Faculty Bibliography

BACKGROUND: Adrenergic receptor blockers used in the treatment of heart failure have distinct receptor affinity profiles. We hypothesized that alpha-adrenergic-blocking effects of carvedilol would limit vasoconstriction in response to adrenergic stimuli when compared with metoprolol. METHODS AND RESULTS: Forearm vascular resistance responses to isometric handgrip and cold pressor test were determined by plethysmography before and during adrenergic receptor blockade in prospective randomized trials. Acute effects were assessed in a crossover trial in normal subjects (single dose of 25 mg carvedilol, 100 mg metoprolol tartrate, and placebo). Chronic effects (25 mg carvedilol BID versus 200 mg extended-release metoprolol succinate daily for 6 months) were assessed in a parallel group trial of chronic heart failure subjects. In normal subjects, carvedilol decreased forearm vascular resistance responses to adrenergic stimuli when compared with metoprolol and placebo (isometric handgrip -3.5 U for carvedilol versus -1.2 U for metoprolol and -2.2 U for placebo, P=0.15; cold pressor test 3.1+/-8.9 U for carvedilol versus 9.0+/-2.7 U for metoprolol and 8.2+/-5.8 U for placebo, P<0.05). In heart failure subjects, vasomotor responses to isometric handgrip and cold pressor test did not differ between treatment groups. CONCLUSIONS: Acute administration of carvedilol attenuates the vasoconstriction response to adrenergic stimuli when compared with placebo and metoprolol in normal subjects, whereas chronic administration of carvedilol does not attenuate the vasoconstrictor response to adrenergic stimuli when compared with metoprolol in heart failure subjects. These data suggest that long-term benefits of carvedilol in heart failure are not mediated by alpha-adrenergic blockade

BACKGROUND: Cachexia is a common problem in chronic heart failure (CHF) that may be partly mediated by activation of the sympathetic nervous system. The effects of beta-adrenergic receptor blocker (BB) therapy on body weight in cachectic and noncachectic subjects with CHF has not been previously reported. METHODS AND RESULTS: Body weight and plasma norepinephrine, leptin, and insulin levels were measured in 27 subjects with CHF before and after 6 months of beta-adrenergic receptor blockade with carvedilol or long-acting metoprolol. Before BB therapy, baseline weight, plasma leptin, and plasma insulin levels did not differ between cachectic and noncachectic subjects. Baseline plasma norepinephrine levels were increased in cachectic subjects when compared with noncachectic subjects (930+/-248 pg/mL versus 503+/-109 pg/mL, P=.063). After 6 months of BB therapy, subjects with baseline cachexia demonstrated significantly greater weight gain (+5.2+/-9.6 versus +0.8+/-5.0 kg, P=.027), greater increase in plasma leptin levels (+3.7+/-3.9 versus +1.2+/-4.3 ng/mL, P=.030), and greater decrease in plasma norepinephrine levels (-374+/-261 versus -41+/-122 pg/mL, P=.012) when compared with noncachectic subjects. CONCLUSIONS: Six months of BB therapy with carvedilol or long-acting metoprolol is associated with differential effects on body weight and hormonal levels in cachectic and noncachectic subjects with CHF. Further work is needed to determine the role the sympathetic nervous system in the pathogenesis of cachexia in patients with CHF

BACKGROUND: Plasma aldosterone levels are elevated in patients with chronic heart failure (CHF) taking angiotensin-converting enzyme (ACE) inhibitors. Elevated aldosterone levels may reflect incomplete inhibition of the vascular converting enzyme during long-term ACE inhibition. We simultaneously measured plasma aldosterone levels and the degree of inhibition of the vascular converting enzyme in patients with CHF. METHODS AND RESULTS: Thirty-four subjects with CHF receiving the maximum recommended doses of ACE inhibitors for a duration of 3 to 105 months were studied. The pressor response to exogenous angiotensin I (AI) was measured and normalized for the pressor response to angiotensin II (AII) to assess inhibition of the vascular converting enzyme (AII/AI ratio). Aldosterone levels were determined by solid-phase radioimmunoassay. Eleven of the 34 subjects had plasma aldosterone levels above the upper limit of normal, ie, >15.0 ng/dL. Seven of these 11 subjects (64%) had an AII/AI ratio < or =0.05, indicating complete inhibition of the vascular converting enzyme. In the entire cohort, the AII/AI ratio did not correlate with the duration of ACE inhibitor therapy. CONCLUSIONS: Plasma aldosterone levels are elevated in patients with CHF during long-term ACE inhibitor therapy despite complete inhibition of the vascular converting enzyme. Complete inhibition of the vascular converting enzyme does not obviate the need for aldosterone receptor blockade in patients with CHF

OBJECTIVE: Dexrazoxane is an antioxidant prodrug that on hydrolysis is converted into an intracellular iron chelator. We hypothesized that the antioxidant effects of dexrazoxane would prevent homocysteine-induced endothelial dysfunction in the brachial artery of normal human subjects. METHODS AND RESULTS: Ten healthy volunteers completed a randomized, double-blind, crossover study. Plasma homocysteine levels and brachial artery endothelium-dependent (flow-mediated dilation [FMD]) and endothelium-independent (sublingual nitroglycerin) responses were measured before and 4 hours after ingestion of L-methionine (100 mg/kg), preceded by intravenous administration of dexrazoxane (500 mg/m2) or placebo over 30 minutes. After placebo, oral methionine increased plasma homocysteine (from 5.1+/-0.4 micromol/L at baseline to 14.2+/-1.3 micromol/L at 4 hours, P<0.001) and decreased FMD (from 3.8+/-0.7% at baseline to 1.2+/-0.5% at 4 hours, P=0.02). Dexrazoxane did not change homocysteine concentrations after methionine administration (14.9+/-1.1 micromol/L at 4 hours, P=0.29 versus placebo) but did completely abrogate the homocysteine-induced reduction in FMD (from 3.5+/-0.5% at baseline to 5.9+/-1.1% at 4 hours, P<0.01 versus placebo). Endothelium-independent responses to sublingual nitroglycerin did not differ after the administration of placebo and dexrazoxane. CONCLUSIONS: Administration of the novel antioxidant agent dexrazoxane prevents homocysteine-induced impairment of vascular endothelial function in the brachial artery of healthy subjects

Vasomotor responses to intraarterial administration of acetylcholine are mediated by release of nitric oxide, prostaglandins, and an unidentified hyperpolarizing factor from vascular endothelial cells. The contribution of endothelium-derived hyperpolarizing factor (EDHF) to the vasodilatory response to acetylcholine in the skeletal muscle circulation of patients with congestive heart failure (CHF) has not been previously characterized. Accordingly, to specifically assess the role of EDHF, the regional vascular effects of sequential administration of acetylcholine and nitroglycerin in the brachial artery were determined in the forearm circulation with strain-gauge venous occlusion plethysmography in patients with CHF and in normal subjects during combined systemic inhibition of cyclooxygenase activity with indomethacin and regional inhibition of nitric oxide synthase activity with l-N(G)-monomethylarginine (l-NMMA). After administration of indomethacin, infusion of l-NMMA significantly decreased the forearm blood flow response to acetylcholine in normal subjects (5.4 +/- 1.2 to 3.5 +/- 0.6 ml/min/100 ml, p < 0.05) but not in patients with CHF (5.7 +/- 1.3 to 5.7 +/- 1.4 ml/min/100 ml). Infusion of l-NMMA did not change forearm blood flow responses to nitroglycerin in either group. The presence of a noncyclooxygenase, non-nitric-oxide relaxing factor indicates that EDHF, rather than nitric oxide, may be the predominant endothelium-derived substance mediating vasodilation in response to acetylcholine in patients with CHF

Natriuretic peptides are a family of endogenous peptide hormones with vasodilating, natriuretic, diuretic, and lusitropic properties. Administration of pharmacologic doses of exogenous natriuretic peptides may provide therapeutic benefit in patients with chronic heart failure. In controlled clinical trials, short-term administration of nesiritide (human brain natriuretic peptide) to patients with heart failure is associated with improved resting hemodynamics, modest increases in sodium excretion, evidence of suppression of neurohormonal activation, and improvements in symptoms of heart failure. Additional trials to determine the clinical efficacy and safety of nesiritide are warranted. (c)2001 by CHF, Inc

Systemic oxygen uptake and deep femoral vein oxygen content were determined at peak exercise in 53 patients with chronic heart failure with impaired systolic function (mean left ventricular ejection fraction 0.18; n = 41) or preserved systolic function (mean left ventricular ejection fraction 0.70; n = 12) and in 6 age-matched sedentary normal subjects. At peak exercise, deep femoral vein oxygen content in heart failure patients with impaired systolic function and preserved systolic function were similar, both significantly lower than that of normal subjects (2.5 +/- 0.1, 2.9 +/- 0.2, and 5.0 +/- 0.1 ml/100 ml, respectively; P < 0.05). Deep femoral venous oxygen content was lower in patients with the greater impairment of aerobic capacity, regardless of the underlying systolic function (r = 0.72, P < 0.01). Fractional oxygen extraction in the skeletal muscle at peak exercise is enhanced in patients with chronic heart failure when compared with normal subjects, in proportion to the degree of aerobic impairment

OBJECTIVES: To determine the acute effects of type 5 phosphodiesterase inhibition with sildenafil on flow-mediated vasodilation in the brachial artery of patients with chronic heart failure. BACKGROUND: Impaired endothelium-dependent, flow-mediated vasodilation in patients with heart failure is partly attributable to hyporesponsiveness of cyclic guanosine monophosphate (cGMP) mediated vasorelaxation effector mechanisms in vascular smooth muscle. The effect of inhibition of cGMP degradation with sildenafil, a specific type 5 cGMP phosphodiesterase inhibitor, on flow-mediated dilation in heart failure is unknown. METHODS: Flow-mediated vasodilation after release of 1, 3 and 5 min of transient arterial occlusion was measured in the brachial artery with high resolution two-dimensional ultrasound imaging in 48 patients with chronic heart failure before and 1 h after randomized, double-blind assignment to a single oral dose of sildenafil 12.5, 25 or 50 mg or matching placebo. RESULTS: In response to oral administration of a single dose of study drug, the change in flow-mediated vasodilation after release of 1, 3 and 5 min of arterial occlusion was significantly greater in patients receiving sildenafil 25 mg (3.3 +/- 1.9, 3.8 +/- 1.8 and 4.0 +/- 1.8%, respectively, p < 0.05) and patients receiving sildenafil 50 mg (3.7 +/- 1.3, 4.1 +/- 1.1, 3.9 +/- 1.3%, respectively, p < 0.05) than that of patients receiving placebo (0.7 +/- 1.1, 0.2 +/- 1.2, 0.6 +/- 0.8%, respectively). CONCLUSIONS: Acute type 5 phosphodiesterase inhibition with sildenafil 25 and 50 mg increases endothelium-dependent, flow-mediated vasodilation in patients with chronic heart failure when compared with placebo