIT-CRT randomized patients with mild HF symptoms to resynchronization therapy vs. control with an average follow-up of 3.3 years and a total of 191 deaths. HF events were centrally adjudicated for receiving i.v. decongestive therapy in an outpatient setting, or an augmented HF regimen during a hospital stay. Patients were compared according to whether their first HF was an out- or inpatient event. The first primary event was non-fatal outpatient HF, non-fatal inpatient HF, and death in 52, 331, and 78 patients, respectively. Patients with inpatient HF tended to be older and more likely to have HF of ischaemic aetiology than subjects who developed outpatient HF events. The risk of death following either type of non-fatal HF events was extremely high [hazard ratio (HR) 12.4, 95% confidence interval (CI) 9.1-16.9 for inpatient HF; HR 10.7, 95% CI 6.1-18.7 for outpatient HF] compared with subjects without non-fatal HF events. Allocation to CRT-D was associated with significant reduction in both types of HF. CONCLUSION: Outpatient management of worsening HF portends a high risk of death, similar to inpatient HF events, and may be equally sensitive to the effects of therapy. These findings suggest that outpatient HF events should be considered in publicly reported outcomes measures and future HF clinical trials. TRIAL REGISTRATION: NCT01294449.

Organ-specific responses to circulatory disturbances in heart failure: new insights.

Recent studies have provided new insights into the pathophysiology of congestive heart failure. Organ-specific responses to circulatory disturbances may differ via a hypoperfusion state and a venous congestion state. The liver and the kidneys serve as a good example of a differential injury pattern based on the predominant circulatory insult. Cardiorenal syndrome appears to be a kidney-specific response to predominantly right-sided backward heart failure ("congestive state"), rather than forward heart failure. Despite significant progress in our understanding of cardiorenal interactions, there is no specific therapy for the cardiorenal syndrome, which is a marker of the severity of the heart failure state.

Malnutrition as assessed by nutritional risk index is associated with worse outcome in patients admitted with acute decompensated heart failure: an ACAP-HF data analysis.

Malnutrition is common at hospital admission and tends to worsen during hospitalization. This controlled population study aimed to determine if serum albumin or moderate and severe nutritional depletion by Nutritional Risk Index (NRI) at hospital admission are associated with increased length of hospital stay (LOS) in patients admitted with acute decompensated heart failure (ADHF). Serum albumin levels and lymphocyte counts were retrospectively determined at hospital admission in 1740 consecutive patients admitted with primary and secondary diagnosis of ADHF. The Nutrition Risk Score (NRI) developed originally in AIDS and cancer populations was derived from the serum albumin concentration and the ratio of actual to usual weight, as follows: NRI = (1.519 × serum albumin, g/dL) + {41.7 × present weight (kg)/ideal body weight(kg)}. Patients were classified into four groups as no, mild, moderate or severe risk by NRI. Multiple logistic regressions were used to determine the association between nutritional risk category and LOS.Three hundred and eighty-one patients (34%) were at moderate or severe nutritional risk by NRI score. This cohort had lower BMI (24 ± 5.6 kg/m(2)), albumin (2.8±0.5 g/dL), mean NRI (73.5±9) and lower eGFR (50±33 mL/min per 1.73 m(2)). NRI for this cohort, adjusted for age, was associated with LOS of 10.1 days. Using the Multiple Logistic regression module, NRI was the strongest predictor for LOS (OR 1.7, 95% CI: 1.58-1.9; P=0.005), followed by TIMI Risk Score [TRS] (OR 1.33, 95% CI: 1.03-1.71; P=0.02) and the presence of coronary artery disease (OR 2.29, 95%CI: 1.03-5.1; P=0.04). Moderate and severe NRI score was associated with higher readmission and death rates as compared to the other two groups.Nutritional depletion as assessed by Nutritional Risk Index is associated with worse outcome in patients admitted with ADHF. Therefore; we recommend adding NRI to further risk stratify these patients.

Continuous infusion of furosemide combined with low-dose dopamine compared to intermittent boluses in acutely decompensated heart failure is less nephrotoxic and carries a lower readmission at thirty days.

INTRODUCTION: Furosemide is a potent loop diuretic that is widely used in the management of heart failure. Several reports have suggested that continuous intravenous administration of loop diuretics may be superior to intermittent administration. In addition the effect of low-dose dopamine to improve renal perfusion might be of benefit to this patient cohort. METHODS: We retrospectively evaluated 116 consecutive cardiac care unit patients, who were admitted with acute decompensated heart failure and were divided into two equal groups according to diuretic protocol. Group A patients received furosemide by continuous infusion combined with low-dose dopamine infusion. Group B patients received bolus therapy of intravenous furosemide. The effect on renal function and readmission rate was recorded. RESULTS: Among 116 patients (60% males, average age 71, range 46-96 years) 41% had ischemic cardiomyopathy, NYHA functional Class was 3.5 ± 0.5 and average EF was 21% ± 7%. On admission, patients in Group A had creatinine (Cr) 2.3 ± 0.2 mg/dL, blood urea nitrogen (BUN) 49.2 ± 25 mg/100 ml and median b-type natriuretic peptid (BNP) 1340 pg/mL, compared to group B patients with Cr 1.7 ± 1.2 mg/dL, BUN 32 ± 22 mg/100 ml and median BNP 1106 pg/mL. The average furosemide dose in group A was 7.9 ± 3.5 mg/hr compared to 7.6 ± 2.7 mg/hr for group B (p=NS). At the end of the study, patients in group A had lower Cr 1.8 ± 0.9 (p=0.0001), lower BUN 43.6 ± 22.9 (p=NS), an increase in estimated glomerular filtration rate 57.4 ± 27.4, a shorter hospital stay (p=0.015) and lower readmission rates at 30 days (p=0.0003). CONCLUSIONS: Continuous infusion of furosemide in addition to low-dose dopamine is safe, effective and less nephrotoxic than intermittent boluses in patients admitted with acute decompensated heart failure and portends a shorter hospital stay and lower readmission rates at 30 days.

Effect of adding nitroglycerin to early diuretic therapy on the morbidity and mortality of patients with chronic kidney disease presenting with acute decompensated heart failure.

BACKGROUND: Loop diuretics are considered first-line therapy for patients with acute decompensated heart failure (ADHF). Adding nitroglycerin (NTG) to diuretic therapy for alleviation of acute shortness of breath has been advocated in our institution. We evaluated the benefits of adding NTG to diuretics in the emergency department for patients with ADHF and chronic kidney disease (CKD). METHODS: 430 consecutive patients with ADHF who were admitted with a chief complaint of dyspnea were included in this retrospective study. Patients were divided into 3 groups. Group A patients were treated with neither diuretics nor NTG; Group B patients were treated with diuretics only; and Group C patients were treated with both diuretics and NTG. Estimated glomerular filtration rate (GFR) was calculated according to the Cockcroft-Gault formula. Follow-up was 36 ± 9 (mean ± standard deviation [SD]) months. Primary endpoints were readmission rate at 30 days and mortality at 24 months. RESULTS: 430 patients were included in this study (42% men; age, 69 ± 14 [mean ± SD] years); mean New York Heart Association class was 2.4 ± 0.7 (mean ± SD) and mean ejection fraction was 28% ± 17% (mean ± SD). Group A included 257 (59%) patients, Group B had 127 (29%) patients, and Group C had 46 (11%) patients. Group C patients were older (mean age, 72 ± 13 years) with lower body mass index (26 ± 7 kg/m2), lower estimated GFR (55.8 ± 38 mL/min per 1.73 m2), higher B-type natriuretic peptide levels (1112 ± 876 pg/mL; P = nonsignificant [NS]), and higher systolic and diastolic blood pressures on admission (P = 0.001). The primary endpoint was assessed as a composite of all-cause mortality and ADHF readmission seen in 143 (56%) Group A patients, 68 (53%) Group B patients, and 22 (48%) Group C patients (P = NS). At 30 days there were 53 (12%) readmissions--26 in Group A, 20 in Group B, and 7 in Group C (P = NS). However, survival at 24 months was higher in Group C (87%) compared with Groups A (79%) and B (82%) (P = 0.002). Using the Cox proportional-hazards regression module, early administration of NTG and Lasix (95% confidence interval [CI], 1.06-1.62; P = 0.01) followed by CKD stage (95% CI, 1.00-1.35; P = 0.04) were the only predictors for survival. CONCLUSION: There is a role for early administration of NTG in addition to diuretic therapy in patients admitted to the emergency department with ADHF, with resultant decreased length of stay and a trend toward a decrease in the composite endpoint of all-cause mortality and ADHF readmission. The mortality benefit at 2 years reported in our study is thought-provoking and raises a premise to be proven in randomized clinical trials.

Rationale and design of the treatment of hyponatremia based on lixivaptan in NYHA class III/IV cardiac patient evaluation (THE BALANCE) study.

Hyponatremia is a common electrolyte disorder in patients with heart failure (HF) associated with cognitive dysfunction and increased mortality and rehospitalization rates. Loop diuretics worsen renal function, produce neurohormonal activation, and induce electrolyte imbalances. Lixivaptan is a selective, oral vasopressin V(2) -receptor antagonist that improves hyponatremia by promoting electrolyte-free aquaresis without significant side effects. The Treatment of Hyponatremia Based on Lixivaptan in NYHA Class III/IV Cardiac Patient Evaluation (BALANCE) study is a randomized, double-blind, placebo-controlled, phase 3 trial designed to evaluate the effects of lixivaptan on serum sodium in patients hospitalized with worsening heart failure (target N= 650), signs of congestion and serum sodium concentrations <135 mEq/L. Other endpoints include assessment of dyspnea, body weight, cognitive function, and days of hospital-free survival. Patients are randomized 1:1 to lixivaptan or matching placebo for 60 days, with a 30-day safety follow-up. Doses of lixivaptan or placebo are adjusted based on serum sodium and volume status. Lixivaptan was shown to increase serum sodium and reduce body weight, without renal dysfunction or hypokalemia. BALANCE seeks to address unmet questions regarding the use of vasopressin antagonists including their effects on cognitive function and clinical outcomes in patients with hyponatremia and worsening heart failure.

Advances in systolic heart failure.

Heart failure due to systolic dysfunction has enormous global impact. Medical management based on an understanding of the pathophysiology of the disease as well as its neurohormonal mechanisms has greatly advanced over the past 25 years. Below is a review of recent and emerging data on epidemiology and diagnosis of heart failure due to systolic dysfunction and the current and future management techniques to ameliorate this disease. At the end, we will highlight three significant trials in the field in 2009 that will impact heart failure care: STICH, MADIT-CRT, and HeartMate II.

Right ventricular dysfunction is a strong predictor of developing atrial fibrillation in acutely decompensated heart failure patients, ACAP-HF data analysis.

BACKGROUND: Heart failure and atrial fibrillation (AFib) are the twin epidemics of modern cardiovascular disease. The incidence of new-onset AFib in acute decompensated heart failure (ADHF) patients is difficult to predict and the short- and long-term outcomes of AFib in a cohort of patients admitted with ADHF are unknown. METHODS AND RESULTS: A total of 904 patients admitted with ADHF were studied. Incidence of AFib on admission was recorded and a multivariate analysis was performed using echocardiographic parameters to specify the predictors of AFib incidence in this cohort. In 904 ADHF patients (57% male, mean age 69 ± 14 years), 81% had history of hypertension, 40% were diabetics, and 51% were smokers. A total of 63% of the patients had known heart failure (HF) with mean ejection fraction of 34% ± 21%, and 33% of the patients had ischemic cardiomyopathy as the etiology of HF. Echocardiographic parameters were: left atrial (LA) diameter 4.5 ± 0.8 cm, left ventricular end-systolic 4.1 ± 1.3 cm, left ventricular end-diastolic 5.3 ± 1.1 cm. Right ventricular dysfunction (RVD) was present in 34% of the patients. A total of 191 (21%) patients subsequently developed AFib with two thirds of the cases occurring in patients with RVD. Using a univariate analysis, older age (OR 1.02; P < .0001), history of HF (OR 2.93; P < .0001), LA dilation (OR 1.58; P < .0001), the presence of left ventricular hypertrophy (OR 3.01, P < .0001), and RVD (OR 4.93; P < .00001) were the strongest predictors for AFib. Controlling for LA size and left ventricular hypertrophy using a forward stepwise regression, RVD remained the strongest predictor (OR 4.45; P < .0001). Patients with RVD had more events (cardiac readmission and mortality) than those with normal RV (56% versus 38%; P < .00001), notably; all-cause mortality was 4.7%/year in the abnormal RV group versus 2.9%/year in the normal RV group; P < .05. RV function analyses by echocardiography further risk stratified these patients based on their rhythm categorizing those patients with abnormal RV and AFib as the ones with the worse prognosis. CONCLUSION: RV dysfunction is a strong predictor for developing AFib in acutely decompensated systolic failure patients. Patients with AFib and RVD have the worse outcome specially when is combined with LV dysfunction, therefore; evaluation of RV function may substantiate the difference in HF prognosis.

Ablation vs medical therapy in the setting of symptomatic atrial fibrillation and left ventricular dysfunction.

Small, single-center studies suggest that catheter ablation of atrial fibrillation (AF) can improve ventricular function and reduce symptoms in patients with left ventricular (LV) dysfunction. However, ablation has not been compared with a pharmacologic strategy for AF. The authors evaluated patients with AF and symptomatic LV dysfunction (ejection fraction < or =45%) referred for pulmonary vein isolation (PVI). They compared these patients with a matched cohort treated medically for AF and LV dysfunction via a retrospective case-control method. Fifteen patients (14 men, 56+/-11 years, 10 [67%] paroxysmal AF) with AF for 4+/-3 years underwent PVI. Baseline ejection fraction was 37%+/-6% and New York Heart Association (NYHA) class was 2.0+/-1.0. Fifteen controls (13 men, 63+/-14 years, 11 [73%] paroxysmal AF) with AF for 5+/-4 years were treated medically for AF. Baseline ejection fraction was 34%+/-11% and NYHA class was 2.0+/-0.7. The groups were similar in all respects. During a follow-up of 16+/-13 months after complete PVI, ejection fraction improved (P=.001) to 50%+/-13% and normalized in 8 patients (53%). NYHA class improved to 1.3+/-0.5 (P=.01). In the medically treated group, after follow-up of 16+/-12 months, no improvement in ejection fraction (36%+/-12%) or NYHA class (1.8+/-0.7) was seen. Compared with pharmacologic therapy, PVI significantly improved LV function and NYHA class in patients with AF and symptomatic LV dysfunction. These provocative findings provide potent rationale for a randomized clinical trial comparing ablation with pharmacologic therapy.

Novel pathway for sudden cardiac death prevention.

Sudden cardiac death is one of the leading causes of death in the United States, accounting for an estimate 350,000 deaths each year. The US Congress passed a resolution in late September 2008 designating October as "National Sudden Cardiac Arrest Awareness Month." In an effort to raise awareness for preventing unnecessary deaths because of sudden cardiac death, the resolution "calls upon the people of the United States to observe this month with appropriate programs and activities." The response from our institute was to develop a novel pathway named ESCAPE-which is an evidence-based novel pathway for low Ejection fraction and Sudden Cardiac death Awareness and Prevention Eligibility. The main objective of this program is to demonstrate that implementing a simple novel pathway for primary prevention of sudden cardiac arrest leads to an increase in the number of patients with low ejection fraction (

Beta-blockers for primary prevention of heart failure in patients with hypertension insights from a meta-analysis.

OBJECTIVES: This study sought to evaluate the efficacy of beta-blockers (BBs) for primary prevention of heart failure (HF) in patients with hypertension. BACKGROUND: The American College of Cardiology/American Heart Association staging for HF classifies patients with hypertension as stage A HF, for which BBs are a treatment option. However, the evidence to support this is unknown. METHODS: We conducted a MEDLINE/EMBASE/CENTRAL search of randomized controlled trials that evaluated BB as first-line therapy for hypertension with follow-up for at least 1 year and with data on new-onset HF. The primary outcome was new-onset HF. Secondary outcomes were all-cause mortality, cardiovascular mortality, myocardial infarction, and stroke. RESULTS: Among the 12 randomized controlled trials, which evaluated 112,177 patients with hypertension, BBs reduced blood pressure by 12.6/6.1 mm Hg when compared with placebo, resulting in a 23% (trend) reduction in HF risk (p = 0.055). When compared with other agents, the antihypertensive efficacy of BBs was comparable, which resulted in similar but no incremental benefit for HF risk reduction in the overall cohort (risk ratio: 1.00; 95% confidence interval: 0.92 to 1.08), in the elderly (> or =60 years) or in the young (<60 years). Analyses of secondary outcomes showed that BBs confirmed similar but no incremental benefit for the outcomes of all-cause mortality, cardiovascular mortality, and myocardial infarction but increased stroke risk by 19% in the elderly. CONCLUSIONS: In hypertensive patients, primary prevention of HF is strongly dependent on blood pressure reduction. When compared with other antihypertensive agents, there was similar but no incremental benefit of BBs for the prevention of HF. However, given the increased risk of stroke in the elderly, BBs should not be considered as first-line agents for prevention of HF.

Metoprolol reverses left ventricular remodeling in patients with asymptomatic systolic dysfunction: the REversal of VEntricular Remodeling with Toprol-XL (REVERT) trial.

BACKGROUND: There are no randomized, controlled trial data to support the benefit of beta-blockers in patients with asymptomatic left ventricular systolic dysfunction. We investigated whether beta-blocker therapy ameliorates left ventricular remodeling in asymptomatic patients with left ventricular systolic dysfunction. METHOD AND RESULTS: Patients with left ventricular ejection fraction <40%, mild left ventricular dilation, and no symptoms of heart failure (New York Heart Association class I) were randomly assigned to receive extended-release metoprolol succinate (Toprol-XL, AstraZeneca) 200 mg or 50 mg or placebo for 12 months. Echocardiographic assessments of left ventricular end-systolic volume, end-diastolic volume, mass, and ejection fraction were performed at baseline and at 6 and 12 months. The 149 patients randomized to the 3 treatment groups (200 mg, n=48; 50 mg, n=48; and placebo, n=53) were similar with regard to all baseline characteristics including age (mean, 66 years), gender (74% male), plasma brain natriuretic peptide (79 pg/mL), left ventricular end-diastolic volume index (110 mL/m2), and left ventricular ejection fraction (27%). At 12 months in the 200-mg group, there was a 14+/-3 mL/m2 decrease (least square mean+/-SE) in end-systolic volume index and a 6+/-1% increase in left ventricular ejection fraction (P<0.05 versus baseline and placebo for both). The decrease in end-diastolic volume index (14+/-3) was different from that seen at baseline (P<0.05) but not with placebo. In the 50-mg group, end-systolic and end-diastolic volume indexes decreased relative to baseline but were not different from what was seen with placebo, whereas ejection fraction increased by 4+/-1% (P<0.05 versus baseline and placebo). CONCLUSION: Beta-blocker therapy can ameliorate left ventricular remodeling in asymptomatic patients with left ventricular systolic dysfunction.

Beta-blockers to prevent symptomatic heart failure in patients with stage A and B heart failure.

beta-blockers have been well-studied in the treatment of the symptomatic stages of chronic heart failure. Frequently physicians treat patients with asymptomatic left ventricular (LV) dysfunction and patients with hypertension on beta-blockers without clear evidence that there is value in doing so. Chronic heart failure poses an extraordinary economic burden; any effective therapy that limits the progression to symptomatic heart failure can probably reduce monetary expenditures in addition to potentially reducing morbidity and mortality. In this article, we review the available literature on using beta-blockers in stage A and B heart failure to prevent progression to the symptomatic stages. The literature reveals that there is no benefit in using beta-blockers to treat essential hypertension. In patients who experience LV dysfunction post-myocardial infarction, even if asymptomatic, there is improved mortality and a trend toward a reduction in progression to symptomatic heart failure. In patients with asymptomatic chronic LV dysfunction there are data that beta-blockers reduce LV dimensions and improve ejection fraction. Patients with hypertension should not be given beta-blockers as primary treatment. All patients with asymptomatic LV dysfunction should be treated with a beta-blocker, regardless of whether they experienced myocardial infarction.