Impact of chronic congestive heart failure on pharmacokinetics and vasomotor effects of infused nitrite.

BACKGROUND AND PURPOSE: Nitrite (NO2⁻) has recently been shown to represent a potential source of NO, in particular under hypoxic conditions. The aim of the current study was to compare the haemodynamic effects of NO2⁻ in healthy volunteers and patients with stable congestive heart failure (CHF). EXPERIMENTAL APPROACH: The acute haemodynamic effects of brachial artery infusion of NO2⁻ (0.31 to 7.8 µmol·min⁻¹) was assessed in normal subjects (n = 20) and CHF patients (n = 21). KEY RESULTS: NO2⁻ infusion was well tolerated in all subjects. Forearm blood flow (FBF) increased markedly in CHF patients at NO2⁻ infusion rates which induced no changes in normal subjects (ANOVA: F = 5.5; P = 0.02). Unstressed venous volume (UVV) increased even with the lowest NO2⁻ infusion rate in all subjects (indicating venodilation), with CHF patients being relatively hyporesponsive compared with normal subjects (ANOVA: F = 6.2; P = 0.01). There were no differences in venous blood pH or oxygen concentration between groups or during NO2⁻ infusion. Venous plasma NO2⁻ concentrations were lower in CHF patients at baseline, and rose substantially less with NO2⁻ infusion, without incremental oxidative generation of nitrate, consistent with accelerated clearance in these patients. Plasma protein-bound NO concentrations were lower in CHF patients than normal subjects at baseline. This difference was attenuated during NO2⁻ infusion. Prolonged NO2⁻ exposure in vivo did not induce oxidative stress, nor did it induce tolerance in vitro. CONCLUSIONS AND IMPLICATIONS: The findings of arterial hyper-responsiveness to infused NO2⁻ in CHF patients, with evidence of accelerated transvascular NO2⁻ clearance (presumably with concomitant NO release) suggests that NO2⁻ effects may be accentuated in such patients. These findings provide a stimulus for the clinical exploration of NO2⁻ as a therapeutic modality in CHF.

The role of vascular myoglobin in nitrite-mediated blood vessel relaxation.

AIMS: This work investigates the role of myoglobin in mediating the vascular relaxation induced by nitrite. Nitrite, previously considered an inert by-product of nitric oxide metabolism, is now believed to play an important role in several areas of pharmacology and physiology. Myoglobin can act as a nitrite reductase in the heart, where it is plentiful, but it is present at a far lower level in vascular smooth muscle-indeed, its existence in the vessel wall is controversial. Haem proteins have been postulated to be important in nitrite-induced vasodilation, but the specific role of myoglobin is unknown. The current study was designed to confirm the presence of myoglobin in murine aortic tissue and to test the hypothesis that vascular wall myoglobin is important for nitrite-induced vasodilation. METHODS AND RESULTS: Aortic rings from wild-type and myoglobin knockout mice were challenged with nitrite, before and after exposure to the haem-protein inhibitor carbon monoxide (CO). CO inhibited vasodilation in wild-type rings but not in myoglobin-deficient rings. Restitution of myoglobin using a genetically modified adenovirus both increased vasodilation to nitrite and reinstated the wild-type pattern of response to CO. CONCLUSION: Myoglobin is present in the murine vasculature and contributes significantly to nitrite-induced vasodilation.

Metabolic modulator perhexiline corrects energy deficiency and improves exercise capacity in symptomatic hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy patients exhibit myocardial energetic impairment, but a causative role for this energy deficiency in the pathophysiology of hypertrophic cardiomyopathy remains unproven. We hypothesized that the metabolic modulator perhexiline would ameliorate myocardial energy deficiency and thereby improve diastolic function and exercise capacity. METHODS AND RESULTS: Forty-six consecutive patients with symptomatic exercise limitation (peak Vo(2) <75% of predicted) caused by nonobstructive hypertrophic cardiomyopathy (mean age, 55±0.26 years) were randomized to perhexiline 100 mg (n=24) or placebo (n=22). Myocardial ratio of phosphocreatine to adenosine triphosphate, an established marker of cardiac energetic status, as measured by (31)P magnetic resonance spectroscopy, left ventricular diastolic filling (heart rate normalized time to peak filling) at rest and during exercise using radionuclide ventriculography, peak Vo(2), symptoms, quality of life, and serum metabolites were assessed at baseline and study end (4.6±1.8 months). Perhexiline improved myocardial ratios of phosphocreatine to adenosine triphosphate (from 1.27±0.02 to 1.73±0.02 versus 1.29±0.01 to 1.23±0.01; P=0.003) and normalized the abnormal prolongation of heart rate normalized time to peak filling between rest and exercise (0.11±0.008 to -0.01±0.005 versus 0.15±0.007 to 0.11±0.008 second; P=0.03). These changes were accompanied by an improvement in primary end point (peak Vo(2)) (22.2±0.2 to 24.3±0.2 versus 23.6±0.3 to 22.3±0.2 mL · kg(-1) · min(-1); P=0.003) and New York Heart Association class (P<0.001) (all P values ANCOVA, perhexiline versus placebo). CONCLUSIONS: In symptomatic hypertrophic cardiomyopathy, perhexiline, a modulator of substrate metabolism, ameliorates cardiac energetic impairment, corrects diastolic dysfunction, and increases exercise capacity. This study supports the hypothesis that energy deficiency contributes to the pathophysiology and provides a rationale for further consideration of metabolic therapies in hypertrophic cardiomyopathy.

Reduced in vivo skeletal muscle oxygen consumption in patients with chronic heart failure--a study using Near Infrared Spectrophotometry (NIRS).

AIM: We used Near Infrared Spectrophotometry (NIRS) during arterial occlusion to measure resting skeletal muscle oxygen consumption in chronic heart failure (CHF) patients and in age-matched healthy volunteers (HVs). METHODS: Fifteen CHF patients (ten males) and eleven HVs (six males) had echocardiographic evaluation followed by measurement of the oxygen consumption of the brachioradialis muscle using NIRS. This involved continuous measurement of the oxygenated haemoglobin concentration ([Oxy-Hb]) and deoxy-haemoglobin concentration ([Deoxy-Hb]) with an Oxiplex TS NIRS probe first under basal overnight fasted resting conditions followed by 1 min of forearm arterial occlusion. A linear decline was observed in [Oxy-Hb-Deoxy-Hb] during the arterial occlusion and the oxygen consumption rate was calculated from the initial slope observed. RESULTS: CHF patients were 59+/-2.8 years old with Left Ventricular Ejection Fraction (LVEF) 31%+/-2.2 and the HVs were 52+/-4.8 years old with LVEF 62%+/-2.5. The resting muscle oxygen consumption rate was significantly reduced in CHF patients versus HVs (0.04+/-0.01 mlO(2)/min/100 g versus 0.07+/-0.01 mlO(2)/min/100 g) p<0.005. CONCLUSIONS: There is a significant reduction in resting oxygen consumption per gram of tissue in skeletal muscle of patients with CHF.

Hypoxic modulation of exogenous nitrite-induced vasodilation in humans.

BACKGROUND: It has been proposed that under hypoxic conditions, nitrite may release nitric oxide, which causes potent vasodilation. We hypothesized that nitrite would have a greater dilator effect in capacitance than in resistance vessels because of lower oxygen tension and that resistance-vessel dilation should become more pronounced during hypoxemia. The effect of intra-arterial infusion of nitrite on forearm blood flow and forearm venous volumes was assessed during normoxia and hypoxia. METHODS AND RESULTS: Forty healthy volunteers were studied. After baseline infusion of 0.9% saline, sodium nitrite was infused at incremental doses from 40 nmol/min to 7.84 mumol/min. At each stage, forearm blood flow was measured by strain-gauge plethysmography. Forearm venous volume was assessed by radionuclide plethysmography. Changes in forearm blood flow and forearm venous volume in the infused arm were corrected for those in the control arm. The peak percentage of venodilation during normoxia was 35.8+/-3.4% (mean+/-SEM) at 7.84 micromol/min (P<0.001) and was similar during hypoxia. In normoxia, arterial blood flow, assessed by the forearm blood flow ratio, increased from 1.04+/-0.09 (baseline) to 1.62+/-0.18 (nitrite; P<0.05) versus 1.07+/-0.09 (baseline) to 2.37+/-0.15 (nitrite; P<0.005) during hypoxia. This result was recapitulated in vitro in vascular rings. CONCLUSIONS: Nitrite is a potent venodilator in normoxia and hypoxia. Arteries are modestly affected in normoxia but potently dilated in hypoxia, which suggests the important phenomenon of hypoxic augmentation of nitrite-mediated vasodilation in vivo. The use of nitrite as a selective arterial vasodilator in ischemic territories and as a potent venodilator in heart failure has therapeutic implications.

Potential of metabolic agents as adjunct therapies in heart failure.

Heart failure continues to have a significant morbidity and mortality rate despite several recent advances in treatment such as additional neurohumoral blockades and cardiac resynchronization therapy. There is emerging evidence that, irrespective of etiology, heart failure is associated with an energetic disorder and that this may contribute to the pathogenesis of the syndrome. Recently, a number of studies have suggested that some metabolic agents may have potential as adjunctive therapy in patients with heart failure. These agents cause a shift of myocardial-substrate utilization away from free fatty acids toward glucose. Free fatty acid utilization consumes more oxygen to generate an equivalent amount of energy compared with glucose. Some of these agents are also effective antianginals, presumably by reducing the myocardial oxygen requirement. In this review we will discuss some of the current issues and progresses relating to metabolic manipulation in heart failure.