scholarly journals Drug Targets for Heart Failure with Preserved Ejection Fraction: A Mechanistic Approach and Review of Contemporary Clinical Trials

2019 ◽  
Vol 59 (1) ◽  
pp. 41-63 ◽  
Author(s):  
Ravi B. Patel ◽  
Sanjiv J. Shah
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Drug Targets ◽  
Multiple Organ ◽  
Preserved Ejection Fraction ◽  
Research Strategies ◽  
Reduced Ejection Fraction ◽  
Mechanistic Approach ◽  
Organ Systems ◽  
Heterogeneous Nature

Heart failure with preserved ejection fraction (HFpEF) accounts for over half of prevalent heart failure (HF) worldwide, and prognosis after hospitalization for HFpEF remains poor. Due, at least in part, to the heterogeneous nature of HFpEF, drug development has proved immensely challenging. Currently, there are no universally accepted therapies that alter the clinical course of HFpEF. Despite these challenges, important mechanistic understandings of the disease have revealed that the pathophysiology of HFpEF is distinct from that of HF with reduced ejection fraction and have also highlighted potential new therapeutic targets for HFpEF. Of note, HFpEF is a systemic syndrome affecting multiple organ systems. Depending on the organ systems involved, certain novel therapies offer promise in reducing the morbidity of the HFpEF syndrome. In this review, we aim to discuss novel pharmacotherapies for HFpEF based on its unique pathophysiology and identify key research strategies to further elucidate mechanistic pathways to develop novel therapeutics in the future.

Heart Failure with Preserved Ejection Fraction: Mechanisms and Treatment Strategies

2021 ◽  
Vol 73 (1) ◽  
Author(s):  
Kazunori Omote ◽  
Frederik H. Verbrugge ◽  
Barry A. Borlaug
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Treatment Strategies ◽  
Annual Review ◽  
Publication Date ◽  
Preserved Ejection Fraction ◽  
Reduced Ejection Fraction ◽  
Patients With Heart Failure ◽  
Prevalence Of Obesity

Approximately half of all patients with heart failure (HF) have a preserved ejection fraction, and the prevalence is growing rapidly given the aging population in many countries and the rising prevalence of obesity, diabetes, and hypertension. Functional capacity and quality of life are severely impaired in heart failure with preserved ejection fraction (HFpEF), and morbidity and mortality are high. In striking contrast to HF with reduced ejection fraction, there are few effective treatments currently identified for HFpEF, and these are limited to decongestion by diuretics, promotion of a healthy active lifestyle, and management of comorbidities. Improved phenotyping of subgroups within the overall HFpEF population might enhance individualization of treatment. This review focuses on the current understanding of the pathophysiologic mechanisms underlying HFpEF and treatment strategies for this complex syndrome. Expected final online publication date for the Annual Review of Medicine, Volume 73 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Abstract 12849: Changes in N-terminal Pro Brain Natriuretic Peptide Levels Predicts Mortality and Heart Failure Hospitalization in Patients With Heart Failure and Preserved Ejection Fraction

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Gianluigi Savarese ◽  
Camilla Hage ◽  
Ulf Dahlström ◽  
Pasquale Perrone-Filardi ◽  
Lars H Lund
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Brain Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Total Mortality ◽  
Preserved Ejection Fraction ◽  
Reduced Ejection Fraction ◽  
Patients With Heart Failure ◽  
The Impact

Introduction: Changes in N-terminal pro brain natriuretic peptide (NT-proBNP) have been demonstrated to correlate with outcomes in patients with heart failure (HF) and reduced ejection fraction (EF). However the prognostic value of a change in NT-proBNP in patients with heart failure and preserved ejection fraction (HFPEF) is unknown. Hypothesis: To assess the impact of changes in NT-proBNP on all-cause mortality, HF hospitalization and their composite in an unselected population of patients with HFPEF. Methods: 643 outpatients (age 72+12 years; 41% females) with HFPEF (ejection fraction ≥40%) enrolled in the Swedish Heart Failure Registry between 2005 and 2012 and reporting NT-proBNP levels assessment at initial registration and at follow-up were prospectively studied. Patients were divided into 2 groups according the median value of NT-proBNP absolute change that was 0 pg/ml. Median follow-up from first measurement was 2.25 years (IQR: 1.43 to 3.81). Adjusted Cox’s regression models were performed using total mortality, HF hospitalization (with censoring at death) and their composite as outcomes. Results: After adjustments for 19 baseline variables including baseline NT-proBNP, as compared with an increase in NT-proBNP levels at 6 months (NT-proBNP change>0 pg/ml), a reduction in NT-proBNP levels (NT-proBNP change<0 pg/ml) was associated with a 45.2% reduction in risk of all-cause death (HR: 0.548; 95% CI: 0.378 to 0.796; p:0.002), a 50.1% reduction in risk of HF hospitalization (HR: 0.49; 95% CI: 0.362 to 0.689; p<0.001) and a 42.6% reduction in risk of the composite outcome (HR: 0.574; 95% CI: 0.435 to 0.758; p<0.001)(Figure). Conclusions: Reductions in NT-proBNP levels over time are independently associated with an improved prognosis in HFPEF patients. Changes in NT-proBNP could represent a surrogate outcome in phase 2 HFPEF trials.

scholarly journals Targeting Endothelial Function to Treat Heart Failure with Preserved Ejection Fraction: The Promise of Exercise Training

2017 ◽  
Vol 2017 ◽  
pp. 1-17 ◽  
Author(s):  
Andreas B. Gevaert ◽  
Katrien Lemmens ◽  
Christiaan J. Vrints ◽  
Emeline M. Van Craenenbroeck
Keyword(s):  
Heart Failure ◽  
Endothelial Dysfunction ◽  
Exercise Training ◽  
Ejection Fraction ◽  
Current Knowledge ◽  
Beta Blockers ◽  
Preserved Ejection Fraction ◽  
Cellular Mechanisms ◽  
Converting Enzyme Inhibitors ◽  
Reduced Ejection Fraction

Although the burden of heart failure with preserved ejection fraction (HFpEF) is increasing, there is no therapy available that improves prognosis. Clinical trials using beta blockers and angiotensin converting enzyme inhibitors, cardiac-targeting drugs that reduce mortality in heart failure with reduced ejection fraction (HFrEF), have had disappointing results in HFpEF patients. A new “whole-systems” approach has been proposed for designing future HFpEF therapies, moving focus from the cardiomyocyte to the endothelium. Indeed, dysfunction of endothelial cells throughout the entire cardiovascular system is suggested as a central mechanism in HFpEF pathophysiology. The objective of this review is to provide an overview of current knowledge regarding endothelial dysfunction in HFpEF. We discuss the molecular and cellular mechanisms leading to endothelial dysfunction and the extent, presence, and prognostic importance of clinical endothelial dysfunction in different vascular beds. We also consider implications towards exercise training, a promising therapy targeting system-wide endothelial dysfunction in HFpEF.

Abstract 19228: Cost-effectiveness of the CardioMems Implantable Pulmonary Artery Pressure Monitoring System in Patients With Chronic Heart Failure

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Alexander T Sandhu ◽  
Jeremy D Goldhaber-Fiebert ◽  
Mintu P Turakhia ◽  
Daniel W Kaiser ◽  
Paul A Heidenreich
Keyword(s):  
Heart Failure ◽  
Cost Effectiveness ◽  
Ejection Fraction ◽  
Nyha Class ◽  
Case Analysis ◽  
Preserved Ejection Fraction ◽  
Heart Failure Hospitalization ◽  
Reduced Ejection Fraction ◽  
Life Years ◽  
The Cost

Background: For management of heart failure, the value of the CardioMems device remains uncertain. We assessed the cost-effectiveness of the CardioMems device. Methods: We developed a Markov model to determine quality-adjusted life-years (QALYs), cost, and cost-effectiveness of patients with heart failure receiving CardioMems implantation compared to those with routine care. In the main case analysis, we modeled the intervention in the CHAMPION trial cohort, which included patients with NYHA Class III heart failure with a heart failure hospitalization within the past twelve months. We also performed subgroup analyses of patients with preserved ejection fraction or reduced ejection fraction, and a scenario analysis of a second cohort of patients from the CHARM trials with a previous heart failure hospitalization. We obtained event rates and utilities from published trial data; we used costs from literature estimates and Medicare payment data. The main case analysis was calibrated to the hospitalization and survival rates of the CHAMPION trial. Results: In the CHAMPION trial main case analysis, CardioMems reduced lifetime hospitalizations (2.37 versus 3.27), increased months of survival (67 versus 62), increased QALYs (2.66 versus 2.38) and increased costs ($171,132 versus $154,084), yielding a cost of $59,520 per QALY gained or $40,301 per life-year gained. The cost per QALY gained was $71,964 in patients with reduced ejection fraction compared to $34,899 in those with preserved ejection fraction. In less ill patients from the CHARM trials, which included patients with NYHA Class II heart failure, the device cost increased to $110,565 per QALY gained. If the device cost decreased from $17,500 in the main case analysis to $15,000, the intervention would cost less than $50,000 per QALY gained. The duration of effectiveness was initially assumed to be lifelong; if less than 29 months, CardioMems would cost more than $150,000 per QALY gained. Conclusion: The CardioMems device is cost-effective in populations similar to the CHAMPION trial, with a cost of less than $100,000 per QALY gained, if durability of device effectiveness is sustained. Post-marketing surveillance data on the device’s durability will further clarify its value.

Abstract 17264: Predictive Value of Plasma Ceramide C24:0/C16:0 Ratio in Patients With Heart Failure With Preserved Ejection Fraction in the TOPCAT Study

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Linda R Peterson ◽  
Xuntian Jiang ◽  
Hannah Campbell ◽  
Sharon Cresci
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Cell Structure ◽  
Univariate Analysis ◽  
The United States ◽  
Preserved Ejection Fraction ◽  
Bioactive Lipids ◽  
Confidence Bounds ◽  
Liquid Chromatograph ◽  
Reduced Ejection Fraction

Introduction: Heart failure (HF) with preserved ejection fraction (HFpEF) is an “emerging epidemic” as nearly half of all patients with HF have HFpEF. However, most HF biomarkers, including plasma brain natriuretic peptide, have less robust utility in HFpEF than in those with HF with reduced ejection fraction. In order to better understand HFpEF and its associated morbidity and mortality, it is vital to identify robust biomarkers that predict outcomes in patients who suffer from HFpEF. Ceramides are bioactive lipids involved in signaling, cell death programs, mitochondrial function, and cell structure. Our group showed that the ratio of specific plasma ceramides (C24:0/C16:0) is inversely related to primary incident HF and to death in large community-based cohorts. Whether plasma C24:0/C16:0 has utility in prediction of secondary events/outcomes in patients with HFpEF is unclear. Hypothesis: We hypothesized that there is an association between plasma C24:0/16:0 ratio and outcomes in HFpEF. Methods: Data and plasma was obtained from 477 subjects in the TOPCAT study via the BioLINCC biobank. Plasma ceramides C24:0 and C16:0 were measured using targeted liquid chromatograph/tandem mass spectrometry. Results: Inclusion criteria for TOPCAT was age >50 years, ejection fraction of 45% or higher and diagnosis of HF. Subjects were randomized to treatment with spironolactone or placebo. In the 477 subjects who provided samples to BioLINCC, the mean age was 69.3 years; 47% were women; 43.9% were from the United States; 94.4% had hypertension; 31 were African American. Mean follow-up was 3.3 years. Univariate analysis showed that time to hospitalization for heart failure was inversely related to plasma C24:0/C16:0 concentration (Hazard ratio 0.901 [Confidence bounds 0.82,0.99], P = 0.026. Conclusions: Plasma ceramide (C24:0/C16:0) is inversely related to time to hospitalization in patients with HFpEF. Plasma C24:0/C16:0 may be a useful new biomarker in HFpEF and may point to novel, targetable pathophysiologic pathways .

scholarly journals MR-proANP and incident cardiovascular disease in patients with type 2 diabetes with and without heart failure with preserved ejection fraction

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Jesper Jensen ◽  
Morten Schou ◽  
Caroline Kistorp ◽  
Jens Faber ◽  
Tine W. Hansen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Type 2 Diabetes ◽  
Ejection Fraction ◽  
Natriuretic Peptides ◽  
Continuous Variable ◽  
Preserved Ejection Fraction ◽  
Reduced Ejection Fraction ◽  
Increased Risk ◽  
Definition Of

Abstract Background Mid-regional pro-atrial natriuretic peptide (MR-proANP) is a useful biomarker in outpatients with type 2 diabetes (T2D) to diagnose heart failure (HF). Elevated B-type natriuretic peptides are included in the definition of HF with preserved ejection fraction (HFpEF) but little is known about the prognostic value of including A-type natriuretic peptides (MR-proANP) in the evaluation of patients with T2D. Methods We prospectively evaluated the risk of incident cardiovascular (CV) events in outpatients with T2D (n = 806, mean ± standard deviation age 64 ± 10 years, 65% male, median [interquartile range] duration of diabetes 12 [6–17] years, 17.5% with symptomatic HFpEF) according to MR-proANP levels and stratified according to HF-status including further stratification according to a prespecified cut-off level of MR-proANP. Results A total of 126 CV events occurred (median follow-up 4.8 [4.1–5.3] years). An elevated MR-proANP, with a cut-off of 60 pmol/l or as a continuous variable, was associated with incident CV events (p < 0.001). Compared to patients without HF, patients with HFpEF and high MR-proANP (≥ 60 pmol/l; median 124 [89–202] pmol/l) and patients with HF and reduced ejection fraction (HFrEF) had a higher risk of CV events (multivariable model; hazard ratio (HR) 2.56 [95% CI 1.64–4.00] and 3.32 [1.64–6.74], respectively). Conversely, patients with HFpEF and low MR-proANP (< 60 pmol/l; median 46 [32–56] pmol/l) did not have an increased risk (HR 2.18 [0.78–6.14]). Conclusions Patients with T2D and HFpEF with high MR-proANP levels had an increased risk for CV events compared to patients with HFpEF without elevated MR-proANP and compared to patients without HF, supporting the use of MR-proANP in the definition of HFpEF from a prognostic point-of-view.

scholarly journals Skeletal Muscle Function, Structure, and Metabolism in Patients With Heart Failure With Reduced Ejection Fraction and Heart Failure With Preserved Ejection Fraction

2020 ◽  
Vol 13 (12) ◽  
Author(s):  
Tarek Bekfani ◽  
Mohamed Bekhite Elsaied ◽  
Steffen Derlien ◽  
Jenny Nisser ◽  
Martin Westermann ◽  
...  
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Fatty Acid ◽  
Ejection Fraction ◽  
Oral Anticoagulation ◽  
Muscle Function ◽  
Muscle Endurance ◽  
Acid Oxidation ◽  
Preserved Ejection Fraction ◽  
Reduced Ejection Fraction

Background: Reduced exercise capacity in patients with heart failure (HF) could be partially explained by skeletal muscle dysfunction. We compared skeletal muscle function, structure, and metabolism among clinically stable outpatients with HF with preserved ejection fraction, HF with reduced ejection fraction, and healthy controls (HC). Furthermore, the molecular, metabolic, and clinical profile of patients with reduced muscle endurance was described. Methods: Fifty-five participants were recruited prospectively at the University Hospital Jena (17 HF with preserved ejection fraction, 18 HF with reduced ejection fraction, and 20 HC). All participants underwent echocardiography, cardiopulmonary exercise testing, 6-minute walking test, isokinetic muscle function, and skeletal muscle biopsies. Expression levels of fatty acid oxidation, glucose metabolism, atrophy genes, and proteins as well as inflammatory biomarkers were assessed. Mitochondria were evaluated using electron microscopy. Results: Patients with HF with preserved ejection fraction showed compared with HF with reduced ejection fraction and HC reduced muscle strength (eccentric extension: 13.3±5.0 versus 18.0±5.9 versus 17.9±5.1 Nm/kg, P =0.04), elevated levels of MSTN-2 (myostatin-2), FBXO-32 (F-box only protein 32 [Atrogin1]) gene and protein, and smaller mitochondrial size ( P <0.05). Mitochondrial function and fatty acid and glucose metabolism were impaired in HF-patients compared with HC ( P <0.05). In a multiple regression analysis, GDF-15 (growth and differentiation factor 15), CPT1B (carnitine palmitoyltransferase IB)-protein and oral anticoagulation were independent factors for predicting reduced muscle endurance after adjusting for age (log10 GDF-15 [pg/mL] [B, −54.3 (95% CI, −106 to −2.00), P =0.043], log10 CPT1B per fold increase [B, 49.3 (95% CI, 1.90–96.77), P =0.042]; oral anticoagulation present [B, 44.8 (95% CI, 27.90–61.78), P <0.001]). Conclusions: Patients with HF with preserved ejection fraction have worse muscle function and predominant muscle atrophy compared with those with HF with reduced ejection fraction and HC. Inflammatory biomarkers, fatty acid oxidation, and oral anticoagulation were independent factors for predicting reduced muscle endurance.

Sign in / Sign up

Export Citation Format

Share Document