Blockade In Heart Failure Research Articles

Angiotensin receptor-neprilysin inhibitor adherence and outcomes in heart failure with reduced ejection fraction.

Whether medication adherence to angiotensin receptor-neprilysin inhibitor (ARNI) in real-world practice is associated with the reduced risk of all-cause mortality or hospitalization relative to that with traditional renin-angiotensin system (RAS) blockade remains unclear. This study investigated the influence of medication adherence of ARNI and traditional RAS blockade in heart failure with reduced ejection fraction (HFrEF). We conducted a nationwide longitudinal cohort study with patients with HFrEF using data from the Korean National Health Insurance Service data (2017-2021) covering the entire population. A total of 13483 patients with HFrEF who received ARNI were matched 1:1 with 13483 patients who received traditional RAS blockade using propensity score matching. The primary outcome was a composite of all-cause mortality or any hospitalization within one year. Medication adherence was assessed by calculating the proportion of days covered (PDC) relative to total medication prescribed. ARNI and traditional RAS blockade adherence rates were directly compared to analyse their respective associations with the primary outcome. Patients in the ARNI group had a lower rate of the primary outcome than those in the traditional RAS blockade group [hazard ratio (HR) 0.78; 95% confidence interval (CI) 0.75-0.81; P<0.001]. Mean PDC values spanning 1year were 92.6±14.5% and 90.9±17.7% in the ARNI and RAS blockade groups, respectively (P<0.001). Among patients with PDC≥80%, the risk of primary outcome was significantly lower in the ARNI group than in the RAS blockade group (HR 0.75; 95% CI 0.72-0.78; P<0.001) while a risk reduction with ARNI was not observed among patients with PDC<80% (HR 0.95; 95% CI 0.85-1.05; P=0.313). The beneficial effect was more pronounced among patients with PDC≥80% than that among patients with PDC<80% (P for interaction <0.001). In a real-world cohort with HFrEF, ARNI was superior to traditional RAS blockade in reducing the risk of all-cause mortality and hospitalization. The benefit of ARNI was pronounced among patients with high medication adherence but not among those with low medication adherence, highlighting the importance of adherence to ARNI treatment for HFrEF. PARADE-HF ClinicalTrials.gov number, NCT05329727.

RAS blocker effects on first HF hospitalization or CV death does not differ in Black and non-Black patients with HFrEF.

Shen L, Lee MMY, Jhund PS, et al. Revisiting race and the benefit of RAS blockade in heart failure: a meta-analysis of randomized clinical trials. JAMA. 2024;331:2094-2104. 38809561.

Revisiting Race and the Benefit of RAS Blockade in Heart Failure

Concerns have arisen that renin-angiotensin system (RAS) blockers are less effective in Black patients than non-Black patients with heart failure and reduced ejection fraction (HFrEF). To determine whether the effects of RAS blockers on cardiovascular outcomes differ between Black patients and non-Black patients with HFrEF. MEDLINE and Embase databases through December 31, 2023. Randomized trials investigating the effect of RAS blockers on cardiovascular outcomes in adults with HFrEF that enrolled Black and non-Black patients. Individual-participant data were extracted following Preferred Reporting Items for Systematic Reviews and Meta-analyses Independent Personal Data (PRISMA-IPD) reporting guidelines. Effects were estimated using a mixed-effects model using a 1-stage approach. The primary outcome was first hospitalization for HF or cardiovascular death. The primary analysis, based on the 3 placebo-controlled RAS inhibitor monotherapy trials, included 8825 patients (9.9% Black). Rates of death and hospitalization for HF were substantially higher in Black than non-Black patients. The hazard ratio (HR) for RAS blockade vs placebo for the primary composite was 0.84 (95% CI, 0.69-1.03) in Black patients and 0.73 (95% CI, 0.67-0.79) in non-Black patients (P for interaction = .14). The HR for first HF hospitalization was 0.89 (95% CI, 0.70-1.13) in Black patients and 0.62 (95% CI, 0.56-0.69) in non-Black patients (P for interaction = .006). Conversely, the corresponding HRs for cardiovascular death were 0.83 (95% CI, 0.65-1.07) and 0.84 (95% CI, 0.77-0.93), respectively (P for interaction = .99). For total hospitalizations for HF and cardiovascular deaths, the corresponding rate ratios were 0.82 (95% CI, 0.66-1.02) and 0.72 (95% CI, 0.66-0.80), respectively (P for interaction = .27). The supportive analyses including the 2 trials adding an angiotensin receptor blocker to background angiotensin-converting enzyme inhibitor treatment (n = 16 383) gave consistent findings. The mortality benefit from RAS blockade was similar in Black and non-Black patients. Despite the smaller relative risk reduction in hospitalization for HF with RAS blockade in Black patients, the absolute benefit in Black patients was comparable with non-Black patients because of the greater incidence of this outcome in Black patients.

Interleukin-1 blockade in heart failure: an on-treatment and off-treatment cardiorespiratory fitness analysis.

Interleukin-1 (IL-1) blockade may improve exercise capacity in patients with heart failure (HF) patients. The extent of the improvement and its persistence beyond discontinuation of IL-1 blockade is unknown. The primary objective was to determine changes in cardiorespiratory fitness and cardiac function on-treatment with IL-1 blocker, anakinra, and off-treatment, after treatment cessation. We performed cardiopulmonary exercise testing, Doppler echocardiography, and biomarkers in 73 patients with HF, 37 (51%) females, 52 (71%) Black-African-American, before and after treatment with anakinra 100mg daily. In a subset of 46 patients, testing was also repeated after treatment cessation. Quality of life was assessed in each patient using standardized questionnaires. Data are presented as median and interquartile range. Treatment with anakinra for 4 [2-12] weeks was associated with a significant improvement in high-sensitivity C-reactive protein (from 6.2 [3.3-15.4] to 1.4 [0.8-3.4] mg/L, P<0.001), peak oxygen consumption (VO2peak , from 13.9 [11.6-16.6] to 15.2 [12.9-17.4] mL/kg/min, P<0.001). Ventilatory efficiency, exercise time, Doppler-derived signs and biomarkers of elevated intracardiac pressures, and quality-of-life measures also improved with anakinra. In the 46 patients in whom off-treatment data were available 12 [4-12] weeks later, many of the favourable changes seen with anakinra were largely reversed (from 1.5 [1.0-3.4] to 5.9 [1.8-13.1], P=0.001 for C-reactive protein, and from 16.2 [14.0-18.4] to 14.9 [11.5-17.8] mL/kg/min, P=0.017, for VO2peak ). These data validate IL-1 as an active and dynamic modulator of cardiac function and cardiorespiratory fitness in HF.

TNF-α signaling: TACE inhibition to put out the burning heart.

More than 20 years ago, Seta and colleagues hypothesized that cytokines, which are activated by myocardial injury, significantly drive heart failure progression and would therefore be effective targets to treat cardiac dysfunction. Unfortunately, several clinical trials inhibiting key cytokines like tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (Il-1β) turned out negative or even revealed adverse clinical effects. Providing a potential mechanistic explanation for the ineffectiveness of TNF-α blockade in heart failure, novel findings demonstrate that the membrane-bound precursor form of TNF-α, transmembrane TNF-α (tmTNF-α), mediates cardioprotective effects during pressure overload-induced cardiac remodeling. This study suggests that preventing tmTNF-α cleavage by targeting the TNF-α converting enzyme (TACE) rather than inhibiting TNF-α signaling altogether might be a valuable therapeutic approach.

Abstract 15527: Association Between Adrenergic Receptor Modulation and the Risk of Heart Failure: A Two-sample Mendelian Randomization Study

Introduction: The impact of the sympathetic nervous system (SNS) modulation on the risk of heart failure (HF) outside of ß1 receptor blockade remains controversial. Methods: We performed a two-sample Mendelian randomization (MR) study using common independent genetic variants located in the cis region of genes encoding the 9 SNS receptors (α1 A, B, D, α2 A, B, C and ß 1, 2 and 3) that were associated at genome-wide significance (P-value ≤ 5х10 –8 ) with blood pressure (BP) and/or heart rate (HR) in published genome-wide association studies (GWAS) available for BP and HR. Variants were filtered out by Linkage Disequilibrium clumping (LD R 2 &gt; 0.1) and based on their minor allele frequency (MAF &lt; 0.01). The effects of selected variants on the genetic risk of HF were extracted from a GWAS of HF from the HERMES consortium, based on a non-overlapping sample population. MR estimates were obtained using the Wald estimator for a single variant or the inverse variance weighted method for multiple variants. Results: 542,362 controls and 40,805 HF cases were evaluated. Independent variants in genes encoding 4 SNS receptors associated with BP or HR were identified as follows: α1A (diastolic BP), α2B (diastolic BP and HR), ß1 and ß2 (diastolic and systolic BP). MR analysis of α1A and ß1, weighted by their effects on diastolic BP, estimated an association with a higher risk of HF, while α2B variants were associated with a lower risk. We found no evidence for an effect of ß2. A similar relationship with systolic BP was found for ß1 and ß2. HR increasing effect of α2B variants was associated with a decreased odd of HF. Conclusions: Mindful of pleiotropic effects, these findings are consistent with the known benefits of ß1 blockade in HF and support a similar role for α1A blockade; conversely, they suggest a detrimental lowering effect of BP and HR through α2B modulation that deserves further studies. No evidence for a role of ß2 in HF was found.

Effectiveness by gender and age of renin-angiotensin system blockade in heart failure-A national register-based cohort study.

PurposeInvestigate effectiveness by gender and age and equity implications of treatment with renin‐angiotensin system blockade (RASb) in heart failure (HF) patients.MethodsIn this population‐based register study, we used inpatient data from 2006 to 2010 for patients age 20 years or older with no HF hospitalisation for minimum of 1 year before an index hospitalisation. A wash‐out period for RASb of 6 months preceding admission was used.Hospital data were linked with drug dispensation data and cause of death data. The associations between time‐dependent RASb exposure and all‐cause death and HF death, respectively, were examined by Cox regression models. Interactions by gender and age were also investigated on the multiplicative and additive scales.ResultsThirty thousand seven hundred twenty‐one patients were analysed. Fifty‐one percent were women. Median age was 83. Fifty‐three percent of women and 64% of men received RASb after the index hospitalisation. Younger patients were more likely to receive RASb than older ones. One‐year mortality was 28%. RASb was associated with an overall hazard ratio (HR) for all‐cause death of 0.72 (95% confidence interval 0.69‐0.75), and an HR of 0.85 (0.77‐0.93) for HF death. Interaction analyses showed HRs for all‐cause death associated with RASb between 0.12 (0.10‐0.13) in the youngest, and 0.80 (0.76‐0.84) in the oldest patients.ConclusionsRASb appeared effective for women and men and for patients of all ages in this hospitalised HF cohort. No gender difference in effectiveness was found. RASb exposure was low overall, indicating a need for improved adherence to treatment guidelines. Treatment with RASb may be inequitable for women and older patients.

Effects of dual blockade in heart failure and renal dysfunction: Systematic review and meta-analysis.

Objective:The effect of dual renin–angiotensin system (RAS) inhibition in heart failure (HF) is still controversial. Systematic reviews have shown that dual RAS blockade may reduce mortality and hospitalizations, yet it has been associated with the increased risk of renal dysfunction (RD). Surprisingly, although RD in patients with HF is frequent, the effect of combining RAS inhibitors in HF patients with RD has never been studied in a meta-analysis.Methods:A systematic review and meta-analysis of randomized clinical trials involving HF patients with RD who received dual blockade analyzing death, cardiovascular (CV) death or HF hospitalization, and adverse events.Results:Out of 2258 screened articles, 12 studies were included (34,131 patients). Compared with monotherapy, dual RAS inhibition reduced hazard ratio of death to 0.94 (p=0.07) and significantly reduced CV death or HF hospitalization to 0.89 (p=0.0006) in all individuals, and to 0.86 (p=0.005) in patients with RD and to 0.91 (p=0.04) without RD. Nevertheless, dual RAS blockade significantly increased the risk of renal impairment (40%), hyperkalemia (44%), and hypotension (42%), although discontinuation of treatment occurs only in 3.68% versus 2.19% (p=0.00001).Conclusions:Dual RAS inhibition therapy reduces the risk of CV death or HF hospitalization. However, cautions monitoring for specific adverse events may be warranted.

Arrhythmogenic cardiac alternans in heart failure is suppressed by late sodium current blockade by ranolazine

Cardiac alternans is promoted by heart failure (HF)-induced calcium (Ca2+) cycling abnormalities. Late sodium current (INa,L) is enhanced in HF and promotes Ca2+ overload; however, mechanisms underlying an antiarrhythmic effect of INa,L blockade in HF remain unclear. The purpose of this study was to determine whether ranolazine suppresses cardiac alternans in HF by normalizing Ca2+ cycling. Transmural dual optical mapping of Ca2+ transients and action potentials was performed in wedge preparations from 8 HF and 8 control (normal) dogs. Susceptibility to action potential duration alternans (APD-ALT) and Ca2+ transient alternans (Ca-ALT) was compared at baseline and with ranolazine (5-10 μM). HF increased APD- and Ca-ALT compared to normal (both P <.05), and ranolazine suppressed APD- and Ca-ALT in both groups (P <.05). The incidence of spatially discordant alternans (DIS-ALT) was increased by HF (8/8) compared to normal (4/8; P <.05), and ranolazine decreased DIS-ALT in HF (4/8; P <.05).Not only did ranolazine mitigate HF-induced Ca2+ overload, it also attenuated APD-ALT to Ca-ALT gain (amount of APD-ALT produced by Ca-ALT). In HF, APD-ALT to Ca-ALT gain was significantly increased (0.55 ± 0.02) compared to normal (0.44 ± 0.02; P <.05) and was normalized by ranolazine (0.36 ± 0.05; P <.05), representing a complementary mechanism by which INa,L blockade suppressed cardiac alternans. Ranolazine attenuated arrhythmogenic cardiac alternans in HF, both by suppressing Ca-ALT and decreasing the coupling gain of APD-ALT to Ca-ALT. Blockade of INa,L may reverse impaired Ca2+ cycling to mitigate cardiac alternans, representing a mechanism underlying the antiarrhythmic benefit of INa,L blockade in HF.

Renin-angiotensin blockade in heart failure with preserved ejection fraction: a systematic review and meta-analysis.

Studies with angiotensin‐converting enzyme inhibitors (ACE‐Is) and angiotensin receptor blockers (ARBs) in patients with heart failure with preserved ejection fraction (HFpEF) have yielded inconsistent results. To conduct a systematic review and meta‐analysis of all evidence for ACE‐I and ARBs in patients with HFpEF, we searched PubMed, Ovid SP, Embase, and Cochrane database to identify randomized trials and observational studies that compared ACE‐I or ARBs against placebo or standard therapy in HFpEF patients. Random‐effect models were used to pool the data, and I 2 testing was performed to assess the heterogeneity of the included studies. A total of 13 studies (treatment arm = 8676 and control arm = 8608) were analysed. Pooled analysis of randomized trials for ACE‐I and ARBs (n = 6) did not show any effect on all‐cause mortality [relative risk (RR) = 1.02, 95% confidence interval (CI) = 0.93–1.11, P = 0.68, I 2 = 0%], while results from observational studies showed a significant improvement (RR = 0.91, 95% CI = 0.87–0.95, P = 0.005, I 2 = 81.5%). In pooled analyses of all studies, ACE‐I showed a reduction of all‐cause mortality (RR = 0.91, 95% CI = 0.87–0.95, P = 0.01). There was no reduction in cardiovascular mortality seen, but in pooled analysis of randomized trials, there was a trend towards reduced HF hospitalization risk (RR = 0.91, 95% CI = 0.83–1.01, I 2 = 0%, P = 0.074). These data suggest that ACE‐I and ARBs may have a role in improving outcomes of patients with HFpEF, underscoring the need for future research with careful patient selection, and trial design and conduct.

Advances in understanding the renin-angiotensin-aldosterone system (RAAS) in blood pressure control and recent pivotal trials of RAAS blockade in heart failure and diabetic nephropathy.

The renin-angiotensin-aldosterone system (RAAS) plays a fundamental role in the physiology of blood pressure control and the pathophysiology of hypertension (HTN) with effects on vascular tone, sodium retention, oxidative stress, fibrosis, sympathetic tone, and inflammation. Fortunately, RAAS blocking agents have been available to treat HTN since the 1970s and newer medications are being developed. In this review, we will (1) examine new anti-hypertensive medications affecting the RAAS, (2) evaluate recent studies that help provide a better understanding of which patients may be more likely to benefit from RAAS blockade, and (3) review three recent pivotal randomized trials that involve newer RAAS blocking agents and inform clinical practice.

Transient Receptor Potential Canonical (TRPC)/Orai1-dependent Store-operated Ca2+ Channels: NEW TARGETS OF ALDOSTERONE IN CARDIOMYOCYTES

Store-operated Ca(2+) entry (SOCE) has emerged as an important mechanism in cardiac pathology. However, the signals that up-regulate SOCE in the heart remain unexplored. Clinical trials have emphasized the beneficial role of mineralocorticoid receptor (MR) signaling blockade in heart failure and associated arrhythmias. Accumulated evidence suggests that the mineralocorticoid hormone aldosterone, through activation of its receptor, MR, might be a key regulator of Ca(2+) influx in cardiomyocytes. We thus assessed whether and how SOCE involving transient receptor potential canonical (TRPC) and Orai1 channels are regulated by aldosterone/MR in neonatal rat ventricular cardiomyocytes. Molecular screening using qRT-PCR and Western blotting demonstrated that aldosterone treatment for 24 h specifically increased the mRNA and/or protein levels of Orai1, TRPC1, -C4, -C5, and stromal interaction molecule 1 through MR activation. These effects were correlated with a specific enhancement of SOCE activities sensitive to store-operated channel inhibitors (SKF-96365 and BTP2) and to a potent Orai1 blocker (S66) and were prevented by TRPC1, -C4, and Orai1 dominant negative mutants or TRPC5 siRNA. A mechanistic approach showed that up-regulation of serum- and glucocorticoid-regulated kinase 1 mRNA expression by aldosterone is involved in enhanced SOCE. Functionally, 24-h aldosterone-enhanced SOCE is associated with increased diastolic [Ca(2+)]i, which is blunted by store-operated channel inhibitors. Our study provides the first evidence that aldosterone promotes TRPC1-, -C4-, -C5-, and Orai1-mediated SOCE in cardiomyocytes through an MR and serum- and glucocorticoid-regulated kinase 1 pathway.

Anti-inflammatory panacea? The expanding therapeutics of interleukin-1 blockade.

Blockade of interleukin (IL)-1 signaling is one of the oldest biologic therapies, yet the use of these agents is on the rise as the role of IL-1 activation is being recognized in a wide spectrum of inflammatory disorders. This review will cover established and emerging uses of IL-1 antagonism in rheumatic diseases. Expanding off-label indications for IL-1 blockade include neutrophil-dominant skin diseases, including pyoderma gangrenosum, hidradenitis supperativa, and pustular psoriasis. There is also increasing evidence for the use of IL-1 blockade in heart failure associated with rheumatic diseases. Somatic mosaicism in NLRP3 may explain the onset of later-in-life presentations of periodic fevers which are responsive to IL-1 blockade. Of importance, clinical response to anti-IL-1 therapy does not always denote protection from autoinflammatory disease complications such as macrophage activation syndrome or amyloidosis. Indications for IL-1 blocking therapies will likely continue to broaden, but given the rarity of many rheumatic diseases which respond to such treatment, rigorous, large clinical trials for each indication are unlikely to occur. Thus, recommended use of these medications will often fall to the discretion of the astute physician. However, medication cost and hurdles of insurance approval, rather than drug efficacy, may be the primary limitation for more widespread use.

Store Operated Calcium Channels, New Targets of Aldosterone in Cardiomyocytes

Recently, the Store-Operated Ca2+ Entry (SOCE) has emerged as an important mechanism in cardiac pathology. However, the signals that upregulate SOCE in the heart remain unexplored. Clinical trials have emphasized the beneficial role of mineralocorticoid receptor (MR) signaling blockade in heart failure and associated arrhythmias. Accumulated evidences suggest that the mineralocorticoid hormone, aldosterone, through activation of its receptor (MR), might be a key regulator of Ca2+ influx in cardiomyocytes.We thus assessed whether and how SOCE involving TRPCs (Transient Receptor Potential Canonical) and Orai1 channels are regulated by aldosterone/MR in ventricular cardiomyocytes.Molecular screening using qRT-PCR and western-blot demonstrated that aldosterone treatment for 24 h specifically increased the mRNA and/or protein levels of Orai1, TRPC1, TRPC4, TRPC5 and STIM1 through MR activation. These effects were correlated with a specific enhancement of SOCE sensitive to SOC inhibitors (SKF-96365 and BTP2), to the potent Orai1 blocker, S66 and were prevented by TRPC1, TRPC4 and Orai1 dominant negative-mutants, or TRPC5 siRNA. Mechanistic approach showed that upregulation of Serum and Glucocorticoid-regulated Kinase 1 (SGK1) mRNA expression by aldosterone is involved in enhanced SOCE. Functionally, 24 h aldosterone-enhanced SOCE is associated with increased diastolic [Ca2+]i which is blunted by SOC inhibitors.Our study provides the first evidence that aldosterone promotes TRPC1, TRPC4, TRPC5 and Orai1-mediated SOCE in cardiomyocytes, through MR and SGK1 pathway.

Exercise capacity and ventilatory efficiency with afferent blockade in heart failure (884.3)

Increased locomotor muscle afferent feedback may be linked to the reduced exercise capacity (peak VO2) and poor ventilatory efficiency (high VE/VCO2 slope) observed in heart failure (HF). We examined the relationship between peak VO2 and change in VE/VCO2 with afferent inhibition during exercise in HF. 9 HF (60±6 yr) and 9 controls (CTL) (63±7 yr) completed 3 visits. Visit 1: cycle exercise to volitional exhaustion. Visits 2‐ 3: 5 min constant‐load cycling (65% of peak work) randomized to lumbar intrathecal fentanyl injection (afferent block) or placebo. VO2, ventilation (VE), carbon dioxide production (VCO2), and end‐tidal CO2 (PETCO2) were measured. In HF, peak work (120±34 vs 176±54 W, p&lt;0.05) and VO2 (18.4±2.7 vs 27.2±4.7 ml/kg/min, p&lt;0.05) were reduced, whereas VE/VCO2 slope was elevated (39.7±1.8 vs 35.3±0.8, p&lt;0.05) compared with CTL. With afferent inhibition, HF patients had a greater reduction in VE/VCO2 (‐18.8±8.1 vs ‐5.4±13.3%, p&lt;0.05) and increase in PETCO2 (20.3±10.5 vs 6.1±9.5%, p&lt;0.01) during constant‐load cycling. Lower VO2peak was related to a greater decline in VE/VCO2 and rise in PETCO2 after afferent inhibition in HF (r=0.82, p&lt;0.01 and r=‐0.69, p&lt;0.05, respectively) but not CTL (p&gt;0.05). Our data demonstrate that patients with the lowest VO2peak have the greatest improvement in VE/VCO2, suggesting a close link between afferent feedback, ventilatory efficiency and exercise capacity in HF.Grant Funding Source: Supported by AHA 12GRNT11630027 and National Center for Advancing Translational Science KL2TR000136.

Effect of Spironolactone on Diastolic Function and Exercise Capacity in Patients With Heart Failure With Preserved Ejection Fraction

Diastolic heart failure (ie, heart failure with preserved ejection fraction) is a common condition without established therapy, and aldosterone stimulation may contribute to its progression. To assess the efficacy and safety of long-term aldosterone receptor blockade in heart failure with preserved ejection fraction. The primary objective was to determine whether spironolactone is superior to placebo in improving diastolic function and maximal exercise capacity in patients with heart failure with preserved ejection fraction. The Aldo-DHF trial, a multicenter, prospective, randomized, double-blind, placebo-controlled trial conducted between March 2007 and April 2012 at 10 sites in Germany and Austria that included 422 ambulatory patients (mean age, 67 [SD, 8] years; 52% female) with chronic New York Heart Association class II or III heart failure, preserved left ventricular ejection fraction of 50% or greater, and evidence of diastolic dysfunction. Patients were randomly assigned to receive 25 mg of spironolactone once daily (n=213) or matching placebo (n=209) with 12 months of follow-up. The equally ranked co-primary end points were changes in diastolic function (E/e') on echocardiography and maximal exercise capacity (peak VO2) on cardiopulmonary exercise testing, both measured at 12 months. Diastolic function (E/e') decreased from 12.7 (SD, 3.6) to 12.1 (SD, 3.7) with spironolactone and increased from 12.8 (SD, 4.4) to 13.6 (SD, 4.3) with placebo (adjusted mean difference, -1.5; 95% CI, -2.0 to -0.9; P < .001). Peak VO2 did not significantly change with spironolactone vs placebo (from 16.3 [SD, 3.6] mL/min/kg to 16.8 [SD, 4.6] mL/min/kg and from 16.4 [SD, 3.5] mL/min/kg to 16.9 [SD, 4.4] mL/min/kg, respectively; adjusted mean difference, +0.1 mL/min/kg; 95% CI, -0.6 to +0.8 mL/min/kg; P = .81). Spironolactone induced reverse remodeling (left ventricular mass index declined; difference, -6 g/m2; 95% CI, -10 to-1 g/m2; P = .009) and improved neuroendocrine activation (N-terminal pro-brain-type natriuretic peptide geometric mean ratio, 0.86; 95% CI, 0.75-0.99; P = .03) but did not improve heart failure symptoms or quality of life and slightly reduced 6-minute walking distance (-15 m; 95% CI, -27 to -2 m; P = .03). Spironolactone also modestly increased serum potassium levels (+0.2 mmol/L; 95% CI, +0.1 to +0.3; P < .001) and decreased estimated glomerular filtration rate (-5 mL/min/1.73 m2; 95% CI, -8 to -3 mL/min/1.73 m2; P < .001) without affecting hospitalizations. In this randomized controlled trial, long-term aldosterone receptor blockade improved left ventricular diastolic function but did not affect maximal exercise capacity, patient symptoms, or quality of life in patients with heart failure with preserved ejection fraction. Whether the improved left ventricular function observed in the Aldo-DHF trial is of clinical significance requires further investigation in larger populations. clinicaltrials.gov Identifier: ISRCTN94726526; Eudra-CT No: 2006-002605-31.

The hypothalamic paraventricular nucleus may not be at the heart of sympathetic outflow

Heart failure (HF) is associated with activation of various neurohumoral factors including the renin–angiotensin–aldosterone and sympathetic nervous systems. In HF patients, elevated sympathetic nerve activity (SNA) is reflected by increased whole body, as well as regional (e.g. cardiac and renal) noradrenaline spillover (Kaye et al. 1994; Petersson et al. 2005), and increased sympathetic nerve discharge (Leimbach et al. 1986). Importantly, the degree of sympathoexcitation predicts mortality in HF patients (Petersson et al. 2005). Consequently, an immense amount of research effort has been directed towards the identification of mechanisms and circuitry underlying elevated SNA in HF. Neurons of the hypothalamic paraventricular nucleus (PVH) regulate SNA in a variety of physiological conditions and pathophysiological states through mono- and polysynaptic projections to the medulla and spinal cord (Guyenet, 2006). Evidence from studies, largely conducted in anaesthetized rodents, suggests HF activates PVH neurons through a reduction in GABAergic function (Patel, 2000). A critical question is the extent to which PVH neurons contribute to elevated SNA in HF. In this issue of The Journal of Physiology, Ramchandra and colleagues (2013) provide novel data utilizing chronic SNA recordings in conscious sheep to address this important question. Interruption of PVH neurotransmission by radiofrequency ablation or neuronal inhibition by microinjection of glycine or the GABAA agonist muscimol failed to lower cardiac and/or renal SNA in both control and HF sheep. Furthermore, blockade of PVH GABAA receptors with injection of bicuculline increased cardiac SNA, mean arterial blood pressure and heart rate in control but not HF sheep. The absence of sympathetic-cardiovascular responses to GABAA receptor activation or blockade in HF versus control sheep confirms a reduced GABAergic function in the PVH. More importantly, these findings challenge the general notion that PVH neurons contribute to sympathoexcitation in HF. Several issues may explain the discrepancies between the present and past studies: (1) differences between anaesthetized versus conscious animals, (2) differences in the central nervous system circuitry/mechanisms between HF models (i.e. coronary ligation versus ventricular pacing), and (3) the possibility that PVH neurons contribute to the development, but not maintenance, of elevated SNA in HF. A second intriguing finding is the differential contribution of PVH neurons to cardiac and renal sympathoinhibitory responses to volume expansion. In conscious sheep, PVH inhibition with injection of the GABAA agonist muscimol reversed the renal, but not the cardiac, sympathoinhibition during intravenous infusion of gelofusine. At least two critical questions arise from these findings. First, PVH neurons abundantly express the vesicular glutamate transporter but are not GABAergic (e.g. GAD67 positive) (Stocker et al. 2006). If volume expansion reduces the discharge of spinally projecting PVH neurons (Lovick & Coote, 1988), why does further inhibition using muscimol reverse the sympathoinhibition? Second, how do PVH neurons differentially regulate SNA to various end organs? The notion that PVH neurons can selectively increase SNA to one organ but not to another has been reported previously (Deering & Coote, 2000; Ward et al. 2011). Therefore, are there distinct populations of PVH neurons that regulate renal versus cardiac versus muscle SNA? Do these neurons receive different anatomical and neurochemical inputs? Previous studies have utilized transneuronal viruses to map the neuronal circuitry associated with a specific end-organ, but limited data exist to demonstrate whether PVH and other central nuclei contain overlapping or distinct populations of neurons to permit differential regulation of SNA. The findings of Ramchandra and colleagues (2013) provide evidence against a role of PVH neurons in elevating SNA in HF but emphasize the ability of PVH neurons to differentially control sympathetic outflow to distinct end-organs. The present findings highlight our limited understanding of how many CNS structures are anatomically and neurochemically connected to coordinate sympathetic outflow to a variety of organs.

Hemodynamic, Hormonal, and Renal Effects of (Pro)Renin Receptor Blockade in Experimental Heart Failure

The (pro)renin receptor (P)RR is implicated in blood pressure regulation and the pathophysiology of heart failure (HF). The effects of (P)RR blockade in HF have not been previously investigated. Eight sheep received on 2 separate days a vehicle control and incremental intravenous boluses of a (P)RR antagonist, ovine handle region peptide (HRP) (1, 5, and 25 mg at 90-minute intervals), both before (normal) and after induction of HF by rapid left ventricular pacing. In normal sheep, HRP reduced heart rate (P<0.001) and hematocrit (P=0.019) compared with time-matched control data, without significantly affecting any other hemodynamic, hormonal, or renal variables. In sheep with HF, HRP treatment induced progressive falls in mean arterial pressure (P<0.001) in association with decreases in left atrial pressure (P<0.001), peripheral resistance (P=0.014), and hematocrit (P<0.001). Cardiac contractility tended to decline (P=0.096), whereas cardiac output was unaltered. HRP administration produced a dose-dependent decrease in plasma renin activity (P=0.004), with similar trends observed for plasma angiotensin II and aldosterone (P=0.093 and P=0.088, respectively). Circulating natriuretic peptides, endothelin-1, and catecholamine levels were unchanged. HRP also induced a reduction in plasma sodium concentrations relative to control (P=0.024), a natriuresis (P=0.046), and a tendency for creatinine excretion and clearance to improve. (P)RR antagonism in experimental HF resulted in cardiovascular and renal benefits in association with inhibition of the renin-angiotensin-aldosterone system. These findings suggest that (P)RR contributes to pressure/volume regulation in HF and identifies the receptor as a potential therapeutic target in this disease.

Aldosterone and the mineralocorticoid receptor

For decades, the role of aldosterone was thought to be limited to salt and water homeostasis control. This traditional view of the action of aldosterone restricted to sodium reabsorption in epithelial tissues must be revisited. Clinical trials have demonstrated the therapeutic benefit of MR blockade in heart failure of various origins. The beneficial effects of MR inhibition in patients with heart diseases emphasize the importance of this receptor in cardiovascular tissue. Significant progress have been made in understanding the pathological situations in which MR blockade is beneficial as well as the mechanisms underlying the deleterious effects of MR activation. Experimental studies indicated that chronic activation of the MR in target tissues induces structural and functional changes in the heart, kidneys and blood vessels. These deleterious effects include cardiac and renal fibrosis, inflammation and vascular remodeling. Aldosterone is generally considered as the main ligand of MR. However, MRs bind mineralocorticoids and glucocorticoids with equal affinity. Since the selectivity enzyme 11 beta hydroxysteroid dehydrogenase type II (11 beta HSD2) is not active in cardiomyocytes, the question of which ligand activates MR in these cells is thus the subject of intense debate. The interaction of MR activation with other important players in cardiac pathophysiology, such as salt, oxidative stress, and Ang II, suggests that the combined use of MR antagonists and other drugs may have synergic beneficial effects. Experimental data also suggest that MR antagonists could have wider use than they do today and perhaps extended to various systemic diseases that affect cardiac function.

Effect of Beta-Blocker Therapy on Rehospitalization Rates in Women Versus Men With Heart Failure and Preserved Ejection Fraction

Beta blockers are empirically used in many patients with heart failure (HF) and preserved ejection fraction (HFpEF) because they allow more time for diastolic filling and because they improve outcomes in patients with systolic HF. However, recent data suggest that impaired chronotropic and vasodilator responses to exercise, which can worsen with beta blockade, may play a key role in the pathophysiology of HFpEF. We prospectively examined the association between beta-blocker therapy after hospitalization for decompensated HF and HF rehospitalization at 6 months in 66 consecutive patients with HFpEF (71 +/- 13 years old, 68% women, 42% Black). Subjects were stratified based on receiving (BB+; 15 men, 28 women) or not receiving (BB-) beta-blockers at hospital discharge. In men, HF rehospitalization occurred less frequently in the BB+ than in the BB- group, albeit nonsignificantly (20% vs 50%, p = 0.29). In women, HF rehospitalization occurred more frequently in the BB+ than in the BB- group (75% vs 18%, p <0.001). In univariate analyses, discharge beta-blocker was associated with HF rehospitalization in women (odds ratio [OR] 14.00, 95% confidence interval [CI] 3.09 to 63.51, p = 0.001), but not in men (OR 0.25, 95% CI 0.03 to 1.92, p = 0.18). In a forward logistic regression model that offered all univariate predictors of HF rehospitalization, discharge beta blocker remained an independent predictor of HF rehospitalization in women (OR 11.06, 95% CI 1.98 to 61.67, p = 0.006). In conclusion, this small observational study suggests that beta-blocker therapy may be associated with a higher risk of HF rehospitalization in women with HFpEF. The risks and benefits of beta-blocker therapy in patients with HFpEF should be evaluated in randomized, controlled trials.