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Inhaled Sodium Nitrite Improves Rest and Exercise Hemodynamics in Heart Failure With Preserved Ejection Fraction.

ABSTRACT: Abnormalities in nitric oxide signaling play a pivotal role in heart failure with preserved ejection fraction (HFpEF). Intravenous sodium nitrite, which is converted to nitric oxide in vivo, improves hemodynamics in HFpEF, but its use is limited by the need for parenteral administration. Nitrite can also be administered using a novel, portable micronebulizer system suitable for chronic use.Determine whether inhaled nitrite improves hemodynamics in HFpEF.In a double-blind, randomized, placebo-controlled, parallel-group trial, subjects with HFpEF (n=26) underwent cardiac catheterization with simultaneous expired gas analysis at rest and during exercise before and after treatment with inhaled sodium nitrite (90 mg) or placebo. The primary end point was the pulmonary capillary wedge pressure during exercise. Before study drug administration, HFpEF subjects displayed an increase in pulmonary capillary wedge pressure with exercise from 20±6 to 34±7 mm?Hg (P<0.0001). After study drug administration, exercise pulmonary capillary wedge pressure was substantially improved by nitrite as compared with placebo (baseline-adjusted mean 25±5 versus 31±6 mm?Hg; analysis of covariance P=0.022). Inhaled nitrite reduced resting pulmonary capillary wedge pressure (-4±3 versus -1±2 mm?Hg; P=0.002), improved pulmonary artery compliance (+1.5±1.1 versus +0.6±0.9 mL/mm?Hg), and decreased mean pulmonary artery pressures at rest (-7±4 versus -3±4 mm?Hg; P=0.007) and with exercise (-10±6 versus -5±6 mm?Hg; P=0.05). Nitrite reduced right atrial pressures, with no effect on cardiac output or stroke volume.Acute administration of inhaled sodium nitrite reduces biventricular filling pressures and pulmonary artery pressures at rest and during exercise in HFpEF. Further study is warranted to evaluate chronic effects of inhaled nitrite in HFpEF.This single center randomized clinical trial is registered at clinicaltrials.gov (NCT02262078).

SUBMITTER: Borlaug BA

PROVIDER: S-EPMC5026595 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Inhaled Sodium Nitrite Improves Rest and Exercise Hemodynamics in Heart Failure With Preserved Ejection Fraction.

Borlaug Barry A BA Melenovsky Vojtech V Koepp Katlyn E KE

Circulation research 20160725 7

<h4>Rationale</h4>Abnormalities in nitric oxide signaling play a pivotal role in heart failure with preserved ejection fraction (HFpEF). Intravenous sodium nitrite, which is converted to nitric oxide in vivo, improves hemodynamics in HFpEF, but its use is limited by the need for parenteral administration. Nitrite can also be administered using a novel, portable micronebulizer system suitable for chronic use.<h4>Objective</h4>Determine whether inhaled nitrite improves hemodynamics in HFpEF.<h4>Me ...[more]

PMID: 27458234

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Project description:BACKGROUND:Pulmonary hypertension (PH) is associated with poor outcomes, yet specific treatments only exist for a small subset of patients. The most common form of PH is that associated with left heart disease (Group 2), for which there is no approved therapy. Nitrite has shown efficacy in preclinical animal models of Group 1 and 2 PH, as well as in patients with left heart failure with preserved ejection fraction (HFpEF). We evaluated the safety and efficacy of a potentially novel inhaled formulation of nitrite in PH-HFpEF patients as compared with Group 1 and 3 PH. METHODS:Cardiopulmonary hemodynamics were recorded after acute administration of inhaled nitrite at 2 doses, 45 and 90 mg. Safety endpoints included change in systemic blood pressure and methemoglobin levels. Responses were also compared with those administered inhaled nitric oxide. RESULTS:Thirty-six patients were enrolled (10 PH-HFpEF, 20 Group 1 pulmonary arterial hypertension patients on background PH-specific therapy, and 6 Group 3 PH). Drug administration was well tolerated. Nitrite inhalation significantly lowered pulmonary, right atrial, and pulmonary capillary wedge pressures, most pronounced in patients with PH-HFpEF. There was a modest decrease in cardiac output and systemic blood pressure. Pulmonary vascular resistance decreased only in Group 3 PH patients. There was substantial increase in pulmonary artery compliance, most pronounced in patients with PH-HFpEF. CONCLUSIONS:Inhaled nitrite is safe in PH patients and may be efficacious in PH-HFpEF and Group 3 PH primarily via improvements in left and right ventricular filling pressures and pulmonary artery compliance. The lack of change in pulmonary vascular resistance likely may limit efficacy for Group 1 patients. TRIAL REGISTRATION:ClinicalTrials.gov NCT01431313 FUNDING. This work was supported in part by the NIH grants P01HL103455 (to MAS and MTG), R01HL098032 (to MTG), and R01HL096973 (to MTG), and Mast Therapeutics, Inc.

Project description:BackgroundBoth secondary tricuspid regurgitation (STR) and heart failure with preserved ejection fraction (HFpEF) are relevant public health problems in the elderly population, presenting with potential overlaps and sharing similar risk factors. However, the impact of severe STR on hemodynamics and cardiorespiratory adaptation to exercise in HFpEF remains to be clarified.AimTo explore the impact of STR on exercise hemodynamics and cardiorespiratory adaptation in HFpEF.MethodsWe analyzed invasive hemodynamics and gas-exchange data obtained at rest and during exercise from HFpEF patients with severe STR (HFpEF-STR), compared with 1:1 age-, sex-, and body mass index (BMI)- matched HFpEF patients with mild or no STR (HFpEF-controls).ResultsTwelve HFpEF with atrial-STR (mean age 72 years, 92% females, BMI 28 Kg/m2) and 12 HFpEF-controls patients were analyzed. HFpEF-STR had higher (p < 0.01) right atrial pressure than HFpEF-controls both at rest (10 ± 1 vs. 5 ± 1 mmHg) and during exercise (23 ± 2 vs. 14 ± 2 mmHg). Despite higher pulmonary artery wedge pressure (PAWP) at rest in HFpEF-STR than in HFpEF-controls (17 ± 2 vs. 11 ± 2, p = 0.04), PAWP at peak exercise was no more different (28 ± 2 vs. 29 ± 2). Left ventricular transmural pressure and cardiac output (CO) increased less in HFpEF-STR than in HFpEF-controls (interaction p-value < 0.05). This latter was due to lower stroke volume (SV) values both at rest (48 ± 9 vs. 77 ± 9 mL, p < 0.05) and at peak exercise (54 ± 10 vs. 93 ± 10 mL, p < 0.05). Despite these differences, the two groups of patients laid on the same oxygen consumption isophlets because of the increased peripheral oxygen extraction in HFpEF-STR (p < 0.01). We found an inverse relationship between pulmonary vascular resistance and SV, both at rest and at peak exercise (R 2 = 0.12 and 0.19, respectively).ConclusionsSevere STR complicating HFpEF impairs SV and CO reserve, leading to pulmonary vascular de-recruitment and relative left heart underfilling, undermining the typical HFpEF pathophysiology.

Project description:BackgroundThe correlation between echocardiographic parameters and hemodynamics data in patients with heart failure with preserved ejection fraction (HFpEF) is unclear. It is important to find a non-invasive echocardiographic parameter for predicting exercise pulmonary capillary wedge pressure (PCWP).AimThis study sought to determine the correlation between echocardiographic parameters and hemodynamics data at rest and during exercise in HFpEF patients.Methods and resultsThis study was a cross-sectional cohort exploratory analysis of baseline data from the ILO-HOPE trial. A total of 34 HFpEF patients were enrolled. The average age was 70 ± 12 years, and most (74%) were women. The patients underwent invasive cardiac catheterization and expired gas analysis at rest and during exercise. Echocardiography including tissue Doppler imaging was performed, and global longitudinal strain and other novel diastolic function indexes were analyzed at rest and during exercise. At rest, no significant correlation was noted between resting PCWP and echocardiographic parameters. However, a significant correlation was observed between post-exercise PCWP and stress E/e' (septal, lateral, and mean) ratio (p = 0.003, 0.031, 0.012). Moreover, post-exercise ΔPCWP showed a good correlation with stress E/e' (septal, lateral, and mean; all p ≤ 0.001) and global longitudinal strain (GLS) during exercise (p = 0.03). After multivariate regression analysis with adjustment for possible confounding factors including age and sex, there was still a significant correlation between post-exercise ΔPCWP and E/e' (r = 0.62, p < 0.001 for E/e'mean).ConclusionOnly stress echocardiography derived tissue Doppler E/e' ratio is closely correlated with abnormal exercise hemodynamics (PCWP and post-exercise ΔPCWP) in HFpEF. This echocardiographic marker is substantially more sensitive than other novel echocardiographic parameters during exercise, and may have significant diagnostic utility for ambulatory HFpEF patients with dyspnea.Clinical trial registrationhttps://www.clinicaltrials.gov, identifier NCT03620526.

Project description:Background Recent studies have suggested that cardiac nitrosative stress mediated by pathological overproduction of nitric oxide (NO) via inducible NO synthase (iNOS) contributes to the pathogenesis of heart failure with preserved ejection fraction (HFpEF). Other studies have suggested that endothelial NO synthase (eNOS) dysfunction and attenuated NO bioavailability contribute to HFpEF morbidity and mortality. We sought to further investigate dysregulated NO signaling and to examine the effects of a NO-based dual therapy (sodium nitrite+hydralazine) following the onset of HFpEF using a "2-hit" murine model. Methods and Results Nine-week-old male C57BL/6 N mice (n=15 per group) were treated concurrently with high-fat diet and N(ω)-nitro-L-arginine methyl ester (L-NAME) (0.5 g/L per day) via drinking water for 10 weeks. At week 5, mice were randomized into either vehicle (normal saline) or combination treatment with sodium nitrite (75 mg/L in the drinking water) and hydralazine (2.0 mg/kg IP, BID). Cardiac structure and function were monitored with echocardiography and invasive hemodynamic measurements. Cardiac mitochondrial respiration, aortic vascular function, and exercise performance were also evaluated. Circulating and myocardial nitrite were measured to determine the bioavailability of NO. Circulating markers of oxidative or nitrosative stress as well as systemic inflammation were also determined. Severe HFpEF was evident by significantly elevated E/E', LVEDP, and Tau in mice treated with L-NAME and HFD, which was associated with impaired NO bioavailability, mitochondrial respiration, aortic vascular function, and exercise capacity. Treatment with sodium nitrite and hydralazine restored NO bioavailability, reduced oxidative and nitrosative stress, preserved endothelial function and mitochondrial respiration, limited the fibrotic response, and improved exercise capacity, ultimately attenuating the severity of "two-hit" HFpEF. Conclusions Our data demonstrate that nitrite, a well-established biomarker of NO bioavailability and a physiological source of NO, is significantly reduced in the heart and circulation in the "2-hit" mouse HFpEF model. Furthermore, sodium nitrite+hydralazine combined therapy significantly attenuated the severity of HFpEF in the "2-hit" cardiometabolic HFpEF. These data suggest that supplementing NO-based therapeutics with a potent antioxidant and vasodilator agent may result in synergistic benefits for the treatment of HFpEF.

Project description:Heart failure with preserved ejection fraction (HFPEF) involves failure of cardiovascular reserve in multiple domains. In HFPEF animal models, dietary sodium restriction improves ventricular and vascular stiffness and function. We hypothesized that the sodium-restricted dietary approaches to stop hypertension diet (DASH/SRD) would improve left ventricular diastolic function, arterial elastance, and ventricular-arterial coupling in hypertensive HFPEF.Thirteen patients with treated hypertension and compensated HFPEF consumed the DASH/SRD (target sodium, 50 mmol/2100 kcal) for 21 days. We measured baseline and post-DASH/SRD brachial and central blood pressure (via radial arterial tonometry) and cardiovascular function with echocardiographic measures (all previously invasively validated). Diastolic function was quantified via the parametrized diastolic filling formalism that yields relaxation/viscoelastic (c) and passive/stiffness (k) constants through the analysis of Doppler mitral inflow velocity (E-wave) contours. Effective arterial elastance (Ea) end-systolic elastance (Ees) and ventricular-arterial coupling (defined as the ratio Ees:Ea) were determined using previously published techniques. Wilcoxon matched-pairs signed-rank tests were used for pre-post comparisons. The DASH/SRD reduced clinic and 24-hour brachial systolic pressure (155 ± 35 to 138 ± 30 and 130 ± 16 to 123 ± 18 mm Hg; both P=0.02), and central end-systolic pressure trended lower (116 ± 18 to 111 ± 16 mm Hg; P=0.12). In conjunction, diastolic function improved (c=24.3 ± 5.3 to 22.7 ± 8.1 g/s; P=0.03; k=252 ± 115 to 170 ± 37 g/s(2); P=0.03), Ea decreased (2.0 ± 0.4 to 1.7 ± 0.4 mm Hg/mL; P=0.007), and ventricular-arterial coupling improved (Ees:Ea=1.5 ± 0.3 to 1.7 ± 0.4; P=0.04).In patients with hypertensive HFPEF, the sodium-restricted DASH diet was associated with favorable changes in ventricular diastolic function, arterial elastance, and ventricular-arterial coupling.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00939640.

Project description:BackgroundDespite exercise being one of few strategies to improve outcomes for individuals with heart failure with preserved ejection fraction (HFpEF), exercise clinical trials in HFpEF are plagued by poor interventional adherence. Over the last 2 decades, our research team has developed, tested, and refined Heart failure Exercise And Resistance Training (HEART) Camp, a multicomponent behavioral intervention to promote adherence to exercise in HF. We evaluated the effects of this intervention designed to promote adherence to exercise in HF focusing on subgroups of participants with HFpEF and heart failure with reduced ejection fraction (HFrEF).Methods and resultsThis randomized controlled trial included 204 adults with stable, chronic HF. Of those enrolled, 59 had HFpEF and 145 had HFrEF. We tested adherence to exercise (defined as ≥120 minutes of moderate-intensity [40%-80% of heart rate reserve] exercise per week validated with a heart rate monitor) at 6, 12, and 18 months. We also tested intervention effects on symptoms (Patient-Reported Outcomes Measurement Information System-29 and dyspnea-fatigue index), HF-related health status (Kansas City Cardiomyopathy Questionnaire), and physical function (6-minute walk test). Participants with HFpEF (n = 59) were a mean of 64.6 ± 9.3 years old, 54% male, and 46% non-White with a mean ejection fraction of 55 ± 6%. Participants with HFpEF in the HEART Camp intervention group had significantly greater adherence compared with enhanced usual care at both 12 (43% vs 14%, phi = 0.32, medium effect) and 18 months (56% vs 0%, phi = 0.67, large effect). HEART Camp significantly improved walking distance on the 6-minute walk test (η2 = 0.13, large effect) and the Kansas City Cardiomyopathy Questionnaire overall (η2 = 0.09, medium effect), clinical summary (η2 = 0.16, large effect), and total symptom (η2 = 0.14, large effect) scores. In the HFrEF subgroup, only patient-reported anxiety improved significantly in the intervention group.ConclusionsA multicomponent, behavioral intervention is associated with improvements in long-term adherence to exercise, physical function, and patient-reported outcomes in adults with HFpEF and anxiety in HFrEF. Our results provide a strong rationale for a large HFpEF clinical trial to validate these findings and examine interventional mechanisms and delivery modes that may further promote adherence and improve clinical outcomes in this population.Clinical trial registrationURL: https://clinicaltrials.gov/. Unique identifier: NCT01658670.

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Inhaled Sodium Nitrite Improves Rest and Exercise Hemodynamics in Heart Failure With Preserved Ejection Fraction.

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Inhaled Sodium Nitrite Improves Rest and Exercise Hemodynamics in Heart Failure With Preserved Ejection Fraction.

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