Neurohormonal Blockade in Heart Failure.
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ABSTRACT:
SUBMITTER: von Lueder TG
PROVIDER: S-EPMC5494151 | biostudies-literature | 2017 Apr
REPOSITORIES: biostudies-literature
Publications
Neurohormonal Blockade in Heart Failure.
von Lueder Thomas G TG Kotecha Dipak D Atar Dan D Hopper Ingrid I
Cardiac failure review 20170401 1
A key feature of chronic heart failure (HF) is the sustained activation of endogenous neurohormonal systems in response to impaired cardiac pumping and/or filling properties. The clinical use of neurohormonal blockers has revolutionised the care of HF patients over the past three decades. Drug therapy that is active against imbalance in both the autonomic and renin-angiotensin-aldosterone systems consistently reduces morbidity and mortality in chronic HF with reduced left ventricular ejection fr ...[more]
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Project description:Importance:Left ventricular assist devices (LVADs) improve outcomes in patients with advanced heart failure, but little is known about the role of neurohormonal blockade (NHB) in treating these patients. Objective:To analyze the association between NHB blockade and outcomes in patients with LVADs. Design, Setting, and Participants:This retrospective cohort analysis of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) included patients from more than 170 centers across the United States and Canada with continuous flow LVADs from 2008 to 2016 who were alive with the device in place at 6 months after implant. The data were analyzed between February and November 2019. Exposures:Patients were stratified based on exposure to NHB and represented all permutations of the following drug classes: angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, ?-blockers, and mineralocorticoid antagonists. Main Outcomes and Measures:The outcomes of interest were survival at 4 years and quality of life at 2 years based on Kansas City Cardiomyopathy Questionnaire scores and a 6-minute walk test. Results:A total of 12?144 patients in INTERMACS met inclusion criteria, of whom 2526 (20.8% ) were women, 8088 (66.6%) were white, 3024 (24.9%) were African American, and 753 (6.2%) were Hispanic; the mean (SD) age was 56.8 (12.9) years. Of these, 10?419 (85.8%) were receiving NHB. Those receiving any NHB medication at 6 months had a better survival rate at 4 years compared with patients not receiving NHB (56.0%; 95% CI, 54.5%-57.5% vs 43.9%; 95% CI, 40.5%-47.7%). After sensitivity analyses with an adjusted model, this trend persisted with patients receiving triple therapy with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, ?-blocker, and mineralocorticoid antagonist having the lowest hazard of death compared with patients in the other groups (hazard ratio, 0.34; 95% CI, 0.28-0.41). Compared with patients not receiving NHB, use of NHB was associated with a higher Kansas City Cardiomyopathy Questionnaire score (66.6; bootstrapped 95% CI, 65.8-67.3 vs 63.0; bootstrapped 95% CI, 60.1-65.8; P?=?.02) and a 6-minute walk test (1103 ft; bootstrapped 95% CI, 1084-1123 ft vs 987 ft; bootstrapped 95% CI, 913-1060 ft; P?<?.001). Conclusions and Relevance:Among patients with LVADs who tolerated NHB therapy, continued treatment was associated with improved survival and quality of life. The optimal heart failure regimen for patients after LVAD implant may be the initiation and continuation of guideline-directed medical therapy.
| S-EPMC6865330 | biostudies-literature
Project description:ObjectivesThe purpose of this study was to describe the prevalence and prognosis of HF stages in the community; to evaluate if preclinical HF stages are characterized by elevation of pro-inflammatory (C-reactive protein), neurohormonal activation (B-type natriuretic peptide, renin and aldosterone), and cardiac stress biomarkers (high-sensitivity troponin I, ST-2, and growth differentiation factor-15).BackgroundThe American Heart Association/American College of Cardiology heart failure (HF) classification has 3 stages. Knowledge regarding the community burden of HF stages is limited, and data on the biomarker profile associated with HF stages are scarce, although higher concentrations of certain biomarkers are associated with preclinical HF.MethodsWe evaluated 6,770 participants (mean age 51 years; 54% women) from the Framingham Study, defining 4 stages: 1) healthy: no risk factors; 2) stage A: presence of HF risk factors (hypertension, diabetes, obesity, coronary artery disease), no cardiac structural/functional abnormality; 3) stage B: presence of prior myocardial infarction, valvular disease, left ventricular (LV) systolic dysfunction, LV hypertrophy, regional wall motion abnormality, or LV enlargement; 4) stage C/D: prevalent HF.ResultsThe prevalence of HF stages A and B were 36.5% and 24.2%, respectively, rising with age (odds ratio: 1.70 [95% confidence interval: 1.64 to 1.77] per decade increment). In age- and sex-adjusted models, we observed a gradient of increasing biomarker levels across HF stages (p < 0.05; n = 3,416). Adjusting for age and sex, mortality rose across HF stages (232 deaths, mean follow-up 7 years), with 2- and 8-fold mortality risks for stages B and C/D, respectively, compared with healthy.ConclusionsApproximately 60% of our sample has preclinical HF, and those in stage B had higher concentrations of HF biomarkers and experienced a substantial mortality risk.
| S-EPMC8450920 | biostudies-literature
Project description:AimsPulmonary hypertension (PH) represents an important phenotype among the broader spectrum of patients with heart failure with preserved ejection fraction (HFpEF), but its mechanistic basis remains unclear. We hypothesized that activation of endothelin and adrenomedullin, two counterregulatory pathways important in the pathophysiology of PH, would be greater in HFpEF patients with worsening PH, and would correlate with the severity of haemodynamic derangements and limitations in aerobic capacity and cardiopulmonary reserve.Methods and resultsPlasma levels of C-terminal pro-endothelin-1 (CT-proET-1) and mid-regional pro-adrenomedullin (MR-proADM), central haemodynamics, echocardiography, and oxygen consumption (VO2) were measured at rest and during exercise in subjects with invasively-verified HFpEF (n = 38) and controls free of HF (n = 20) as part of a prospective study. Plasma levels of CT-proET-1 and MR-proADM were highly correlated with one another (r = 0.89, P < 0.0001), and compared to controls, subjects with HFpEF displayed higher levels of each neurohormone at rest and during exercise. C-terminal pro-endothelin-1 and MR-proADM levels were strongly correlated with mean pulmonary artery (PA) pressure (r = 0.73 and 0.65, both P < 0.0001) and pulmonary capillary wedge pressure (r = 0.67 and r = 0.62, both P < 0.0001) and inversely correlated with PA compliance (r = -0.52 and -0.43, both P < 0.001). As compared to controls, subjects with HFpEF displayed right ventricular (RV) reserve limitation, evidenced by less increases in RV s' and e' tissue velocities, during exercise. Baseline CT-proET-1 and MR-proADM levels were correlated with worse RV diastolic reserve (ΔRV e', r = -0.59 and -0.67, both P < 0.001), reduced cardiac output responses to exercise (r = -0.59 and -0.61, both P < 0.0001), and more severely impaired peak VO2 (r = -0.60 and -0.67, both P < 0.0001).ConclusionSubjects with HFpEF display activation of the endothelin and adrenomedullin neurohormonal pathways, the magnitude of which is associated with pulmonary haemodynamic derangements, limitations in RV functional reserve, reduced cardiac output, and more profoundly impaired exercise capacity in HFpEF. Further study is required to evaluate for causal relationships and determine if therapies targeting these counterregulatory pathways can improve outcomes in patients with the HFpEF-PH phenotype.Clinical trial registrationNCT01418248; https://clinicaltrials.gov/ct2/results? term=NCT01418248&Search=Search.
| S-EPMC7963136 | biostudies-literature
Project description:Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent syndrome with multifaceted pathophysiology. All approaches to neurohormonal modulation were shown not to improve survival in HFpEF, despite their well-established efficacy in heart failure with reduced ejection fraction (HFrEF). This might be attributed to suboptimal study design, inadequate diagnostic criteria, or statistical power, but is also likely to reflect a lack of consideration for its clinical heterogeneity. The attention then shifted to the phenotypic heterogeneity of HFpEF, with the ultimate goal of developing therapies tailored to individual patient phenotypes. Recently, the sodium-glucose co-transporter-2 inhibitor (SGLT2i) empagliflozin has been found to reduce the combined risk of cardiovascular death or hospitalization for HF in patients with HFpEF, a result driven by a reduction in HF hospitalizations. This paper recapitulates the journey from the failure of trials on neurohormonal antagonists to the attempts of personalized approaches and the new perspectives of SGLT2i therapy for HFpEF.
| S-EPMC9902425 | biostudies-literature
Project description:AimsTo optimize guideline-directed medical therapy for heart failure, patients may require the initiation of multiple neurohormonal antagonists (NHAs) during and following hospitalization. The safety of this approach for older adults is not well established.Methods and resultsWe conducted an observational cohort study of 207 223 Medicare beneficiaries discharged home following a hospitalization for heart failure with reduced ejection fraction (HFrEF) (2008-2015). We performed Cox proportional hazards regression to examine the association between the count of NHAs initiated within 90 days of hospital discharge (as a time-varying exposure) and all-cause mortality, all-cause rehospitalization, and fall-related adverse events over the 90 day period following hospitalization. We calculated inverse probability-weighted hazard ratios (IPW-HRs) with 95% confidence intervals (CIs) comparing initiation of 1, 2, or 3 NHAs vs. 0. The IPW-HRs for mortality were 0.80 [95% CI (0.78-0.83)] for 1 NHA, 0.70 [95% CI (0.66-0.75)] for 2, and 0.94 [95% CI (0.83-1.06)] for 3. The IPW-HRs for readmission were 0.95 [95% CI (0.93-0.96)] for 1 NHA, 0.89 [95% CI (0.86-0.91)] for 2, and 0.96 [95% CI (0.90-1.02)] for 3. The IPW-HRs for fall-related adverse events were 1.13 [95% CI (1.10-1.15)] for 1 NHA, 1.25 [95% CI (1.21-1.30)] for 2, and 1.64 [95% CI (1.54-1.76)] for 3.ConclusionsInitiating 1-2 NHAs among older adults within 90 days of HFrEF hospitalization was associated with lower mortality and lower readmission. However, initiating 3 NHAs was not associated with reduced mortality or readmission and was associated with a significant risk for fall-related adverse events.
| S-EPMC10192242 | biostudies-literature
Project description:Objective:This study evaluated the associations between the natriuretic peptide activity and the neurohormonal response in non-obese and obese outpatients with and without heart failure (HF). Background:Obesity-related HF may be a distinct subtype of HF. Obesity is associated with lower plasma concentrations of natriuretic peptides. The associations between obesity and neurohormonal activation estimated by mid-regional pro-adrenomedullin (MR-proADM) and copeptin in patients with HF is not elucidated. Methods:This prospective cohort-study included 392 outpatients ?60years, plus ?1 risk-factor(-s) for HF (hypertension, ischemic heart disease, atrial fibrillation, diabetes, chronic kidney disease), and without known HF. Patients were categorized 'non-obese' BMI = 18.5-29.9 kg/m2 (n = 273) and 'obese' BMI ? 30 kg/m2 (n = 119). The diagnosis of HF required signs, symptoms, and abnormal echocardiography. NT-proBNP, MR-proANP, MR-proADM, and copeptin were analyzed. Results:Obese patients were younger, had a higher prevalence of diabetes and chronic kidney disease, but a lower prevalence of atrial fibrillation. A total of 39 (14.3%) non-obese and 26 (21.8%) obese patients were diagnosed with HF. In obese patients, HF was not associated with higher plasma concentrations of NT-proBNP (Estimate: 0.063; 95%CI: -0.037-1.300; P = 0.064), MR-proANP (Estimate: 0.207; 95%CI: -0.101-0.515; P = 0.187), MR-proADM (Estimate: 0.112; 95%CI: -0.047-0.271; P = 0.168), or copeptin (Estimate: 0.093; 95%CI: -0.333-0.518; P = 0.669). Additionally, obese patients with HF had lower plasma concentrations of NT-proBNP (Estimate: -0.998; 95%CI: -1.778-0.218; P = 0.012), and MR-proANP (Estimate: -0.488; 95%CI: -0.845-0.132; P = 0.007) compared to non-obese patients with HF, whereas plasma concentrations of MR-proADM (Estimate: 0.066; 95%CI: -0.119-0.250; P = 0.484) and copeptin (Estimate: 0.140; 95%CI: -0.354-0.633; P = 0.578) were comparable. Conclusions:Patients with obesity-related HF have natriuretic peptide deficiency and lack of increased plasma concentrations of MR-proADM and copeptin suggesting that patients with obesity-related HF have a blunted overall neurohormonal activity.
| S-EPMC7218759 | biostudies-literature
Project description: Not available
| S-EPMC7508271 | biostudies-literature
Project description:?-Arrestin (?arr)-1 and ?-arrestin-2 (?arrs) are universal G-protein-coupled receptor adapter proteins that negatively regulate cardiac ?-adrenergic receptor (?AR) function via ?AR desensitization and downregulation. In addition, they mediate G-protein-independent ?AR signaling, which might be beneficial, for example, antiapoptotic, for the heart. However, the specific role(s) of each ?arr isoform in cardiac ?AR dysfunction, the molecular hallmark of chronic heart failure (HF), remains unknown. Furthermore, adrenal ?arr1 exacerbates HF by chronically enhancing adrenal production and hence circulating levels of aldosterone and catecholamines. Herein, we sought to delineate specific roles of ?arr1 in post-myocardial infarction (MI) HF by testing the effects of ?arr1 genetic deletion on normal and post-MI cardiac function and morphology. We studied ?arr1 knockout (?arr1KO) mice alongside wild-type controls under normal conditions and after surgical MI. Normal (sham-operated) ?arr1KO mice display enhanced ?AR-dependent contractility and post-MI ?arr1KO mice enhanced overall cardiac function (and ?AR-dependent contractility) compared with wild type. Post-MI ?arr1KO mice also show increased survival and decreased cardiac infarct size, apoptosis, and adverse remodeling, as well as circulating catecholamines and aldosterone, compared with post-MI wild type. The underlying mechanisms, on one hand, improved cardiac ?AR signaling and function, as evidenced by increased ?AR density and procontractile signaling, via reduced cardiac ?AR desensitization because of cardiac ?arr1 absence, and, on the other hand, decreased production leading to lower circulating levels of catecholamines and aldosterone because of adrenal ?arr1 absence. Thus, ?arr1, via both cardiac and adrenal effects, is detrimental for cardiac structure and function and significantly exacerbates post-MI HF.
| S-EPMC3889868 | biostudies-literature
Project description:Although therapy with mineralocorticoid receptor antagonists (MRAs) is recommended for patients with chronic heart failure (HF) with reduced ejection fraction and in post-infarction HF, it has not been studied well in acute HF (AHF) despite being commonly used in this setting. At high doses, MRA therapy in AHF may relieve congestion through its natriuretic properties and mitigate the effects of adverse neurohormonal activation associated with intravenous loop diuretics. The ATHENA-HF (Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure) trial is a randomized, double-blind, placebo-controlled study of the safety and efficacy of 100 mg/day spironolactone versus placebo (or continued low-dose spironolactone use in participants who are already receiving spironolactone at baseline) in 360 patients hospitalized for AHF. Patients are randomized within 24 h of receiving the first dose of intravenous diuretics. The primary objective is to determine if high-dose spironolactone, compared with standard care, will lead to greater reductions in N-terminal pro-B-type natriuretic peptide levels from randomization to 96 h. The secondary endpoints include changes in the clinical congestion score, dyspnea relief, urine output, weight change, loop diuretic dose, and in-hospital worsening HF. Index hospital length of stay and 30-day clinical outcomes will be assessed. Safety endpoints include risk of hyperkalemia and renal function. Differences among patients with reduced versus preserved ejection fraction will be determined. (Study of High-dose Spironolactone vs. Placebo Therapy in Acute Heart Failure [ATHENA-HF]; NCT02235077).
| S-EPMC5010507 | biostudies-literature
Project description:Background Despite the belief that heart failure therapies are not effective in transthyretin cardiac amyloidosis, data are limited. We tested the association of neurohormonal blockade use with survival. Methods and Results A total of 309 consecutive patients with transthyretin cardiac amyloidosis were identified. Medication inventory was obtained at baseline and subsequent visits. Exposure included a neurohormonal blockade class (β-blocker [βB], angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, and mineralocorticoid antagonist) at baseline and subsequent visits. βB was modeled as baseline use, time-varying use, and in an inverse probability treatment weighted model. Primary outcome was all-cause mortality analyzed with adjusted Cox proportional hazards models. Continuing compared with stopping βB during follow-up was tested. Mean age was 73.2 years, 84.1% were men, and 17.2% had atrial fibrillation/flutter at baseline. At the time of study entry, 49.8% were on βBs, 35.0% were on angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and 23.9% were on mineralocorticoid antagonists. For the total cohort, there was a trend toward harm in the unadjusted model for baseline βB use, but this was neutral after adjustment. When βB use was analyzed as a time-varying exposure, there was no association with mortality. βB discontinuation was associated with decreased mortality for the total cohort. Findings were consistent in inverse probability treatment weighted models. For angiotensin-converting enzyme inhibitor/angiotensin receptor blocker or mineralocorticoid antagonist use, there was no association with mortality after adjustment for the total cohort. Conclusions There was no association of neurohormonal blockade use with survival in transthyretin cardiac amyloidosis. For the total cohort, deprescribing βB may be associated with improved survival. Additional studies are needed to confirm these findings.
| S-EPMC9075255 | biostudies-literature