Prasad Gunaruwan

Metabolic Modulation With Perhexiline in Chronic Heart Failure: A Randomized, Controlled Trial of Short-Term Use of a Novel Treatment

Background— Chronic heart failure (CHF) is a major cause of morbidity and mortality that requires a novel approach to therapy. Perhexiline is an antianginal drug that augments glucose metabolism by blocking muscle mitochondrial free fatty acid uptake, thereby increasing metabolic efficiency. We assessed the effects of perhexiline treatment in CHF patients. Methods and Results— In a double-blind fashion, we randomly assigned patients with optimally medicated CHF to either perhexiline (n=28) or placebo (n=28). The primary end point was peak exercise oxygen consumption (&OV0312;o2max), an important prognostic marker. In addition, the effect of perhexiline on myocardial function and quality of life was assessed. Quantitative stress echocardiography with tissue Doppler measurements was used to assess regional myocardial function in patients with ischemic CHF. 31P magnetic resonance spectroscopy was used to assess the effect of perhexiline on skeletal muscle energetics in patients with nonischemic CHF. Treatment with perhexiline led to significant improvements in &OV0312;o2max (16.1±0.6 to 18.8±1.1 mL · kg−1 · min−1; P<0.001), quality of life (Minnesota score reduction from 45±5 to 34±5; P=0.04), and left ventricular ejection fraction (24±1% to 34±2%; P<0.001). Perhexiline treatment also increased resting and peak dobutamine stress regional myocardial function (by 15% and 24%, respectively) and normalized skeletal muscle phosphocreatine recovery after exercise. There were no adverse effects during the treatment period. Conclusions— In patients with CHF, metabolic modulation with perhexiline improved &OV0312;o2max, left ventricular ejection fraction, symptoms, resting and peak stress myocardial function, and skeletal muscle energetics. Perhexiline may therefore represent a novel treatment for CHF with a good safety profile, provided that the dosage is adjusted according to plasma levels.

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 &mgr;mol/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 &mgr;mol/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.

Lack of rapid aldosterone effects on forearm resistance vasculature in health

Objectives Systemic infusions of aldosterone cause an acute increase in systemic vascular resistance (SVR) in healthy subjects. It is not clear whether this is due to a direct effect on the vasculature or the result of increased sympathetic tone. We investigated the short-term effects of locally infused aldosterone on the forearm resistance bed. Methods In this dose response study, we assessed the effects of incremental doses (10, 50, 100 ng/minute) of intrabrachial aldosterone on forearm blood flow (FBF), using conventional strain gauge plethysmography. Arterial blood pressure was monitored continuously, using finger photo-plethysmography. Forearm vascular resistance (FVR) was calculated. FBF and FVR were also measured in the non-infused arm. Changes in FBF and FVR in the infused arm were corrected for those occurring in the control arm. Results Plasma aldosterone levels in the venous effluent of the infused arm increased in a dose-dependent fashion, from 113.3±17.9 pg/ml at baseline to 297.8±51.8 pg/ml at 10 ng/minute (p=<0.01), 743.9±105.9 pg/ml at 50 ng/min (p=<0.001 vs. baseline) and 1230.6±73.7 pg/ml at 100 ng/min (p=<0.0005 vs. baseline). Plasma concentrations of aldosterone in the control arm did not change significantly vs. baseline. The corrected FBF (+4.1±10.3%) and corrected FVR (+4.3±11.3%) did not change significantly even at peak infusion rates. Conclusions Local intra-arterial infusion of aldosterone had no acute effect on forearm resistance vessels in healthy male volunteers.

Effects of exogenous and endogenous natriuretic peptides on forearm vascular function in chronic heart failure

Objective—Natriuretic peptides (NPs) reduce central venous pressure in patients with chronic heart failure (cHF) despite attenuation of arterial, renal, and humoral effects. This suggests a preserved venodilator response. This study had 4 aims: to compare the venodilator effects of human NPs in patients with cHF; to assess the contribution of basal ANP and BNP levels to regulation of forearm vascular volume (FVV); to test the hypothesis that venous ANP responsiveness is preserved in cHF; and to assess the involvement of endothelial nitric oxide-synthase (eNOS) in NP-induced vascular effects. Methods and Results—Venous and arterial forearm vascular responses to incremental intra-arterial doses of ANP, Urodilatin, BNP, CNP, or the ANP receptor antagonist A71915 were studied in 53 patients and 11 controls. ANP receptor antagonism reduced FVV by 4.4%±1.2% (P<0.05). The forearm blood flow (FBF) response to ANP was significantly blunted in patients versus controls (P<0.01), whereas FVV increased similarly in both groups (maximum 14.7% and 13.4%, both P<0.001). The eNOS blockade reduced ANP-induced FBF changes in controls but not in patients (P<0.05), whereas similar reductions in FVV changes were seen in groups (both P<0.001). Conclusions—In cHF venous, but not arterial, ANP responsiveness is preserved. Arterial endothelial dysfunction may contribute to NP resistance.

Atrial Natriuretic Peptide Regulates Regional Vascular Volume and Venous Tone in Humans

Objective—To date, the contribution of basal atrial natriuretic peptide (ANP) levels to resting vascular function in humans is unknown. In the present study we sought to investigate the role of ANP in regulating regional vascular volume and venous tone in healthy subjects. Methods and Results—We used radionuclide plethysmography to examine the effects of ANP and the ANP-receptor antagonist A71915 on forearm vascular volume. Creating pressure/volume relations, we determined changes in vascular volume, compliance, and tone. Performing dose-ranging studies, we additionally assessed the potency and specificity of A71915 in the forearm resistance vasculature. Equilibrium blood pool scintigraphy was then used to assess the effects of systemic administration of A71915 on regional intestinal vascular volume. Infusion of ANP increased forearm vascular volume in a dose-dependent manner (maximum 20%; P <0.001), exerting a maximum venodilating effect at plasma levels similar to that seen in heart failure. A71915 increased venous tone, thereby decreasing vascular volume by 9.6±1.1%, P <0.001 (forearm), and 2.6±0.5%, P =0.01 (intestinal beds). At an infusion ratio of 50:1, A71915 almost completely abolished the effects of ANP on forearm blood flow. Conclusions—ANP locally regulates regional vascular volume and tone without affecting compliance.

Effects of bradykinin on venous capacitance in health and treated chronic heart failure.

In the present study, we investigated the effects of basal and intra-arterial infusion of bradykinin on unstressed forearm vascular volume (a measure of venous tone) and blood flow in healthy volunteers (n=20) and in chronic heart failure patients treated with ACEIs [ACE (angiotensin-converting enzyme) inhibitors] (n=16) and ARBs (angiotensin receptor blockers) (n=14). We used radionuclide plethysmography to examine the effects of bradykinin and of the bradykinin antagonists B9340 [B1 (type 1)/B2 (type 2) receptor antagonist] and HOE140 (B2 antagonist). Bradykinin infusion increased unstressed forearm vascular volume in a similar dose-dependent manner in healthy volunteers and ARB-treated CHF patients (healthy volunteers maximum 12.3±2.1%, P<0.001 compared with baseline; ARB-treated CHF patients maximum 9.3±3.3%, P<0.05 compared with baseline; P=not significant for difference between groups), but the increase in unstressed volume in ACEI-treated CHF patients was higher (maximum 28.8±7.8%, P<0.001 compared with baseline; P<0.05 for the difference between groups). In contrast, while the increase in blood flow in healthy volunteers (maximum 362±9%, P<0.001) and in ACEI-treated CHF patients (maximum 376±12%, P<0.001) was similar (P=not significant for the difference between groups), the increase in ARB-treated CHF patients was less (maximum 335±7%, P<0.001; P<0.05 for the difference between groups). Infusion of each receptor antagonist alone similarly reduced basal unstressed volume and blood flow in ACEI-treated CHF patients, but not in healthy volunteers or ARB-treated CHF patients. In conclusion, bradykinin does not contribute to basal venous tone in health, but in ACEI-treated chronic heart failure it does. In ARB-treated heart failure, venous responses to bradykinin are preserved but arterial responses are reduced compared with healthy controls. Bradykinin-mediated vascular responses in both health and heart failure are mediated by the B2, rather than the B1, receptor.

Rapid Nongenomic Aldosterone Effects in the Human Forearm

To the Editor: Deducing the physiological role of aldosterone from studies using systemic infusions of hormone is difficult because of the interdependent nature of many of the often counter-regulatory organ responses that are evoked. It is because of such general limitations that venous occlusion plethysmography (VOP), combined with intra-arterial drug infusion, has been used extensively to study (regional) human vascular physiology in vivo. Using this technique, Schmidt et al1 report rapid nongenomic effects of aldosterone …