Benefit In Heart Failure Research Articles

PP.11.16] THE COMBINATION DRUG VALSARTAN/SACUBITRIL (LCZ696) REDUCED PULSE WAVE VELOCITY AND AORTIC SYSTOLIC BLOOD PRESSURE IN PATIENTS WITH HEART FAILURE WITH REDUCED EJECTION FRACTION

Objective: Dual neprilysin inhibition and angiotensin receptor blockade with LCZ696 has been shown therapeutic benefits in chronic heart failure (CHF) patients. The aim of the study was to assess LCZ696 effects on parameters of arterial stiffness in stable heart failure with reduced ejection fraction (HFrEF). Design and method: In the open-label follow-up to PARADIGM HF study 18 patients with stable HFrEF (16 male, 69 ± 9 years (M ± SD), arterial hypertension 83%, previous myocardial infarction 89%, diabetes mellitus 39%, dyslipidemia 56%, LVEF 32 ± 4%, serum creatinine 118 ± 21 μmol/l, eGFR 56 ± 13 ml/min/1.73m2, potassium 4.45 ± 0.35 mmol/l) were enrolled. Patients received a stable background treatment for at least a month (ACEI 94%, beta-blockers 100%, aldosterone receptor antagonists 83.3%, loop diuretics 72.2%). ACEI treatment was interrupted for 36 h and replaced with LCZ696 100 or 200 mg (11 patients) BID according to baseline brachial BP (mean dose 185.7 ± 36.3 mg BID). Applanation tonometry was performed baseline and after 6 month LCZ696 therapy. Wilcoxon test was considered significant if p < 0.05. Results: Baseline brachial BP decreased from 137.1 ± 22.0/83.4 ± 11.8 to 120.5 ± 13.5/75.1 ± 9.3 mmHg (δ −16.6 ± 14.2/−8.3 ± 10.3 mmHg, p < 0.05), heart rate did not change (78 ± 12 vs 75 ± 15 beats/min (δ −2.7 ± 14.7 beats/min, p > 0.05). Valsartan/sacubitril therapy was associated with significant decrease of carotid-femoral pulse wave velocity (11.5 ± 2.9 vs 10.2 ± 2.9 m/s, p < 0.05), central systolic (125 ± 16 vs 116 ± 15 mmHg, p = 0.005) and diastolic (78 ± 7 vs 74 ± 9 mmHg, p < 0.05) blood pressure. Central pulse pressure (45 ± 11 vs 41 ± 16 mmHg), augmentation pressure (16 ± 7,1 vs 13,8 ± 8,4 mmHg), augmentation index (29 ± 7 vs 28 ± 11%), time to reflected wave (128 ± 8 vs 132 ± 7 ms) did not change significantly (p > 0.05 for all comparisons). Conclusions: In stable patients with heart failure with reduced ejection fraction 6 month valsartan/sacubitril therapy was associated with significant decrease of aortic systolic pressure and pulse wave velocity.

Salt in the diet in patients with heart failure: what to recommend.

Recognizing the relevance of sodium balance in heart failure, it has been presumed that patients with heart failure benefit from a low-sodium diet, though its efficacy and safety are unclear. The purpose of this review is to provide insight into the currently available evidence base for the effects of dietary sodium restriction in patients with chronic heart failure. There has been an increasing body of evidence on the effects of sodium restriction in heart failure; however, both observational and experimental studies have shown mixed results. Recent randomized controlled trial data has even suggested that sodium restriction may have detrimental effects in patients with heart failure. Only a few randomized controlled trials have included clinical outcomes as a primary endpoint. These have been either unpowered to test the association between reduced sodium intake and outcomes, or conducted in the context of an aggressive diuretic treatment and fluid restriction. The effects of a low-sodium diet on clinical outcomes in patients with heart failure remain unclear. Ongoing research into the effects of lowering sodium for patients with chronic or acute heart failure will shed light on the importance of holistic self-care and dietary strategies in heart failure.

Hypertension – state of the art 2015

A conference organised in conjunction with the British Hypertension Society at the Royal College of Physicians (London) assembled an expert panel to present recent advances in the understanding and management of hypertension - the leading reversible risk factor for global morbidity and mortality. Despite recognised therapeutic approaches, less than half of patients on treatment for hypertension achieve blood pressure control to international guideline-based targets. This failure may, in part, be due to uncertainty into optimum treatment strategies, and the PATHWAY studies reporting later this year will hopefully address some outstanding questions relating to the standardised ABCD approach to drug selection. Targeting degradation of natriuretic peptides by LCZ696 (a combination of valsartan and a neutral endopeptidase inhibitor) has demonstrated potential as a novel therapeutic option, with mortality benefits in heart failure beyond that solely attributable to its blood pressure lowering ability. However, critical to any therapeutic strategy is patient involvement, and it is clear that the delivery of patient-centric treatment options is vital to ensure adherence with medication and to facilitate healthier lifestyle decisions.

Heart Failure as a Disruption of Dynamic Circulatory Homeostasis Mediated by the Brain.

Circulatory homeostasis is associated with interactions between multiple organs, and the disruption of dynamic circulatory homeostasis could be considered as heart failure. The brain is the central unit integrating neural and neurohormonal information from peripheral organs and controlling peripheral organs using the autonomic nervous system. Heart failure is worsened by abnormal sympathoexcitation associated with baroreflex failure and/or chemoreflex activation, and by vagal withdrawal, and autonomic modulation therapies have benefits for heart failure. Recently, we showed that baroreflex failure induces striking volume intolerance independent of left ventricular dysfunction. Many studies have indicated that an overactive renin-angiotensin system, excess oxidative stress and excess inflammation, and/or decreased nitric oxide in the brain cause sympathoexcitation in heart failure. We have demonstrated that angiotensin II type 1 receptor (AT1R)-induced oxidative stress in the rostral ventrolateral medulla (RVLM), which is known as a vasomotor center, causes prominent sympathoexcitation in heart failure model rats. Interestingly, systemic infusion of angiotensin II directly affects brain AT1R with sympathoexcitation and left ventricular diastolic dysfunction. Moreover, we have demonstrated that targeted deletion of AT1R in astrocytes strikingly improved survival with prevention of left ventricular remodeling and sympathoinhibition in myocardial infarction-induced heart failure. From these results, we believe it is possible that AT1R in astrocytes, not in neurons, have a key role in the pathophysiology of heart failure. We would like to propose a novel concept that the brain works as a central processing unit integrating neural and hormonal input, and that the disruption of dynamic circulatory homeostasis mediated by the brain causes heart failure.

0525: Gender related differences on cardiac rehabilitation benefits for heart failure

Female heart diseases are underdiagnosed and undertreated. They are also probably under referred to cardiac rehabilitation (CR). The aim of our study is to compare CR benefits between men and women. A total of 442 patients suffering from heart failure were referred to our center for CR between 2010 and 2014. Only 67 were women (15%). All patients had physical examination, electrocardiogram, echocardiography and a cardio-pulmonary exercise test (CPET) before and at the end of CR. Age was similar between men and women with 56.8±12.4 versus 56.2±14.5 years (p: NS). Ischemic heart disease was the main etiology for men (57.6%), but not for women (30%, p<0.05). Patient’s CR characteristics are summarized in table. Abstract 0525 – Table: Patient’s clinical, echocardiographic and CPET’s characteristics Men (n=375) Women (n=67) p Before CR Heart Rate (bpm)80.3±15.7 80.3±15.7 77.3±16.4 NS Systolic blood pressure (mmHg) 109.8±19 102.8±19 <0.05 Left ventricle Ejection Fraction (%) 28.8±8.7 29.3±8.9 NS CPET workload (watts) 76±27 58.1±20 <0.05 Peak oxygen uptake: 15.6±5.2 14.7±4.9 NS – VO2 max (ml/kg/mn) – % of the normal value 56.2±17.8 63.9±22 First ventilatory threshold (VT1) (ml/kg/mn) 10.9±3.4 10.5±4 NS After CR Heart Rate (bpm) 76.8±14.6 75.4±14.3 NS Systolic blood pressure (mmHg) 110.4±20.8 98.5±19.2 NS CPET workload (watts) 92.5±32 67.8±20 <0.05 Peak oxygen uptake: 18.2±5.7 16.1±4.8 NS – VO2 max (ml/kg/mn) – % of the normal value 65.5±19.3 68.5±18 First ventilatory threshold (VT1) (ml/kg/mn) 12.4±3.9 11.9±3.7 NS The benefit on CPET strength was similar (24.8±33 W for men and 22.1±35.4 W for women, p: NS), and also for the VO2 max. There were no differences in treatments at discharge. Women have the same benefits after CR for heart failure. Efforts must be provided to increase their referral to CR.

Abstract 12289: The Nuclear Receptor NR4A1 Regulates Transcriptional Programs Involved in Cardiac Fuel Metabolism and Hypertrophic Growth

The transcriptional coregulators, peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) alpha and beta, are inducible master regulators of mitochondrial biogenesis and metabolism. Studies in rodents and in humans have shown that expression and activity of PGC-1 coactivators is downregulated in the failing heart. Surprisingly, we found that adult mice with cardiac-specific deletion of the PGC-1alpha/beta genes exhibit relatively normal cardiac function despite a significant reduction in mitochondrial state 3 respiration, suggesting the existence of a compensatory energy metabolic pathway. Unbiased transcriptional profiling demonstrated upregulation of the orphan nuclear receptor NR4A1 (Nur77) and the related nuclear receptor NR4A3 (Nor1) in PGC-1 null hearts, consistent with an adaptive response to energetic stress. We found that expression of NR4A1 family members is induced in heart by a variety of physiological stress stimuli. In addition, activation of beta-adrenergic signaling with isoproterenol led to rapid and dramatic induction in the expression of all NR4A members in the mouse heart. To identify cardiac NR4A1 targets, total RNA-seq was performed in neonatal rat ventricular myocytes (NRVMs) overexpressing NR4A1. NR4A1 expression of genes involved in glucose uptake/utilization pathways and high energy phosphate transfer including Slc2a4 (Glut4), Eno3 (enolase 3), and Ckmt2 (mitochondrial creatinine kinase). Consistent with the transcriptomic changes, NR4A1 increased myocyte 2-deoxylglucose uptake and oxygen consumption rates (OCR) in these cells. Interestingly, the RNA-seq data also revealed that NR4A1 overexpression downregulated many cardiac pathologic hypertrophic markers such as ANF and BNP. NR4A1 overexpression also significantly inhibited phenylephrine-induced NRVM hypertrophy. Finally, NR4A1 knockout mice exhibit exuberant cardiac hypertrophy following chronic isoproterenol administration. Taken together, these data suggest NR4A1 serves as a stress-induced transcription factor that regulates fuel metabolism and cardiac remodeling. The long-term goal of this project is to determine if activation of this pathway holds therapeutic benefit in acute heart failure.

Abstract 15821: Safety and Efficacy of Non-invasive Ventilation During Exercise Training in Patients With Acute Heart Failure. A Randomized Prospective Controlled Study

Background: Exercise training (ET) is well established to improve functional capacity and quality of life in patients (pts) with chronic heart failure. However, the ET benefits in acute heart failure (AHF) are unknown. Purpose: We aimed to study the safety and efficacy of ET alone or combined with non-invasive ventilation (NIV) compared to standard medical treatment in hospitalized pts with AHF. Methods: Twenty-nine pts with AHF (68% ischemic), 56±7 years, left ventricle ejection fraction of 25±5%, NTproBNP of 2456±730, 6-minute walk test distance (6MWD = 225±39meters) were randomized into 3 groups: ET + NIV with sub therapeutic positive airway pressure (PAP) (ET,n=9), ET + NIV set to 14 of inspiratory and 8 cmH2O of expiratory PAP, respectively (EV,n=11) and standard treatment (CO,n=9). The ET and EV groups performed a daily session of unloaded exercise on cycle ergometer for 20 min or tolerance limit, for 8 consecutives days. In EV and ET, oxygen pulse saturation (SpO2), heart rate (HR), respiratory rate (RR), blood pressure (BP), blood lactate were measured at baseline (D1), during exercise, and at day 10 (D10). Serious adverse events (death or worsening heart failure) were also assessed on D10. Results: Length of hospital stay was shorter in EV group (17±10 days) compared to ET (23±8 days) and CO (39±15 days) (p&lt;0,05). There were more serious adverse events in CO (66,6%) compared to both EV and ET (15%). Dobutamine use at D10 was less frequent in EV (18,2%) and ET (22,2%) groups than in CO (33,3%) (p&lt;0.05). There was a marked improvement in Δ6MWD between D1 and D10 in EV (Δ127±72 meters), though increase in Δ6MWD was also seen in ET (Δ72±26 meters) and CO (Δ41±19meters), p&lt;0,05. The EV group also showed higher endurance and lower peak HR at end-exercise than ET at D10 (128±10 vs. 92±8 min and 73±12 vs. 104±25 bpm, respectively; p&lt;0,05). There was a similar reduction in NTproBNP levels but no differences were found in BP, SpO2, RR and blood lactate. Conclusion: Aerobic exercise in AHF was safe, reduced length of hospital stay and need for inotropics at D10. NIV + ET increased exercise endurance with lower cardiovascular stress.

Beta Blocker Survival Benefit in Heart Failure is Associated with ADRB1 Ser49Gly Genotype

Beta Blocker Survival Benefit in Heart Failure is Associated with ADRB1 Ser49Gly Genotype

Everything you ever wanted to know about phosphodiesterase 5 inhibitors and the heart (but never dared ask): How do they work?

Phosphodiesterase 5 inhibitors (PDE5i) were developed while investigating novel treatments for coronary artery disease, but their andrological side effects shifted their indication toward the management of erectile dysfunction. Although PDE5i are now also indicated for pulmonary arterial hypertension and there are mounting preclinical and clinical evidences about their potentially beneficial cardiac effects, their use remains controversial and the involved mechanisms remain unclear. This review aimed to analyze the effects of PDE5i administration in various animal and humans models of cardiovascular diseases. Animal studies have shown that PDE5i have protective effects in several models of cardiac disease. In humans, some studies showed that PDE5i improves microvascular and endothelial dysfunction and exerts positive effects in different samples of cardiovascular (CV) impairment. In contrast, other studies found no benefit (and no harm) in heart failure with preserved ejection fraction. The discrepancies in these findings are likely related to the fact that the mechanisms targeted by PDE5i in human disease are still poorly understood and the target population not yet identified. The mechanisms of actions herein reviewed suggest that hypertrophy, microvascular impairment, and inflammation, should be variably present for PDE5i to work. All these conditions frequently coexist in diabetes. A gender responsiveness has also been recently proposed. Continuous PDE5 inhibition may exert cardioprotective effects, improving endothelial function and counteracting cardiac remodeling in some but not all conditions. A better patient selection could help to clarify the controversies on PDE5i use for CV disorders.

(609) - The Effect of Exercise and Resistance Training on Physical Capacity of LVAD Patients - Analysis of Different Age Groups

s S227 HMII may create additional suction of pump and provide more reduction of LV size. However, the additional effects of HMII for LV reverse remodeling or benefit for right heart failure by reducing right ventricular afterload should be carefully analyzed with more cases.

Renal effects of the angiotensin receptor neprilysin inhibitor LCZ696 in patients with heart failure and preserved ejection fraction.

Increases in serum creatinine with renin-angiotensin-aldosterone system (RAAS) inhibitors can lead to unnecessary discontinuation of these agents. The dual-acting angiotensin receptor neprilysin inhibitor LCZ696 improves clinical outcome patients with heart failure with reduced ejection fraction, and pilot data suggest potential benefit in heart failure with preserved ejection fraction (HFpEF). The effects of LCZ696 on renal function have not been assessed. A total of 301 HFpEF patients were randomly assigned to LCZ696 or valsartan in the PARAMOUNT trial. We studied renal function [creatinine, estimated glomerular filtration rate (eGFR), cystatin C, and urinary albumin to creatinine ratio (UACR)] at baseline, 12 weeks, and after 36 weeks of treatment. Worsening renal function (WRF) was determined as an serum creatinine increase of >0.3 mg/dL and/or >25% between two time-points. Mean eGFR at baseline was 65.4 ± 20.4 mL/min per 1.73 m(2) . The eGFR declined less in the LCZ696 group than in the valsartan group (-1.5 vs. -5.2 mL/min per 1.73 m(2) ; P = 0.002). The incidence of WRF was lower in the LCZ696 group (12%) than in the valsartan group (18%) at any time-point, but this difference was not statistically significant (P = 0.18). Over 36 weeks, the geometric mean of UACR increased in the LCZ696 group (2.4-2.9 mg/mmol), whereas it remained stable in the valsartan group (2.1-2.0 mg/mmol; P for difference between groups = 0.016). In patients with HFpEF, therapy with LCZ696 for 36 weeks was associated with preservation of eGFR compared with valsartan therapy, but an increase in UACR.

Effect of study design on the reported effect of cardiac resynchronization therapy (CRT) on quantitative physiological measures: stratified meta-analysis in narrow-QRS heart failure and implications for planning future studies.

BackgroundBiventricular pacing (CRT) shows clear benefits in heart failure with wide QRS, but results in narrow QRS have appeared conflicting. We tested the hypothesis that study design might have influenced findings.Method and ResultsWe identified all reports of CRT‐P/D therapy in subjects with narrow QRS reporting effects on continuous physiological variables. Twelve studies (2074 patients) met these criteria. Studies were stratified by presence of bias‐resistance steps: the presence of a randomized control arm over a single arm, and blinded outcome measurement. Change in each endpoint was quantified using a standardized effect size (Cohen's d). We conducted separate meta‐analyses for each variable in turn, stratified by trial quality. In non‐randomized, non‐blinded studies, the majority of variables (10 of 12, 83%) showed significant improvement, ranging from a standardized mean effect size of +1.57 (95%CI +0.43 to +2.7) for ejection fraction to +2.87 (+1.78 to +3.95) for NYHA class. In the randomized, non‐blinded study, only 3 out of 6 variables (50%) showed improvement. For the randomized blinded studies, 0 out of 9 variables (0%) showed benefit, ranging from −0.04 (−0.31 to +0.22) for ejection fraction to −0.1 (−0.73 to +0.53) for 6‐minute walk test.ConclusionsDifferences in degrees of resistance to bias, rather than choice of endpoint, explain the variation between studies of CRT in narrow‐QRS heart failure addressing physiological variables. When bias‐resistance features are implemented, it becomes clear that these patients do not improve in any tested physiological variable. Guidance from studies without careful planning to resist bias may be far less useful than commonly perceived.

The comparative efficacy and safety of the angiotensin receptor blockers in the management of hypertension and other cardiovascular diseases.

All national guidelines for the management of hypertension recommend angiotensin receptor blockers (ARBs) as an initial or add-on antihypertensive therapy. The eight available ARBs have variable clinical efficacy when used for control of hypertension. Additive blood pressure-lowering effects have been demonstrated when ARBs are combined with thiazide diuretics or dihydropyridine calcium channel blockers, augmenting hypertension control. Furthermore, therapeutic use of ARBs goes beyond their antihypertensive effects, with evidence-based benefits in heart failure and diabetic renal disease particularly among angiotensin-converting enzyme inhibitor-intolerant patients. On the other hand, combining renin-angiotensin system blocking agents, a formerly common practice among medical subspecialists focusing on the management of hypertension, has ceased, as there is not only no evidence of cardiovascular benefit but also modest evidence of harm, particularly with regard to renal dysfunction. ARBs are very well tolerated as monotherapy, as well as in combination with other antihypertensive medications, which improve adherence to therapy and have become a mainstay in the treatment of stage 1 and stage 2 hypertension.

Glucagon-like peptide-1 receptor agonists for diabetes mellitus: a role in cardiovascular disease.

Diabetes mellitus, defined as a fasting plasma glucose of ≥126 mg/dL or a glycosylated hemoglobin A1c level (HbA1c) of ≥6.5%, afflicts ≈12.9% of adults in the United States and nearly 285 million adults worldwide.1,2 Diabetes mellitus is a major risk factor for the development of cardiovascular disease, independently conferring a 2-fold excess risk of coronary heart disease and stroke.3 Macrovascular events in diabetes mellitus remain the leading cause of mortality, and the burden of cardiovascular disease attributable to diabetes mellitus has increased over the past decade.4 An increase in the prevalence of obesity has contributed to the rise in diabetes mellitus. Additionally, obesity independently increases the risk of cardiovascular disease in patients with diabetes mellitus.5 Although strict glycemic control unequivocally reduces the microvascular complications of diabetes mellitus, the macrovascular benefits of intensive therapy have been difficult to establish, with conflicting results from large clinical trials.6–9 Multifactorial strategies are recommended to reduce cardiovascular risk in diabetes mellitus through enhanced glycemic control, blood pressure reduction, lipid management, weight loss, and physical activity.10 Unfortunately, despite aggressive interventions for hyperglycemia, <50% of patients achieve standard HbA1c targets with conventional therapy.11 Polypharmacy is required to achieve glycemic control in the majority of patients within 3 years of diagnosis.12 Although combinations of drug classes can synergistically target multiple pathophysiological defects, novel therapies are required to manage diabetes mellitus and mitigate cardiovascular risks. Dipeptidyl-peptidase IV (DPP-IV) inhibitor and glucagon-like peptide-1 (GLP-1) receptor agonist incretin therapies were developed to complement conventional treatment options for diabetes mellitus. Despite promising initial reports of cardioprotective effects, DPP-IV inhibitors have failed to demonstrate improved cardiovascular outcomes in large clinical trials.13–15 Randomized studies to evaluate cardiovascular outcomes associated with GLP-1 receptor agonists are currently underway. This review presents …

Impact of Castration on Changes in Left Ventricular Diastolic Pressure–Volume Relations Induced by Chronic Adrenergic Stimulation in Rats

A reduced testosterone concentration characterizes heart failure and independently predicts outcomes. Although testosterone replacement therapy may have non cardiac-related therapeutic benefits in heart failure, whether reduced testosterone concentrations protect against adverse left ventricular remodeling (LV dilatation) is uncertain. We therefore evaluated whether surgical castration modifies LV dilatation after 6 months of daily injections of the β-adrenergic receptor (AR) agonist, isoproterenol (ISO) (0.015 mg·kg(-1)·d(-1)), to rats. The extent of LV dilatation and LV systolic chamber dysfunction were determined using both echocardiography and isolated perfused heart procedures. The extent of LV dilatation was determined from LV diastolic pressure-volume (P-V) relationships. As compared with the saline vehicle-treated group, after 6 months of β-AR activation in sham-castrated rats, a marked right shift in the LV diastolic P-V relationship was noted with an increased LV volume intercept at 0 mm Hg diastolic pressure (LV V(0) in milliliters) (ISO = 0.38 ± 0.02, saline vehicle = 0.30 ± 0.02, P < 0.05). However, chronic β-AR activation did not alter LV systolic chamber function either in vivo (LV endocardial fractional shortening, echocardiography) or ex vivo (LV end systolic elastance). Although castration decreased body weight, castration failed to modify the impact of ISO on the LV diastolic P-V relationships or the LV volume intercept at 0 mm Hg diastolic pressure (LV V(0) in milliliters) (castration ISO = 0.35 ± 0.02, castration saline vehicle = 0.27 ± 0.03, P < 0.05). In conclusion, castration does not influence the extent of LV dilatation induced by chronic adrenergic activation in an animal model, where adverse LV remodeling precedes LV systolic chamber dysfunction.

42 Meta-Analysis Identifying the Source of Conflict Between Different Trial Reports on the Effect of CRT in Heart Failure with Narrow QRS Complexes

BackgroundBiventricular pacing (CRT) shows clear benefits in heart failure with wide QRS, but results in patients with narrow QRS have been conflicting. In this meta-analysis we tested the hypothesis that...

Critical appraisal of the obesity paradox in cardiovascular disease: How to manage patients with overweight in heart failure?

Overweight has been shown in multiple studies to carry a survival benefit in heart failure (HF) patients. This finding is, of course, counterintuitive to the well-established role of obesity as a modifiable risk factor for incident cardiovascular disease. The debate on the relevance of this obesity paradox is on-going, and clinical, methodological and teleological aspects are discussed. Particularly, younger age and a seemingly favourable clinical status of obese patients are repeatedly discussed together with the lack of prospective data to question the validity of the observed survival advantage in obese HF patients. Recent risk score calculators, however, have included body weight as an inverse risk factor, i.e. higher body mass index is predicting better outcome. Emerging prospective interventional trials support the concept that in patients with established disease, intentional weight reduction may not necessarily translate into improved outcome. The clinically most relevant consequence from the emerging data is, of course, the practical recommendation on body weight management that we may give our (overweight) patients. While the terminology as a paradox is critically discussed, a more differentiated concept for weight management should be emphasized that distinguishes between healthy subjects and those with an established cardiovascular disease such as heart failure.

Moxonidine-induced central sympathoinhibition improves prognosis in rats with hypertensive heart failure

Enhanced central sympathetic outflow is an indicator of the prognosis of heart failure. Although the central sympatholytic drug moxonidine is an established therapeutic strategy for hypertension, its benefits for hypertensive heart failure are poorly understood. In the present study, we investigated the effects of central sympathoinhibition by intracerebral infusion of moxonidine on survival in a rat model of hypertensive heart failure and the possible mechanisms involved. As a model of hypertensive heart failure, we fed Dahl salt-sensitive rats an 8% NaCl diet from 7 weeks of age. Intracerebroventricular (ICV) infusion of moxonidine (moxonidine-ICV-treated group [Mox-ICV]) or vehicle (vehicle-ICV-treated group [Veh-ICV]) was performed at 14-20 weeks of age, during the increased heart failure phase. Survival rates were examined, and sympathetic activity, left ventricular function and remodelling, and brain oxidative stress were measured. Hypertension and left ventricular hypertrophy were established by 13 weeks of age. At around 20 weeks of age, Veh-ICV rats exhibited overt heart failure concomitant with increased urinary norepinephrine (uNE) excretion as an index of sympathetic activity, dilated left ventricle, decreased percentage fractional shortening, and myocardial fibrosis. Survival rates at 21 weeks of age (n = 28) were only 23% in Veh-ICV rats, and 76% (n = 17) in Mox-ICV rats with concomitant decreases in uNE, myocardial fibrosis, collagen type I/III ratio, brain oxidative stress, and suppressed left ventricular dysfunction. Moxonidine-induced central sympathoinhibition attenuated brain oxidative stress, prevented cardiac dysfunction and remodelling, and improved the prognosis in rats with hypertensive heart failure. Central sympathoinhibition can be effective for the treatment of hypertensive heart failure.

First Clinical Experience with TRV027: Pharmacokinetics and Pharmacodynamics in Healthy Volunteers

TRV027 is a novel β-arrestin biased peptide ligand of the angiotensin II type 1 receptor (AT1R). The compound antagonizes G protein coupling while simultaneously stimulating β-arrestin-mediated signaling. In preclinical studies, TRV027 reversibly reduced blood pressure while preserving renal function in a dog tachypaced heart failure model and stimulating cardiomyocyte contractility in vitro. This profile suggests that TRV027 may have unique benefits in acute heart failure, a condition associated with renin-angiotensin system activation. A first-time-in-human study was conducted with ascending doses of TRV027 to explore its tolerability, pharmacokinetics and pharmacodynamics in healthy volunteers. Subjects' salt intake was restricted to stimulate RAS activation. In this study TRV027 was safe and well tolerated with a short-half-life (ranging between 2.4 and 13.2 minutes) and dose-proportional increases in systemic exposure. Consistent with the pre-clinical findings, TRV027 reduced blood pressure to a greater degree in subjects with RAS activation, measured as elevated plasma renin activity, than in those with normal PRA levels. This study in sodium-restricted healthy subjects suggests that TRV027 will successfully target a core mechanism of acute heart failure pathophysiology. Further clinical studies with TRV027 in patients with heart failure are underway.

Development of a Swine Model of Left Bundle Branch Block for Experimental Studies of Cardiac Resynchronization Therapy

Animal models that mimic human electrical and mechanical dyssynchrony often associated with chronic heart failure would provide an essential tool to investigate factors influencing response to cardiac resynchronization therapy. A standardized closed-chest porcine model of left bundle branch block (LBBB) was developed using 16 pigs. Radiofrequency applications were performed to induce LBBB, which was confirmed by QRS widening, a surface electrocardiogram pattern concordant with LBBB, and a prolonged activation time from endocardial. Echocardiography confirmed abnormal motion of the septum, which was not present at the baseline echocardiogram. High susceptibility of pigs to ventricular fibrillation during the endocardial ablation was overcome by applying high-rate pacing during radiofrequency applications. This is the first study to devise a closed-chest porcine model of LBBB that closely reproduces abnormalities found in patients with electrical and mechanical cardiac dyssynchrony, and provides a useful tool to investigate the basic mechanisms underlying cardiac resynchronization therapy benefits in heart failure.