Neurohormonal Antagonists Research Articles

Clinical Characteristics and Outcomes in Patients with Mismatched Filling Pressures in Advanced Heart Failure: Looking beyond the JVP

Purpose Right atrial (RA) and pulmonary capillary wedge pressure (PCWP) are concordant in the majority of heart failure (HF) patients, allowing estimation of volume status by jugular venous pressure (JVP). Pts with discordant filling pressures have been identified while undergoing transplant evaluation. However, the incidence and outcomes of discordant filling pressures have not been evaluated in pts with chronic advanced HF. Methods and Materials The MEDAMACS screening pilot was a multicenter, prospective, observational study of pts with advanced systolic HF, including 116 pts who underwent right heart catheterization (RHC) within 6 months of enrollment. Three strata were defined: 1. Matched high (MH, RA≥11mmHg +PCWP≥20mmHg) 2. Matched low (ML, RA≤10 mmHg+PCWP≤19mmHg) or 3. Mismatched (MM i.e. RA≤10 mmHg+PCWP≥20mmHg). Pts were assessed for outcomes of death, initiation of inotropes, mechanical circulatory support, or transplant. Results Of the 116 pts in this analysis, 25%, 47%, and 28% pts were in the ML, MH and MM groups respectively. 49 events were recorded by 6 months. The majority of pts with in the MM group had low RA pressure and high PCWP. There were no differences between the 3 groups in baseline demographics, HF etiology, EF, or NYHA class. The MH and MM groups included fewer pts tolerating ACE-inhibitors (ML 76%, MH 50%, MM 58%, p=0.07), and mean Cr was higher in the MM group (ML 1.3 mmol/L, MH 1.6mmol/L, MM 1.8mmol/L, p= 0.02). Six-month event free survival was 75%, 67% and 55% for the ML, MH and MM groups respectively (p=0.249). Conclusions Discordant filling pressures were found in 28% of advanced HF patients on medical therapy and were associated with impaired renal function and lower tolerance of neurohormonal antagonists. Despite limited evidence of congestion by JVP assessment, event rates are high for pts with discordant filling pressures, affirming a role for selective use of invasive hemodynamic assessment in this population.

Medical Management Is The Way To Go For Ventricular Reconstruction Post STICH?

Ventricular remodeling is a complex process mediated by pathogenic factors all of which interact at the cellular, ventricular and systemic levels to cause progressive left ventricular dilation and subsequently a heart failure syndrome. Remodeling is a well-characterized response to insult or injury and is initiated early on by neurohormonal activation. Neurohormonal antagonists have formed the foundation of therapy to alter the progression of remodeling and concomitantly improve outcomes. Surgical ventricular reconstruction was designed as a surgical means to reduce the ventricular radius and in principal decrease ventricular wall stress as defined by the Law of Laplace. Despite optimistic initial results from case series, the Surgical Treatment for Ischemic Heart Failure Trial (STICH) trial, a large randomized trial of ventricular reconstruction in addition to coronary artery bypass surgery (CABG) therapy for management of patients with heart failure with a reduced ejection fraction showed no clinical benefit. We will summarize the evidence that demonstrates the foundational role of neurohormonal blockade in improving outcomes in patients with heart failure with a reduced ejection and the evidence behind its role in “medical ventricular reconstruction”.

Diabetic cardiomyopathy—What do we know about it?

Diabetic cardiomyopathy is defined as the presence of myocardial dysfunction in patients with diabetes in the absence of coronary artery disease, hypertension, or other known cardiac disease. Diabetes has been shown to affect the heart through various cellular mechanisms leading to enhanced myocardial fibrosis, left ventricular hypertrophy, systolic and diastolic dysfunction. With increasing incidence of type II diabetes mellitus, it has continuously rising health and financial implications in both developed and developing countries. Hyperglycaemia seems to be the main deriving force, and careful glycaemic control as well as early administration of neurohormonal antagonists currently remains the mainstay of therapy. Many newer treatment targets are currently being explored. Here we present a brief review of its pathophysiology, association with heart failure symptoms, and management strategies.

Control of Heart Rate and Neurohormonal Activation in Chronic Heart Failure - Important Targets to Improve Outcomes

Since 1987 with the publication of CONSENSUS, neurohormonal antagonism by ACE-inhibition has been an established life-prolonging option in the treatment of chronic systolic heart failure (CHF)(1). When the effect of enalapril could be associated with the degree of neurohormonal activation (2), the mechanism was further clarified. An alternative to ACE-inhibition emerged with angiotensin receptor blockers (ARBs) where life-prolonging options where documented in VALHeFT and CHARM (3, 4). In all international guidelines, these therapies have recommendation class I and evidence levels A and are the modes of therapies which should be initiated first when systolic HF is diagnosed (5).

Pulmonary hypertension and right ventricular failure in left ventricular systolic dysfunction

Pulmonary hypertension and right ventricular failure (RVF) in left ventricular systolic dysfunction (LVSD) is associated with high morbidity and mortality. This review presents an overview of the classification, pathophysiology, natural history, clinical features, prevention and treatment of this common clinical problem with a focus on the most recent studies. Many of the current evidence-based therapeutic agents for pulmonary hypertension in the absence of systolic or diastolic heart failure (e.g. prostaglandins, endothelin antagonists) are not efficacious in pulmonary hypertension with LVSD. Recent clinical evidence strongly supports an evolving role for phosphodiesterase type 5 (PDE5) inhibition in patients with pulmonary hypertension and LVSD. Chronic PDE5 inhibition in the short-to-intermediate duration studies to date significantly reduces pulmonary pressures and pulmonary vascular resistance (PVR), effects reverse right ventricle and left ventricle remodeling, improves ventilator efficiency, improves peak exercise capacity and improves quality of life in selected patients with stable, moderately symptomatic LVSD and pulmonary hypertension. Although long-term outcome studies are currently lacking, chronic PDE5 inhibition should be considered in carefully selected LVSD patients who manifest persistent significant elevation of pulmonary hypertension or PVR or uncontrolled RVF after aggressive management with all standard current evidence-based LVSD therapies (neurohormonal antagonists, diuretics and cardiac resynchronization in appropriate candidates).

Ace inhibitor therapy for heart failure in patients with impaired renal function: a review of the literature

Heart failure syndromes are often associated with multi-organ dysfunction, and concomitant liver, renal, and neurologic involvement is very common. Neuro-hormonal antagonism plays a key role in the management of this syndrome, and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are one of the cornerstones of therapy. Cardiorenal physiology is becoming more recognized in these patients with advanced heart failure, and the role of neuro-hormonal blockade in this setting is vaguely defined in the literature. Often, angiotensin-converting enzyme inhibitors are decreased or even withheld in these circumstances. The purpose of this article is to review the role and pathophysiology of ace inhibition and angiotensin receptor blockade in patients with acute and chronic heart failure syndromes and concomitant cardiorenal physiology.

Design and rationale of studies of neurohormonal blockade and outcomes in diastolic heart failure using OPTIMIZE-HF registry linked to Medicare data

BackgroundHeart failure (HF) is the leading cause of hospitalization for Medicare beneficiaries. Nearly half of all HF patients have diastolic HF or HF with preserved ejection fraction (HF–PEF). Because these patients were excluded from major randomized clinical trials of neurohormonal blockade in HF there is little evidence about their role in HF–PEF. MethodsThe aims of the American Recovery & Reinvestment Act-funded National Heart, Lung, and Blood Institute-sponsored “Neurohormonal Blockade and Outcomes in Diastolic Heart Failure” are to study the long-term effects of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and aldosterone antagonists in four separate propensity-matched populations of HF–PEF patients in the OPTIMIZE-HF (Organized Program to Initiate Life-Saving Treatment in Hospitalized Patients with Heart Failure) registry. Of the 48,612 OPTIMIZE-HF hospitalizations occurring during 2003–2004 in 259 U.S. hospitals, 20,839 were due to HF–PEF (EF ≥40%). For mortality and hospitalization we used Medicare national claims data through December 31, 2008. ResultsUsing a two-step (hospital-level and hospitalization-level) probabilistic linking approach, we assembled a cohort of 11,997 HF–PEF patients from 238 OPTIMIZE-HF hospitals. These patients had a mean age of 75years, mean EF of 55%, were 62% women, 15% African American, and were comparable with community-based HF–PEF cohorts in key baseline characteristics. ConclusionsThe assembled Medicare-linked OPTIMIZE-HF cohort of Medicare beneficiaries with HF–PEF with long-term outcomes data will provide unique opportunities to study clinical effectivenss of various neurohormonal antagonists with outcomes in HF–PEF using propensity-matched designs that allow outcome-blinded assembly of balanced cohorts, a key feature of randomized clinical trials.

Management of chemotherapy induced cardiomyopathy.

Chemotherapy related cardiac dysfunction (CRCD) is a serious complication of anticancer therapy. CRCD can be classified into two types. Type I CRCD is exemplified by anthracyline- induced cardiac dysfunction and type II CRCD is exemplified by trastuzumab- induced cardiac dysfunction. The mechanism of cardiac toxicity in both types is not well defined. Certain risk factors may play a role in developing the cardiac injury, most importantly, the cumulative dose when dealing with anthracycline induced cardiotoxicity. Establishing an early diagnosis and initiating early treatment may be an important step in preventing irreversible cardiac injury especially in type I CRCD. Currently there are no guidelines developed specifically for the treatment of chemotherapy induced cardiomyopathy (CIC), however a few small studies support the use of neurohormonal antagonists in the treatment and prevention of CIC. Large multi- centers trials are needed to establish guidelines for CIC. Until then, we advocate following the American College of Cardiology/ American Heart Association (ACC/AHA) and Heart Failure Society of America (HFSA) guidelines. Additionally, a close collaboration between the patient’s cardiologist and oncologist is strongly recommended in order to establish a long term plan for the patient.

Neurohormonal control of heart failure

For nearly three decades, starting in the early 1970s, the cardiology research laboratories at the University of Minnesota served as the focal point for the discovery and implementation of much of the information we now apply to the management of heart failure. Director Jay Cohn, building on his expertise in hypertension and hemodynamics, led many creative and committed investigators in the exploration of the mechanisms responsible for increased sensitivity to afterload in heart failure. The neurohormonal hypothesis of heart failure led to the development of several pharmacologic tools, such as angiotensin-converting enzyme inhibitors, β-adrenergic blockers, and, later, angiotensin-receptor blockers. By the late 1990s, it was understood that neurohormonal antagonists could prevent the progression of left ventricular remodeling and favorably influence the natural history of heart failure. Neurohormonal blockers are now considered standard therapy. Issues remain to be addressed, including early identification and treatment of patients at risk.

Renal Function in Advanced Heart Failure

Despite recent advances with neurohormonal antagonists and devices, the prognosis of patients with advanced heart failure (HF) remains grave. Renal dysfunction is a common comorbid condition in HF and is associated with adverse outcomes. Current evidence indicates that intrinsic renal disease and inflammation in HF makes the kidney susceptible to hemodynamic compromise and congestion and contributes to a great extent to the development of renal dysfunction. Relief of congestion requires combination treatment with diuretics, neurohormonal antagonists, and occasionally vasodilators as well as inotropes. However, high doses of diuretics may accelerate the development of renal dysfunction by increasing neurohumoral activity and inducing renal structural and functional changes. Ultrafiltration should be reserved for patients with true diuretic resistance. Finally, early identification of the "patient at risk" remains a challenging issue and is limited by the currently used conventional parameters of renal function. However, novel biomarkers of acute kidney ischemia and/or injury are emerging and promise to become a diagnostic option for this patient population.

Prognosis for Patients With Heart Failure With Preserved Ejection Fraction. Is It the Same As Low Ejection Fraction?

Heart failure (HF) is a significant and increasing global public health problem. In the United States, hospital admissions for a principal diagnosis of HF increased from 399 000 in 1979 to 1 093 000 in 2003. 1 The diagnosis of HF continues to be associated with poor quality of life, high morbidity, and high mortality despite contemporary HF management. 2,3 Once admitted to hospital, patients experience high rates of subsequent HF hospitalization and mortality. 2 HF has been traditionally viewed as a failure of contractile function and left ventricular ejection fraction (LVEF) has been widely used to define systolic function, assess prognosis, and select patients for therapeutic interventions. The combination of evidence-based pharmacotherapy (mainly neurohormonal antagonists) and device-based therapies has now resulted in significant improvements in prognosis for patients with HF with low ejection fraction (HF-lowEF), with annualized mortality rates as low as 6% in recent randomized, controlled trials with optimal therapy. 4 However, the population of patients enrolled

Carvedilol Attenuates Inflammatory-Mediated Cardiotoxicity in Daunorubicin-Induced Rats

Cardiotoxicity, which results from intense cardiac oxidative stress and inflammation, is the main limiting factor of the anthracyclines. Carvedilol, a beta blocker that is used as a multifunctional neurohormonal antagonist, has been shown to act not only as an anti-oxidant, but also as an anti-inflammatory drug. This study was designed to evaluate whether carvedilol exerts a protective role against inflammation-mediated cardiotoxicity in the daunorubicin (DNR)-induced rats. Carvedilol was administered orally to the rats every day for 6 weeks at a cumulative dose of 9 mg/kg body weight DNR. DNR significantly induced cardiac damage and worsened cardiac function as well as increased cardiac mast cell density, elevating the myocardial protein and mRNA expression levels of tumor necrosis factor-α, vascular cell adhesion molecule-1, inter-cellular adhesion molecule-1, nuclear factor kappa-B, cyclooxygenase-2, monocyte chemotactic protein -1 and interleukin -6 compared to that in the control group. Cotreatment with carvedilol significantly attenuated the myocardial protein and mRNA expression levels of these inflammatory markers, decreased cardiac mast cell density, improved histological cardiac damage and cardiac functions. In conclusion, inflammation plays a significant role in DNR-induced cardiotoxicity, and carvedilol contributes to cardioprotection against inflammation-mediated cardiotoxicity in DNR-induced rats through its anti-inflammatory mechanism.

Implantable Sensors for Heart Failure

Heart failure (HF) affects more than 5 million Americans, and acute decompensated heart failure (ADHF) has emerged as the leading cause of hospitalization among people over the age of 65 years.1 Importantly, HF is a leading public health concern, and hospitalization expenses related to management of ADHF impose a substantial financial burden on the health care system. Additionally, readmission rates after hospitalization for ADHF may be as high as 50% at 6 months,2 and insights from the ADHERE registry suggest that a majority of patients admitted with ADHF have a history of heart failure.1 These data demonstrate that the majority of patients admitted with ADHF are known to the medical system and to medical providers, thereby creating an opportunity for upstream strategies that may be capable of detecting early HF destabilization and implementing therapies to restabilize the patient and avert hospitalization. The anticipated changes in the health care system—with a focus on bundled payments for disease management—will necessitate robust disease management programs to optimize therapy and minimize recurrent admissions once patients have been diagnosed with HF. Perhaps even more importantly, averting repeat episodes of ADHF is likely to have a stabilizing effect on the progression of HF and may improve long-term morbidity and mortality. The transition from chronic HF to ADHF involves perturbations in multiple intersecting processes including neurohormonal circuits, inflammatory mediators, cardiorenal interactions, and myocardial performance. Concurrently, derangements in comorbid illnesses such as coronary disease, atrial and ventricular arrhythmias, and hypertension also contribute to the pathophysiology of ADHF.3 Ultimately, these multiple pathways lead to an elevation in ventricular filling pressures and signs of vascular congestion, which, in concert with symptoms from impaired cardiac output, lead to the clinical constellation of ADHF. This pathophysiologic paradigm highlights multiple opportunities for detecting early changes in the processes that …

Role of Cardiac Resynchronization in End-Stage Heart Failure Patients Requiring Inotrope Therapy

Background Outcomes among inotrope-treated heart failure (HF) patients receiving cardiac resynchronization therapy (CRT) have not been well characterized, particularly in those requiring intravenous inotropes at the time of implant. Methods We analyzed 759 consecutive CRT-defibrillator recipients who were categorized as never on inotropes (NI; n = 585), weaned from inotropes before implant (PI; n = 124), or on inotropes at implant (II; n = 50). Survival free from heart transplant or ventricular assist device and overall survival were compared using the Social Security Death Index. A patient cohort who underwent unsuccessful CRT implantation and received a standard defibrillator (SD; n = 94) comprised a comparison group. Propensity score analysis was used to control for intergroup baseline differences. Results Compared with the other cohorts, II patients had more comorbidities. Both survival endpoints differed significantly ( P < .001) among the 4 cohorts; II patients demonstrated shorter survival than NI patients, with the PI and SD groups having intermediate survival. After adjusting for propensity scores, overall differences and patterns in survival endpoints persisted ( P < .01), but the only statistically significant pairwise difference was overall survival between the NI and II groups at 12 months (hazard ratio 2.95, 95% confidence interval 1.05-8.35). CRT recipients ever on inotropes (PI and II) and SD patients ever requiring inotropes (n = 17) experienced similar survival endpoints. Among II patients, predictors of hospital discharge free from inotropes after CRT included male gender, older age, and ability to tolerate β-blockade. Conclusions Inotrope-dependent HF patients show significantly worse survival despite CRT than inotrope-naïve patients, in part because of more comorbid conditions at baseline. CRT may not provide a survival advantage over a standard defibrillator among patients who have received inotropes before CRT. Weaning from inotropes and initiating neurohormonal antagonists before CRT should be an important goal among inotrope-dependent HF patients.

Prognostic Value of Blood Urea Nitrogen and Its Variations in Patients With Chronic Heart Failure

cohort of patients with PPCM. Methods: The Utah PPCM Registry was queried for eligible patients age $18 years with a confirmed diagnosis of PPCM (new reduced left ventricular ejection fraction (LVEF) #45%, no known etiology, diagnosed in the last month of pregnancy up to the 5 postpartum month). Patients were grouped according to recovery (LVEF #50%) (Rec) and no recovery (LVEF !50%) (NoRec). Echocardiographic measures of LVEF and left ventricular internal dimension at end-diastole (LVIDD) and medication use were tracked in both groups. Findings: 58 patients were included in the analysis. Average age was 30 years; 36 patients (62%) had recovery of cardiac function. The average time to recovery was 8.9 months. Echocardiographic measures and medication use between the groups are detailed (Table below). Conclusion: Patients with PPCM who have recovery of ventricular function are more likely to have a higher baseline LVEF, smaller left ventricular dimensions, and have increased use of standard heart failure medications. The neurohormonal antagonists studied here appear to have a meaningful impact on clinical characteristics for patients with PPCM and should be used as tolerated.

218: The Use of Neurohormonal Antagonists Is Not Associated with Vasoplegia in Post-Orthotopic Heart Transplant Patients

Postoperative vasoplegia syndrome (PVS) after orthotopic heart transplant (OHT) is poorly understood and portends poor prognosis. Some have argued that aggressive preoperative treatment of neurohormonal antagonists and vasoactive drugs are contributing to PVS. We aim to identify pre-operative determinants for the development of PVS after OHT

Improving survival in the 6 months after diagnosis of heart failure in the past decade: population-based data from the UK

Objective:To investigate the secular trend in survival after a new diagnosis of heart failure in the UK population.Design and Setting:Comparison of all-cause mortality in the 6 months after diagnosis of...

Neurohormonal activation and inflammation in chronic cardiopulmonary disease: a brief systematic review

Chronic cardiopulmonary disease typically induces and maintains (over)activation of several phylogenetically old adaptational and defensive mechanisms. Activation was usually needed for a limited period during acute danger or injury. In chronic disease conditions, however, those mechanisms are kept activated for longer periods. Eventually, irreversible damage is done and this contributes to impaired function and worse prognosis in a variety of chronic disease. Landmark trials in chronic heart failure have provided robust evidence for prognostic benefit for neurohormonal antagonists. Retrospective and epidemiological data for their beneficial effect in chronic obstructive pulmonary disease begin to accumulate and new fields (e.g. cancer and stroke) could be pending in the future.

Metabolic Modulation and Cellular Therapy of Cardiac Dysfunction and Failure

• Introduction • Metabolic modulation - Metabolism in the normal heart - Substrate uptake and oxidation - Oxidative phosphorylation - ATP transport and utilization - Metabolism in heart failure - Changes in substrate utilization - Effects on oxidative phosphorylation - Changes in ATP transport and utilization • Medications that influence metabolism in heart failure (Table 2) • Cell therapy - Skeletal muscle myoblasts - Human embryonic stem cells - Bone marrow derived adult stem cells - Haematopoietic stem cells - Mesenchymal stem cells (MSC) - Endothelial progenitor cells (EPCs) - Cardiac stem cells • Mechanisms of stem cell mediated myocardial regeneration • Clinical applications of stem cells Table 2. Potential metabolic modulators in heart failure (1) Long-chain 3-ketoacyl coenzyme A thiolase inhibitor Trimetazidine (2) CPT I inhibitors Perhexiline Etomoxir Oxfenicin (3) PPAR-γ activators Rosiglitazone Pioglitazone Abstract At present the prevalence of heart failure rises along with aging of the population. Current heart failure therapeutic options are directed towards disease prevention via neurohormonal antagonism (β-blockers, angiotensin converting enzyme inhibitors and/or angiotensin receptor blockers and aldosterone antagonists), symptomatic treatment with diuretics and digitalis and use of biventricular pacing and defibrillators in a special subset of patients. Despite these therapies and device interventions heart failure remains a progressive disease with high mortality and morbidity rates. The number of patients who survive to develop advanced heart failure is increasing. These patients require new therapeutic strategies. In this review two of emerging therapies in the treatment of heart failure are discussed: metabolic modulation and cellular therapy. Metabolic modulation aims to optimize the myocardial energy utilization via shifting the substrate utilization from free fatty acids to glucose. Cellular therapy on the other hand has the goal to achieve true cardiac regeneration. We review the experimental data that support these strategies as well as the available pharmacological agents for metabolic modulation and clinical application of cellular therapy.

The Use of Midodrine in Patients With Advanced Heart Failure

In many patients, the treatment of heart failure (HF) cannot be optimized because of pre-existing or treatment-induced hypotension. Midodrine, a peripheral alpha1-adrenergic agonist may allow for up-titration of neurohormonal antagonist therapy leading to improved outcomes. Ten consecutive patients with HF due to systolic dysfunction and symptomatic hypotension interfering with optimal medical therapy were started on midodrine. After a 6-month follow-up, a higher percentage of patients were on optimal HF therapy (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker mg % of optimal dose 20% vs 57.5%; P<.001) (beta-blockers mg % optimal dose 37.5% vs 75%; P<.001) (spironolactone/eplerenone mg % 43.7% vs 95%; P<.001). This led to an improvement in left ventricular ejection fraction (baseline 24+/-9.4 vs 32.2+/-9.9; P<.001) and clinical outcomes, with a significant reduction in total hospital admissions (32 vs 12; P=.02) and total hospital days (150 vs 58; P=.02).