Faculty Bibliography

The effects of physical training on endothelium-dependent vasodilation in skeletal muscle resistance vessels were investigated in patients with heart failure. Forearm blood flows (ml.min-1.100 ml-1) in response to brachial arterial administration of acetylcholine (5 x 10(-5) and 5 x 10(-4) M at 1 ml/min) and nitroglycerin (5 x 10(-6) and 5 x 10(-5) M at 1 ml/min) were determined by strain-gauge venous occlusion plethysmography before and after 8 wk of daily handgrip exercise in 12 patients with chronic heart failure. After 8 wk of daily handgrip exercise, the vasodilatory responses to acetylcholine significantly increased from pretraining values, i.e., 16.6 +/- 2.0 vs. 8.6 +/- 1.3 ml.min-1.100 ml-1 (P < 0.05) and 27.5 +/- 1.5 vs. 14.6 +/- 1.7 ml.min-1.100 ml-1 (P < 0.05), respectively, whereas the vasodilatory responses to nitroglycerin did not change. Handgrip exercise training appears to specifically enhance endothelium-dependent vasodilation in the forearm skeletal muscle circulation of patients with heart failure

BACKGROUND: Whether increased cardiac output during chronic circulatory support with a left ventricular assist device (LVAD) is associated with improved metabolic vasodilation in the peripheral circulation of patients with congestive heart failure is unknown. METHODS: Forearm blood flow, determined by venous occlusion plethysmography, mean arterial pressure, and cardiac output were measured at rest and after 5 minutes of arterial occlusion (a maximal metabolic vasodilatory stimulus) in 14 patients with severe heart failure before LVAD implantation, and in the early (<4 weeks) and late (8 to 12 weeks) postoperative recovery phases after LVAD implantation. Nine normal subjects served as controls. Vascular conductance was calculated as the ratio of forearm blood flow and mean arterial pressure. RESULTS: Mean arterial pressure and cardiac output increased to normal values in the early and late recovery phases after LVAD implantation. Resting forearm blood flow and vascular conductance were similar to normal subjects in the early and late recovery phases after LVAD implantation. Peak forearm blood flow and vascular conductance were significantly less than control subjects in the early preoperative recovery phase (p < 0.05) but were similar to control subjects in the late postoperative recovery phase after LVAD implantation. CONCLUSIONS: In spite of early normalization of cardiac output, mean arterial pressure, and resting forearm blood flow during chronic circulatory support with the LVAD, peak forearm blood flow, and peak vascular conductance did not increase to values similar to those observed in normal subjects until the late postoperative recovery period. The delayed effect of the LVAD on metabolic vasodilation may be related to flow-dependent changes in the peripheral vasculature of patients with heart failure

The pathogenesis of heart failure is determined by the ventricular and vascular responses to myocellular injury. Experimental and clinical studies suggest that the vascular endothelium may play an important role in modulating progression of ventricular and vascular remodeling in heart failure. Endothelial cell dysfunction has been described in the coronary and skeletal muscle circulations of patients with heart failure and appears to be characterized by decreased endothelial synthesis of nitric oxide and increased production of endothelin-1. The pathogenesis of endothelial dysfunction in heart failure is unknown, but may be related to increased oxidative stress, abnormal regional flow conditions, and cytokine and neurohormonal activation. The specific role of endothelial dysfunction in the pathogenesis of heart failure remains to be determined. If endothelial dysfunction does contribute to progression of disease in early heart failure, specific therapies to enhance endothelial dysfunction may improve long-term morbidity and mortality

Combined therapy with an angiotensin-II type I receptor (AT1) antagonist and an angiotensin-converting enzyme (ACE) inhibitor results in more complete suppression of the renin-angiotensin system. Accordingly, the blood-pressure response and safety of combining AT1-receptor blockade with losartan for ACE inhibition were evaluated in patients with congestive heart failure who were already treated with maximally recommended or tolerated doses of an ACE inhibitor. Forty-three patients with symptomatic congestive heart failure were evaluated biweekly for 1 month before addition of losartan and weekly during administration of losartan at a daily dose of 25 mg for the first week and 50 mg for the second week. Systolic blood pressure, which remained unchanged before addition of losartan, decreased from 122 +/- 18 mm Hg to 112 +/- 17 and 107 +/- 17 mm Hg (p < 0.001) after 1 week of 25 mg and 1 week of 50 mg losartan, respectively. Diastolic blood pressure also significantly decreased. The decreases in blood pressure were well tolerated by all patients, even by those in whom symptomatic hypotension developed during uptitration of ACE inhibition. Serum potassium and sodium and parameters of renal function remained unchanged. Combining AT1-receptor blockade with losartan to maximally recommended or tolerated ACE inhibition appears safe and leads to further vasodilatation in symptomatic patients with 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: 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

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

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

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

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