Effects of Oral Supplementation With Nitrate-Rich Beetroot Juice in Patients With Pulmonary Arterial Hypertension-Results From BEET-PAH, an Exploratory Randomized, Double-Blind, Placebo-Controlled, Crossover Study.

BACKGROUND: The nitrate-nitrite-nitric oxide (NO) pathway may represent a potential therapeutic target in patients with pulmonary arterial hypertension (PAH). We explored the effects of dietary nitrate supplementation, with the use of nitrate-rich beetroot juice (BRJ), in patients with PAH. METHODS AND RESULTS: We prospectively studied 15 patients with PAH in an exploratory randomized, double-blind, placebo-controlled, crossover trial. The patients received nitrate-rich beetroot juice (∼16 mmol nitrate per day) and placebo in 2 treatment periods of 7 days each. The assessments included; exhaled NO and NO flow-independent parameters (alveolar NO and bronchial NO flux), plasma and salivary nitrate and nitrite, biomarkers and metabolites of the NO-system, N-terminal pro-B-type natriuretic peptide, echocardiography, ergospirometry, diffusing capacity of the lung for carbon monoxide, and the 6-minute walk test. Compared with placebo ingestion of BRJ resulted in increases in; fractional exhaled NO at all flow-rates, alveolar NO concentrations and bronchial NO flux, and plasma and salivary levels of nitrate and nitrite. Plasma ornithine levels decreased and indices of relative arginine availability increased after BRJ compared to placebo. A decrease in breathing frequency was observed during ergospirometry after BRJ. A tendency for an improvement in right ventricular function was observed after ingestion of BRJ. In addition a tendency for an increase in the peak power output to peak oxygen consumption ratio (W peak/VO2 peak) was observed, which became significant in patients reaching an increase of plasma nitrite >30% (responders). CONCLUSIONS: BRJ administered for 1 week increases pulmonary NO production and the relative arginine bioavailability in patients with PAH, compared with placebo. An increase in the W peak/VO2 peak ratio was observed after BRJ ingestion in plasma nitrite responders. These findings indicate that supplementation with inorganic nitrate increase NO synthase-independent NO production from the nitrate-nitrite-NO pathway.

Nutritional approaches to ameliorate pulmonary hypertension in broiler chickens.

This article reviews recent nutritional approaches for counteracting the development of pulmonary hypertension syndrome (PHS; ascites) in broiler chickens especially when they are reared at high altitudes. High altitudes impose the sustained stress of hypobaric hypoxia, which reduces the availability of atmospheric oxygen to red blood cells passing through the lungs, thereby causing systemic arterial hypoxaemia (undersaturation of haemoglobin with oxygen), pulmonary arterial hypertension and PHS/ascites in susceptible broilers. Proper nutritional strategies are needed to reduce metabolic activity and prevent the development of ascites especially when modern broilers are reared in regions where the existing altitudes limit the availability of atmospheric oxygen. This article also addresses controversies with regard to broiler nutrition in relation to PHS. For example, the catabolism of protein from feed ingredients incurs increased oxygen consumption, suggesting that feeding reduced-protein diets to broiler chickens may result in reduced PHS incidences. However, experimental and field data indicate that feeding reduced-protein diets to broilers subjected to hypobaric hypoxia increases the development of PHS. Controversies on the nutrition of unsaturated fat in relation to PHS are also discussed. In conclusion, hypoxia, acidosis, vasoconstriction and enhanced metabolic rate are triggers of PHS. Feeding reduced-protein diets might promote the susceptibility of broilers to PHS by decreased dietary intake of arginine, decreased uric acid production and increased lipogenesis. Feeding high-protein diets, dietary arginine supplementation, partial substitution of sodium bicarbonate for sodium chloride, feeding low-fat diets and effective feed restriction programmes can be considered as nutritional approaches to prevent PHS.

[Clinical study on sildenafil in treatment of pregnant women with pulmonary arterial hypertension].

OBJECTIVE: To explored the effect of sildenafil in treatment of pregnant women with pulmonary arterial hypertension. METHODS: From January 2012 to November 2013, 64 pregnant women with pulmonary arterial hypertension (PAH) were randomly divided into group and control group. CONTROL GROUP: 16 cases with mild and 16 cases with moderate PAH. To treatment with low-flow oxygen, low-salt diet therapy, cardiac, etc.sildenafil group: 15 cases were mild pulmonary hypertension, and 17 cases moderate PAH. Treatment sildenafil 25 mg, tid in this study. Then the variation of the blood oxygen saturation, pulmonary artery systolic pressure, hemodynamic parameters and pregnancy outcome, including delivery modes, neonatal weight, morbidity of mother and fetus were compared. RESULTS: (1) Cardiac function and pulmonary hypertension: control group: the proportion of cardiac functional class I-II reduced from 81% (26/32) to 56% (18/32) significantly after treatment (P < 0.05).Sildenafil group:the proportion of cardiac functional class I-II increased from 75% (24/32) to 84% (27/32) significantly after treatment (P < 0.05). Between two groups, the proportion of mild and moderate turning to server PAH patients were significant difference (P < 0.05).(2) The pregnancy outcome of two group: the premature birth rate, low birth weight rate and cesarean section rate of 9% (3/32) , 9% (3/32) and 69% (22/32) in sildenafil group were significantly lower than 16% (5/32), 19% (6/32) and 81% (26/32) in control group (P < 0.05) . The rate of vaginal delivery, term pregnancy and neonatal weight of 31% (10/32) , 91% (29/32) and (3 214 ± 306) g in sildenafil group were different with 19% (6/32) , 84% (27/32) and (3 004 ± 458) g in control group (P < 0.05). (3) Hemodynamic parameters:in control group, arterial partial pressure of oxygen, oxygen saturation and left ventricular ejection fraction, pulmonary systolic pression were (80 ± 5)% to (72 ± 8)%, (87 ± 8) to (83 ± 9) mmHg (1 mmHg = 0.133 kPa), 0.77 ± 0.24 to 0.70 ± 0.38 and (63 ± 9) to (69 ± 12) mmHg before and after treatment, which showed remarkable decreased trends (P < 0.05). The other parameter were not significantly different (P > 0.05).In sildenafil group, arterial partial pressure of oxygen, oxygen saturation and left ventricular ejection fraction, pulmonary systolic pression showed increased trend before and after treatment, which were (80 ± 9)% to (88 ± 9)%, (84 ± 3) to (89 ± 7) mmHg, 0.70 ± 0.32 to 0.79 ± 0.27 (P < 0.05), in the mean time, pulmonary systolic pression showed decreased trend from (65 ± 18) to (60 ± 13) mmHg (P < 0.05) . The other parameter did not show significant different (P > 0.05). CONCLUSIONS: Sildenafil treatment can significantly improve the clinical symptoms, cardiac function and hemodynamic parameters.It also could significantly improve pregnancy outcomes, reduce premature delivery, the incidence of low birth weight children, and cesarean section rate.

A Western-type diet attenuates pulmonary hypertension with heart failure and cardiac cachexia in rats.

Western-type diets (WD) constitute risk factors for disease but may have distinct effects in heart failure (HF) with cardiac cachexia (CC). We evaluated hemodynamic, metabolic, and inflammatory effects of short-term WD intake in pulmonary hypertension (PH) with CC. Male Wistar rats randomly received 60 mg · kg(-1) monocrotaline (M) or vehicle (C) and consumed either a 5.4-kcal · g(-1) WD (35% animal fat, 35% simple carbohydrate, 20% protein, 0.4% Na(+)) or a 2.9-kcal · g(-1) (3% vegetable fat, 60% complex carbohydrate, 16% protein, 0.25% Na(+)) normal diet (ND) for 5 wk. Mortality, energy intake, body weight (BW), metabolism, hemodynamics, histology, apoptosis, gene expression, transcription factors, and plasma cytokines were evaluated. Compared with the C-ND group, the M-ND group had PH, HF, and mortality that were significantly attenuated in M-WD. The extent of myocardial remodeling and apoptosis was higher in M-ND than in C-ND but lower in M-WD than in M-ND, while conversely, energy intake, BW, cholesterol, and TG plasma concentrations were lower in M-ND than in C-ND but higher in M-WD than in M-ND. M-ND had increased myocardial NF-κB transcription factor activity, endothelin-1, and cytokine overexpression and higher circulating cytokine concentrations than C-ND, which were lower in M-WD than in M-ND. PPARα activity, however, was lower in M-ND, but not in M-WD, compared with the respective C groups. WD attenuated PH and CC, ameliorating survival, myocardial function, metabolism, and inflammation, through transcription factor modulation, suggesting a beneficial role in CC.

Therapeutic impact of dietary vitamin D supplementation for preventing right ventricular remodeling and improving survival in pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH), caused by elevated pulmonary vascular resistance, leads to right heart failure and ultimately death. Vitamin D deficiency can predispose individuals to hypertension and left ventricular dysfunction; however, it remains unknown how serum vitamin D level is related to PH and right ventricular (RV) dysfunction. METHODS: Serum 25-hydroxyvitamin D [25(OH)D] levels were assessed in PH patients for an association with disease severity. To examine whether vitamin D supplementation could prevent the development of pulmonary vascular remodeling and RV dysfunction in PH, a rat model of PH was fed either normal chow or a high vitamin D diet. RESULTS: The majority (95.1%) of PH patients had 25(OH)D levels in the insufficiency range, which is associated with increased mean pulmonary artery pressure, increased pulmonary vascular resistance, and decreased cardiac output in PH patients. Vitamin D supplementation significantly increased serum 25(OH)D levels and improved survival in PH rats. Interestingly, while the supplemented rats retained the typical increases in medial thickness of the muscular pulmonary arteries and RV systolic pressure, RV cardiomyocyte hypertrophy and B-type natriuretic peptide expression was significantly attenuated. CONCLUSIONS: Vitamin D deficiency is frequently seen in patients diagnosed with PH and low serum levels of 25(OH)D are associated with severity of PH and RV dysfunction. Vitamin D supplementation in PH rats improved survival via ameliorating pathological RV hypertrophy. These findings suggest an insufficient intake of vitamin D might potentially accelerate RV dysfunction, leading to a crucial clinical impact of vitamin D supplementation in PH.

Grape seed procyanidin extract attenuates hypoxic pulmonary hypertension by inhibiting oxidative stress and pulmonary arterial smooth muscle cells proliferation.

Hypoxia-induced oxidative stress and excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) play important roles in the pathological process of hypoxic pulmonary hypertension (HPH). Grape seed procyanidin extract (GSPE) possesses antioxidant properties and has beneficial effects on the cardiovascular system. However, the effect of GSPE on HPH remains unclear. In this study, adult Sprague-Dawley rats were exposed to intermittent chronic hypoxia for 4 weeks to mimic a severe HPH condition. Hemodynamic and pulmonary pathomorphology data showed that chronic hypoxia significantly increased right ventricular systolic pressures (RVSP), weight of the right ventricle/left ventricle plus septum (RV/LV+S) ratio and median width of pulmonary arteries. GSPE attenuated the elevation of RVSP, RV/LV+S, and reduced the pulmonary vascular structure remodeling. GSPE also increased the levels of SOD and reduced the levels of MDA in hypoxia-induced HPH model. In addition, GSPE suppressed Nox4 mRNA levels, ROS production and PASMCs proliferation. Meanwhile, increased expression of phospho-STAT3, cyclin D1, cyclin D3 and Ki67 in PASMCs caused by hypoxia was down-regulated by GSPE. These results suggested that GSPE might potentially prevent HPH via antioxidant and antiproliferative mechanisms.

Coenzyme Q supplementation in pulmonary arterial hypertension.

Mitochondrial dysfunction is a fundamental abnormality in the vascular endothelium and smooth muscle of patients with pulmonary arterial hypertension (PAH). Because coenzyme Q (CoQ) is essential for mitochondrial function and efficient oxygen utilization as the electron carrier in the inner mitochondrial membrane, we hypothesized that CoQ would improve mitochondrial function and benefit PAH patients. To test this, oxidized and reduced levels of CoQ, cardiac function by echocardiogram, mitochondrial functions of heme synthesis and cellular metabolism were evaluated in PAH patients (N=8) in comparison to healthy controls (N=7), at baseline and after 12 weeks oral CoQ supplementation. CoQ levels were similar among PAH and control individuals, and increased in all subjects with CoQ supplementation. PAH patients had higher CoQ levels than controls with supplementation, and a tendency to a higher reduced-to-oxidized CoQ ratio. Cardiac parameters improved with CoQ supplementation, although 6-minute walk distances and BNP levels did not significantly change. Consistent with improved mitochondrial synthetic function, hemoglobin increased and red cell distribution width (RDW) decreased in PAH patients with CoQ, while hemoglobin declined slightly and RDW did not change in healthy controls. In contrast, metabolic and redox parameters, including lactate, pyruvate and reduced or oxidized gluthathione, did not change in PAH patients with CoQ. In summary, CoQ improved hemoglobin and red cell maturation in PAH, but longer studies and/or higher doses with a randomized placebo-controlled controlled design are necessary to evaluate the clinical benefit of this simple nutritional supplement.