Faculty Bibliography

BACKGROUND: A synergistic interaction between the angiotensin II (Ang II) type 1 receptor and alpha1-adrenergic receptors has been described. We hypothesized that the nonselective beta-antagonist carvedilol, through its alpha1-adrenergic blocking properties, may modulate vascular reactivity to Ang II in patients with chronic heart failure (CHF). Accordingly, we compared the vasopressor response to infused Ang II in patients treated with carvedilol and metoprolol, a selective beta-antagonist. METHODS AND RESULTS: All subjects were treated with carvedilol or metoprolol for at least 3 months. ACE inhibitor therapy was standardized to enalapril 40 mg/d or the maximally tolerated dose. Exogenous Ang II was administered as sequential intravenous bolus injections (2.5 to 30 ng/kg) titrated to a rise in radial artery systolic pressure of > or =20 mm Hg. The dose of Ang II required to elicit a change of 20 mm Hg in radial artery systolic pressure (PD20) defined the vasopressor response to Ang II. Twenty subjects with CHF (mean left ventricular ejection fraction 28+/-9%, New York Heart Association class II [n=13] and III [n=7]) were studied. There was no correlation between plasma Ang II levels and PD20. However, the PD20 was significantly higher in patients treated with carvedilol than in those treated with metoprolol (20 [range 2.5 to 30] versus 5 [range 2.5 to 10] ng/kg, P=0.019). CONCLUSIONS: The vasopressor response to Ang II infusion in patients treated with carvedilol was significantly lower than in patients treated with metoprolol. Whether this is due to the alpha1-adrenergic blocking or other ancillary properties of carvedilol warrants further investigation

BACKGROUND: Anemia frequently occurs in chronic heart failure (CHF) patients and is associated with a poor prognosis. A low hematocrit may result from an increased plasma volume (hemodilution) or from reduced red blood cell volume (true anemia). The prevalence and clinical outcome of CHF patients with hemodilution is unknown. METHODS AND RESULTS: The prevalence of anemia and its effect on outcome was examined in 196 patients with CHF. The prevalence of hemodilution was assessed in a subset of 37 ambulatory anemic patients with I131-tagged albumin to measure red blood cell and plasma volume. Clinical outcome was monitored. Sixty-one percent of the CHF patients were anemic. The prevalence of anemia increased from 33% in patients with New York Heart Association class II heart failure to 68% in class IV CHF patients. Survival was reduced in anemic patients compared with patients with a normal hematocrit (P<0.05). In the subset of 37 anemic patients, 17 patients (46%) had hemodilution and 20 patients (54%) had a true anemia. Nine patients with hemodilution died or underwent urgent transplant compared with 4 patients in the true anemia group (P<0.04). CONCLUSION: Hemodilution is common in CHF patients. Anemia is associated with a poor prognosis in CHF. Patients with hemodilution tend to do worse than patients with true anemia, which suggests that volume overload may be an important mechanism contributing to the poor outcome in anemic CHF patients

BACKGROUND: Patients with chronic heart failure (CHF) are frequently anemic. An increase in hemoglobin could enhance exercise performance by increasing oxygen delivery. We investigated the effect of erythropoietin (EPO) on exercise performance in anemic patients with CHF. METHODS AND RESULTS: Twenty-six anemic patients aged 57+/-11 years were randomized to receive EPO (15 000 to 30 000 IU per week) or placebo for 3 months. Parameters measured at baseline and end therapy included blood parameters (hemoglobin, hematocrit, plasma volume), exercise parameters (peak oxygen consumption [VO2], exercise duration, 6-minute walk), muscle aerobic metabolism (half-time of VO2 and near infrared recovery), and forearm vasodilatory function. EPO was well tolerated by all patients. Twelve patients in the EPO group felt improvement versus 1 in the placebo group (P<0.05). There were significant increases in hemoglobin (11.0+/-0.5 to 14.3+/-1.0 g/dL, P<0.05), peak VO2 (11.0+/-1.8 to 12.7+/-2.8 mL. min(-1) x kg(-1), P<0.05) and exercise duration (590+/-107 to 657+/-119 s, P<0.004) in the EPO group but no significant changes in the control group. Resting and hyperemic forearm vascular resistance and indices of the rate of muscle oxidative capacity were unchanged in both groups. CONCLUSION: EPO significantly enhances exercise capacity in patients with CHF. One mechanism of improvement in VO2 is increased oxygen delivery from increased hemoglobin concentration

Endothelial dysfunction is associated with impairment of aerobic capacity in patients with heart failure and may play a role in the progression of disease. Impaired endothelium-dependent vasodilation in patients with heart failure can be attributed to decreased bioavailability of nitric oxide and attenuated responses to nitric oxide in vascular smooth muscle. Impaired vasodilation in response to nitric oxide derived from vascular endothelium or organic nitrates in vascular smooth muscle may be related in part to increased degradation of the second messenger cyclic guanosine monophosphate by type 5 phosphodiesterase. Sildenafil, a specific type 5 phosphodiesterase inhibitor currently approved for the treatment of erectile dysfunction, has been shown to acutely enhance endothelium-dependent vasodilation in patients with heart failure. Further studies are warranted to characterize the safety and efficacy of type 5 phosphodiesterase inhibition in the treatment of chronic heart failure

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