Faculty Bibliography

BACKGROUND: The pharmacological effects of infusion of human brain natriuretic peptide (hBNP) in patients with severe congestive heart failure have not been characterized previously. METHODS AND RESULTS: Twenty patients with severe congestive heart failure were randomized in a double-blind, placebo-controlled, crossover trial to receive incremental 90-minute infusions of hBNP (0.003, 0.01, 0.03, and 0.1 microgram/kg per minute) or placebo on 2 consecutive days. At the highest completed dose of the hBNP, mean pulmonary artery pressure decreased from 38.3 +/- 1.6 to 25.9 +/- 1.7 mm Hg; mean pulmonary capillary wedge pressure decreased from 25.1 +/- 1.1 to 13.2 +/- 1.3 mm Hg; mean right atrial pressure decreased from 10.9 +/- 1 to 4.8 +/- 1.0 mm Hg; mean arterial pressure decreased from 85.2 +/- 2.0 to 74.9 +/- 1.7 mm Hg; and cardiac index increased from 2.0 +/- 0.1 to 2.5 +/- 0.1 L/min per square meter (all P < .01 versus placebo). Urine volume and urine sodium excretion increased significantly during hBNP infusion when compared with placebo infusion (90 +/- 38 versus 67 +/- 27 mL/h and 2.6 +/- 2.4 versus 1.4 +/- 1.2 mEq/h, respectively, both P < .05 versus placebo), whereas creatinine clearance and urinary potassium excretion did not change. CONCLUSIONS: Infusion of incremental doses of hBNP is associated with favorable hemodynamic and natriuretic effects in patients with severe congestive heart failure

OBJECTIVES: This study was undertaken to investigate the role of endothelium-derived nitric oxide in the regulation of forearm blood flow during exercise in normal subjects and patients with congestive heart failure. BACKGROUND: Nitric oxide-mediated vasodilation in response to muscarinic stimulation is impaired in the peripheral circulation of patients with congestive heart failure. Whether nitric oxide-mediated vasodilation during exercise is also impaired in patients with congestive heart failure is unknown. METHODS: Forearm blood flows (ml/min per 100 ml) were determined during rhythmic hand grip exercise at 15%, 30% and 45% of maximal voluntary contraction by venous occlusion plethysmography before and after regional inhibition of nitric oxide synthesis with administration of L-NG-monomethylarginine (L-NMMA) in the brachial artery of 17 patients with congestive heart failure (mean age 49 years, mean left ventricular ejection fraction 0.22) and 10 age-matched normal subjects. RESULTS: Before administration of L-NMMA in the brachial artery, forearm blood flows in patients with congestive heart failure during rhythmic hand grip exercise at 15%, 30% and 45% of maximal voluntary contraction were slightly but not significantly lower than that of normal subjects ([mean +/- SE] 6.8 +/- 1.0, 8.5 +/- 1.0 and 12.9 +/- 1.7 ml/min per 100 ml, respectively, in patients with congestive heart failure vs. 6.6 +/- 1.2, 11.6 +/- 1.9 and 16.2 +/- 1.9 ml/min per 100 ml, respectively, in normal subjects, p = NS). After administration of L-NMMA in the brachial artery, forearm blood flows in normal subjects significantly decreased by 10% to 21% during hand grip exercise but did not change during exercise in patients with congestive heart failure. CONCLUSIONS: Regional inhibition of nitric oxide synthase with administration of L-NMMA in the brachial artery significantly decreased forearm blood flows during rhythmic hand grip exercise in normal subjects but not in patients with congestive heart failure. These findings suggest that nitric oxide-mediated vasodilation during submaximal exercise is impaired in the forearm circulation of patients with congestive heart failure

BACKGROUND: Clinical trials have shown that beta-adrenergic blocking drugs are effective and well tolerated in patients with mild to moderate heart failure, but the utility and safety of these drugs in patients with advanced disease have not been evaluated. METHODS AND RESULTS: We enrolled 56 patients with severe chronic heart failure into a double-blind, placebo-controlled study of the vasodilating beta-blocker carvedilol. All patients had advanced heart failure, as evidenced by a mean left ventricular ejection fraction of 0.16 +/- 0.01 and a mean maximal oxygen consumption of 13.6 +/- 0.6 mL.kg-1.min-1 despite digitalis, diuretics, and an angiotensin-converting enzyme inhibitor (if tolerated). After a 3-week, open-label, up-titration period, 49 of the 56 patients were assigned (in a double-blind fashion using a 2:1 randomization) to receive either carvedilol (25 mg BID, n = 33) or matching placebo (n = 16) for 14 weeks, while background therapy remained constant. Hemodynamic and functional variables were measured at the start and end of the study. Compared with the placebo group, patients in the carvedilol group showed improved cardiac performance, as reflected by an increase in left ventricular ejection fraction (P = .005) and stroke volume index (P = .010) and a decrease in pulmonary wedge pressure, mean right atrial pressure, and systemic vascular resistance (P = .003, .002, and .017, respectively). In addition, compared with placebo, patients treated with carvedilol benefited clinically, as shown by an improvement in symptom scores (P = .002), functional class (P = .013), and submaximal exercise tolerance (P = .006). The combined risk of death, worsening heart failure, and life-threatening ventricular tachyarrhythmia was lower in the carvedilol group than in the placebo group (P = .028), but carvedilol-treated patients had more dizziness and advanced heart block. CONCLUSIONS: Carvedilol produces clinical and hemodynamic improvement in patients who have severe heart failure despite treatment with angiotensin-converting enzyme inhibitors

Instantaneous blood flow velocity characteristics and vascular impedance spectra derived noninvasively by pulsed Doppler ultrasound and invasively by electromagnetic flow probe were compared in the canine common femoral artery to validate the pulsed Doppler technique for determination of vascular impedance in the peripheral circulation. Although Doppler ultrasonography is routinely performed to evaluate blood flow velocity patterns in the human peripheral circulation; the validity of this technique to derive peripheral vascular impedance has yet to be investigated. Simultaneous measurements of blood flow velocity were determined by both noninvasive pulsed Doppler ultrasound and surgically implanted electromagnetic flow probe in the common femoral artery of eight dogs and compared in both time and frequency domains. Vascular impedance spectra derived from measurements of blood flow velocity determined by Doppler ultrasound and electromagnetic flow probe and simultaneous measurement of arterial pressure by a micromanometer-tipped catheter were obtained at baseline and after intra-arterial injection of acetylcholine in five additional dogs. During the first 10 to 20% of the cardiac cycle, Doppler ultrasound blood flow velocity was transiently greater than the simultaneously recorded electromagnetic blood flow velocity. During the remainder of the cardiac cycle, the two blood flow velocity waveforms were nearly superimposable. The frequency spectra of the blood flow velocity waveforms derived from Doppler ultrasound and electromagnetic flow probes were similar for harmonies less than 10 Hz. Vascular impedance spectra derived from measurements of blood flow velocity determined by Doppler ultrasound and electromagnetic flow probe with simultaneous measurement of arterial pressure by a micromanometer-tipped catheter were similar at baseline and after regional administration of acetylcholine. Mean vascular resistance (impedance at 0 Hz), characteristic impedance, and the first minima of the impedance modulus derived from Doppler ultrasound and electromagnetic flow probe blood flow velocity measurements were closely correlated at baseline and after dilation with acetylcholine (r > or = 0.89, p < 0.05 for all correlations). Doppler ultrasonography is a convenient and accurate technique for determination of vascular impedance in the peripheral circulation

The vascular endothelium releases vasoactive substances that appear to play an important role in the normal regulation of peripheral vasomotor tone. Nitric oxide, endothelins, prostaglandins, and other endothelium-derived vasodilating and vasoconstricting factors are released by the vascular endothelium in response to a diverse array of hormonal, pharmacologic, chemical, and physical stimuli. Shear stress, produced by pulsatile blood flow at the endothelial cell luminal surface, alters endothelial production of several endothelium-derived vasoactive substances, which may contribute to regional regulation of skeletal muscle blood flow during exercise. Abnormal vascular endothelium function has been shown in both experimental and clinical heart failure. Preliminary data suggest that abnormalities of endothelial function may contribute to increased peripheral vasomotor tone during exercise in patients with congestive heart failure

Left ventricular thrombus is highly prevalent in patients with congestive heart failure, but the increase of thromboembolic events is low. Reliable clinical indicators of increased thromboembolic risk are not yet available. Clinical decisions to treat patients who have congestive heart failure with oral anticoagulants must be made on an individual basis

BACKGROUND: Tumor necrosis factor-alpha (TNF alpha), which we and others have shown to be elevated in patients with severe congestive heart failure (CHF), is involved in the regulation of nitric oxide metabolism. Whether increased concentrations of TNF alpha affect nitric oxide-mediated vasodilation in patients with CHF has not been studied previously. METHODS AND RESULTS: Serum concentrations of TNF alpha, interleukin-1 (IL-1), interleukin-2 (IL-2), and interleukin-6 (IL-6) were determined in venous blood (pg/mL) from 17 patients with stable New York Heart Association classes II and III CHF (mean age, 58 +/- 11 years; mean left ventricular ejection fraction, 19.5 +/- 7.3) and 17 age-matched normal subjects with enzyme-linked immunosorbent assays (detection limit of assays, 20 pg/mL). Forearm blood flows were determined with plethysmography (mL/min per 100 mL) in 17 patients and 7 normal subjects in response to brachial artery administration of graded concentrations of acetylcholine (10(-6) mol/L and 10(-5) mol/L) and nitroglycerin (10(-7) mol/L and 10(-6) mol/L). Serum concentrations of TNF alpha were above the detection limits of the assay in 10 of 17 patients with CHF (mean serum concentration, 39.4 +/- 3.8 pg/mL). Forearm blood flow responses to acetylcholine and nitroglycerin were significantly greater in these 10 patients than in the 7 patients without detectable serum TNF alpha and were closely correlated with TNF alpha serum concentrations (r > or = .81, P < .01 and r > or = .65, P < .05 respectively). In 1 of 17 normal subjects, the serum concentration of TNF alpha was just above the detection limit of the assay. Serum concentrations of IL-2 were above the detection limit of the assay in 14 of 17 patients with CHF (mean serum concentration, 112 +/- 19 pg/mL). IL-2 was not detected in the serum of normal subjects. Serum concentrations of IL-1 and IL-6 were below the detection limit of the assays in all patients and normal subjects assayed. CONCLUSIONS: Increased TNF alpha concentrations are closely correlated with forearm blood flow responses to regional administration of acetylcholine and nitroglycerin. The significant correlation between serum concentrations of TNF alpha and forearm blood flow responses to acetylcholine and nitroglycerin suggests that both the inducible and the constitutive forms of nitric oxide synthase are involved in the regulation of peripheral vasomotor tone in patients with CHF

BACKGROUND: Since organic nitroesters and endothelium-derived nitric oxide mediate vasodilation through a final common pathway, that is, by activation of soluble guanylate cyclase in vascular smooth muscle, nitroglycerin (NTG) could specifically enhance the endothelium-dependent vasodilatory response to acetylcholine (Ach) in patients with congestive heart failure (CHF) and endothelial cell dysfunction. Accordingly, the net effects of an intra-arterial infusion of NTG (10(-9) mol/L) on endothelium-dependent and endothelium-independent vasodilation were assessed in the forearm circulation of patients with CHF. METHODS AND RESULTS: The forearm blood flow responses to intra-arterial administration of graded concentrations of Ach (10(-7) to 10(-5) mol/L) were determined by venous occlusion plethysmography (mL/min per 100 mL) in 18 patients with CHF and 5 age-matched normal subjects before and during intra-arterial infusion of NTG (10(-9) mol/L) for 20 minutes. In eight patients, the duration of the infusion of NTG (n = 5) or vehicle control solution (n = 3) was extended to 12 hours with measurement of the forearm blood flow responses to Ach at 20 minutes, 4 hours, and 12 hours. In five additional patients, forearm blood flow response to intra-arterial administration of two doses of phentolamine (0.05 and 0.5 mg) were determined before and during a 20-minute NTG infusion. Regional administration of NTG 10(-9) mol/L did not change resting forearm blood flow in either normal subjects or patients with CHF. Before administration of NTG 10(-9) mol/L, intra-arterial infusions of Ach 10(-7), 10(-5) and 10(-5) mol/L increased forearm blood flow to 14.7 +/- 6.2, 20.2 +/- 4.7, and 38.4 +/- 7.9 mL/min per 100 mL in normal subjects and to 4.1 +/- 0.8, 5.0 +/- 1.1, and 10.6 +/- 2.3 mL/min per 100 mL in patients with CHF. After administration of NTG 10(-9) mol/L for 20 minutes, the vasodilatory response to Ach significantly increased to 5.6 +/- 1.0, 6.9 +/- 1.6, and 17.7 +/- 3.4 mL/min per 100 mL in patients with CHF but did not change in normal subjects. The enhanced forearm blood flow responses to administration of Ach observed after 20 minutes of NTG administration in patients with CHF were sustained throughout a 12-hour NTG infusion. In contrast, regional administration of NTG did not change the vasodilatory responses to phentolamine. CONCLUSIONS: NTG, when administered intra-arterially for 20 minutes at a dose that does not affect resting forearm blood flow, specifically increased the vasodilatory response to intra-arterial administration of Ach in patients with CHF but not in normal subjects. The vasodilatory response to Ach was consistently enhanced by low-dose NTG throughout a 12-hour period. The vasodilating effects of organic nitroesters on the peripheral vasculature of patients with CHF may result in part from an interaction with the vascular endothelium

OBJECTIVES. The aim of this study was to compare peak reactive hyperemic blood flows in the forearm and calf of patients with congestive heart failure and in age- and gender-matched normal subjects. In addition, we attempted to correlate peak oxygen consumption with forearm and calf peak reactive hyperemic flows in the patients with heart failure. BACKGROUND. Disparate results have been reported regarding forearm peak reactive hyperemia in patients with congestive heart failure. Because training significantly increases peak reactive hyperemic flow in normal subjects, we hypothesized that in patients with congestive heart failure who curtail walking because of exertional symptoms, calf peak reactive hyperemic flow would be preferentially attenuated and that impairment of calf vasculature may correlate with peak oxygen consumption. METHODS. Forearm and calf blood flows were measured by venous occlusive plethysmography at rest and after 5 min of arterial occlusion in 46 patients with congestive heart failure and 7 age- and gender-matched normal subjects. Peak oxygen consumption was measured during graded exercise on a bicycle ergometer. RESULTS. Calf peak reactive hyperemic flow was lower in patients with congestive heart failure than in normal subjects (22 +/- 1 vs. 32.5 +/- 3.5 ml/min per 100 ml, p < 0.001), whereas forearm peak reactive hyperemic flows were similar in the two groups. Calf peak reactive hyperemic flow was linearly related to peak oxygen consumption (r = 0.58, p < 0.0001), but forearm peak reactive hyperemic flow was not. Forearm and calf peak reactive hyperemic flows were not related at rest or after 5 min of arterial occlusion in the patients with heart failure. CONCLUSIONS. Calf peak reactive hyperemic flow is reduced in patients with congestive heart failure, whereas forearm peak reactive hyperemic flow is identical to that of age- and gender-matched normal subjects. Calf peak reactive hyperemic flow is linearly related to peak oxygen consumption in patients with congestive heart failure, but forearm peak reactive hyperemic flow is not

Systemic and lower limb skeletal muscle lactate metabolism was studied in 10 men with congestive heart failure by use of a primed continuous intravenous infusion of L-(+)-[U-14C]lactate. Arterial and deep femoral venous blood samples were obtained at rest and during 30 min of submaximal exercise. Systemic lactate metabolic turnover rate (Rd) was determined using Steele's isotopic steady-state equation (Rd = isotopic infusion rate/arterial specific activity). Plasma lactate concentrations in the artery and deep femoral vein did not change significantly from resting values during exercise (1.11 +/- 0.13 vs. 1.26 +/- 0.12 and 1.27 +/- 0.12 vs. 1.30 +/- 0.12 mM, respectively), whereas Rd increased from 22.5 +/- 1.8 to 41.6 +/- 4.8 mumol.kg-1.min-1 (P < 0.005). Rd did not significantly correlate with arterial lactate concentration during rest or exercise. Because of simultaneous uptake and release of lactate in skeletal muscle, arterial and deep femoral venous lactate concentrations are not closely related to either systemic or lower limb skeletal muscle lactate metabolism in patients with congestive heart failure