Alan J. Bank

Endothelium-dependent vasodilation is attenuated in patients with heart failure.

BackgroundEndothelial cells produce a number of substances, collectively termed endothelium derived relaxing factor (EDRF), that promote local relaxation of vascular smooth muscle. Although studies have demonstrated defects in endothelium-dependent vasodilation in animal models of hypertension, atherosclerosis, and heart failure, there are only limited data from human subjects because of the difficulty in obtaining fresh vascular segments. Methods and ResultsTo address the hypothesis that endothelium-dependent vasodilation is attenuated in patients with heart failure, we measured forearm blood flow responses to the intra-arterial administration of methacholine, a known stimulus of EDRF release through muscarinic receptors. In 14 normal subjects, a dosage range of methacholine increased forearm blood flow by 5.26 ± 0.63, 10.50 ± 0.63, and 13.22 ± 0.86 ml/min/100 ml forearm volume (FAV); these responses were 1.98 ± 0.46, 5.48 ± 0.79, and 8.50 ± 1.53 ml/min/100 ml FAV in 14 patients with heart failure. When pooled over all doses, the responses were strikingly less in the patients with heart failure (5.32 ± 0.31 versus 9.52 ± 0.60 ml/min/100 ml FAV; p = 0.0003). In a second study, the average difference in forearm blood flow responses between patients with heart failure and normal subjects with methacholine was significantly greater than the average difference between the groups with nitroprusside (4.04 ± 1.10 versus 2.20 ± 0.71 ml/min/100 ml FAV; p = 0.04). The decreased methacholine responses in the patients with heart failure were not related to age (r = 0.39; p = NS) or etiology because there was no difference in the responses between patients with ischemic heart disease and those with idiopathic cardiomyopathy. ConclusionsThese data suggest that endothelium-dependent vasodilation is attenuated in patients with heart failure. Although the mechanisms of the decreased endothelium-dependent responses in heart failure are not known, this impaired local vasodilation may contribute to characteristic of heart failure.

Effects of cardiac resynchronization on disease progression in patients with left ventricular systolic dysfunction, an indication for an implantable cardioverter-defibrillator, and mildly symptomatic chronic heart failure

Background—The effects of cardiac resynchronization therapy (CRT) in patients with mildly symptomatic heart failure have not been fully elucidated. Methods and Results—The Multicenter InSync ICD Randomized Clinical Evaluation II (MIRACLE ICD II) was a randomized, double-blind, parallel-controlled clinical trial of CRT in NYHA class II heart failure patients on optimal medical therapy with a left ventricular (LV) ejection fraction ≤35%, a QRS ≥130 ms, and a class I indication for an ICD. One hundred eighty-six patients were randomized: 101 to the control group (ICD activated, CRT off) and 85 to the CRT group (ICD activated, CRT on). End points included peak &OV0312;o2, &OV0312;e/&OV0312;co2, NYHA class, quality of life, 6-minute walk distance, LV volumes and ejection fraction, and composite clinical response. Compared with the control group at 6 months, no significant improvement was noted in peak &OV0312;o2, yet there were significant improvements in ventricular remodeling indexes, specifically LV diastolic and systolic volumes (P=0.04 and P=0.01, respectively), and LV ejection fraction (P=0.02). CRT patients showed statistically significant improvement in &OV0312;e/&OV0312;co2 (P=0.01), NYHA class (P=0.05), and clinical composite response (P=0.01). No significant differences were noted in 6-minute walk distance or quality of life scores. Conclusions—In patients with mild heart failure symptoms on optimal medical therapy with a wide QRS complex and an ICD indication, CRT did not alter exercise capacity but did result in significant improvement in cardiac structure and function and composite clinical response over 6 months.

Randomized, Double-Blind, Placebo-Controlled Study of Supplemental Oral l-Arginine in Patients With Heart Failure

BACKGROUNDnPatients with heart failure have reduced peripheral blood flow at rest, during exercise, and in response to endothelium-dependent vasodilators. Nitric oxide formed from L-arginine metabolism in endothelial cells contributes to regulation of blood flow under these conditions. A randomized, double-blind crossover study design was used to determine whether supplemental oral L-arginine can augment peripheral blood flow and improve functional status in patients with moderate to severe heart failure.nnnMETHODS AND RESULTSnFifteen subjects were given 6 weeks of oral L-arginine hydrochloride (5.6 to 12.6 g/d) and 6 weeks of matched placebo capsules in random sequence. Compared with placebo, supplemental oral L-arginine significantly increased forearm blood flow during forearm exercise, on average from 5.1 +/- 2.8 to 6.6 +/- 3.4 mL. min-1. dL-1 (P < .05). Furthermore, functional status was significantly better on L-arginine compared with placebo, as indicated by increased distances during a 6-minute walk test (390 +/- 91 versus 422 +/- 86 m, P < .05) and lower scores on the Living With Heart Failure questionnaire (55 +/- 28 versus 42 +/- 26, P < .05). Oral L-arginine also improved arterial compliance from 1.99 +/- 0.38 to 2.36 +/- 0.30 mL/mm Hg (P < .001) and reduced circulating levels of endothelin from 1.9 +/- 1.1 to 1.5 +/- 1.1 pmol/L (P < .05).nnnCONCLUSIONSnSupplemental oral L-arginine had beneficial effects in patients with heart failure. Further studies are needed to confirm the therapeutic potential of supplemental oral L-arginine and to identify mechanisms of action in patients with heart failure.

Contribution of Collagen, Elastin, and Smooth Muscle to In Vivo Human Brachial Artery Wall Stress and Elastic Modulus

BACKGROUNDnThe contributions of collagen, elastin, and smooth muscle to arterial mechanical properties in the in vivo human artery are not known.nnnMETHODS AND RESULTSnWe used a recently developed intravascular ultrasound technique to measure total brachial artery wall stress and incremental elastic modulus (Einc) in seven normal human subjects at baseline and after intra-arterial norepinephrine (1.2 micrograms) and nitroglycerin (100 micrograms). Then we applied a modified Maxwell model to estimate the elastic modulus of elastin (EE); the recruitment of collagen fibers supporting wall stress; and the differential contributions of collagen, elastin, and smooth muscle to wall stress and Einc over a wide range of pressure and smooth muscle tone. With this model, EE was 3 x 10(6) dynes/cm2. Collagen fibers were recruited increasingly as transmural arterial pressure increased and reached a value of approximately 5% to 6% at 100 mm Hg under each of the conditions studied. Isobaric smooth muscle contraction resulted in a small decrease in total wall stress and no significant change in total Einc while shifting the predominant element contributing to these mechanical parameters from collagen in parallel with the smooth muscle to collagen in series with the smooth muscle. In contrast, isometric smooth muscle contraction produced large increases in total wall stress (from 0.11 x 10(6) dynes/cm2 after nitroglycerin administration to 1.35 x 10(6) dynes/cm2 after norepinephrine administration) and Einc (from 3.84 x 10(6) dynes/cm2 after nitroglycerin administration to 57.8 x 10(6) dynes/cm2 after norepinephrine administration) entirely as a result of the additional contribution of the smooth muscle and its associated series collagen.nnnCONCLUSIONSnThis study describes a technique for determining arterial elastic properties and a model that can be used to estimate a number of mechanical parameters of the human brachial artery in vivo. This technique may be useful in studies of the arterial elastic properties of arteries in patients with vascular pathology.

Use of the Living With Heart Failure Questionnaire to Ascertain Patients' Perspectives on Improvement in Quality of Life versus Risk of Drug-induced Death

Treatments for heart failure, such as flosequinan, may have opposite effects on survival and quality of life. The Living With Heart Failure questionnaire was used to examine patients willingness to risk drug-induced death for improved quality of life. In addition, patients opinions concerning worthwhile improvements in the Living With Heart Failure score were described to provide a perspective for interpreting the results of clinical trials. A sample of 101 patients with heart failure were interviewed in cardiology clinics. Median (interquartile range) Living With Heart Failure questionnaire score were 54 (interquartile range, 34-74). Forty-nine percent of the patients would accept a1 in 100 risk of drug-induced death if the corresponding improvements in the Living With Heart Failure score were 20 (interquartile range, 10-25). In contrast, 40% were willing to accept a risk of drug-induced death equal to or greater than 5 in 100 for significantly (P < .001) smaller score improvements of 5 (interquartile range, 5-10). Living With Heart Failure scores that increase with perceived limitations secondary to heart failure tended to be higher, although not significantly (P = .22), in the subgroup that accepted greater risk of drug-induced death: 45 (interquartile range, 34-73) versus 58 (interquartile range, 42-77). A score improvement of 5, which has been commonly observed in clinical trials, would be sufficient reason for 72% of patients to take a medication that did not have side effects or significant costs. A 5-point improvement was less acceptable when costs or risks were associated with therapy: 52% would pay

In Vivo Human Brachial Artery Elastic Mechanics Effects of Smooth Muscle Relaxation

60 per month and 38% would risk drug-induced death. These data suggest that many patients with heart failure would accept some risk of drug-induced death for improved quality of life. A 5-point improvement in the Living With Heart Failure score may be clinically significant depending on costs and adverse effects. The Living With Heart Failure questionnaire can be used to help patients evaluate the benefits versus risks of medical interventions.

Pulmonary and peripheral vascular factors are important determinants of peak exercise oxygen uptake in patients with heart failure

BACKGROUNDnThe effects of smooth muscle relaxation on arterial wall mechanics are controversial. We used a new, in vivo, noninvasive technique to measure brachial artery wall mechanics under baseline conditions and following smooth muscle relaxation with nitroglycerin (NTG).nnnMETHODS AND RESULTSnEight healthy, normal subjects (6 male, 2 female; age 30+/-3.1 years) participated in the study. The nondominant brachial artery was imaged through a water-filled blood pressure cuff using an external ultrasound wall-tracking system at baseline and following 0.4 mg sublingual NTG. Simultaneous radial artery pressure waveforms were recorded by tonometry. Transmural pressure (TP) was reduced by increasing water pressure in the cuff. Brachial artery area, unstressed area, compliance, stress, strain, incremental elastic modulus (Einc), and pulse wave velocity (PWV) were measured over a TP range from 0 to 100 mm Hg. Baseline area versus TP curves generated 30 minutes apart were not significantly different. NTG significantly shifted area versus TP (P<0.0001) and compliance versus TP (P<0.001) curves upward, whereas the Einc versus TP (P<0.05) and PWV versus TP (P<0. 01) curves were shifted downward. NTG also significantly shifted stress versus strain (P<0.01) and Einc versus strain (P<0.01) curves to the right.nnnCONCLUSIONSnWe conclude that brachial artery elastic mechanics can be reproducibly measured over a wide range of TP and smooth muscle tone using a new noninvasive ultrasound technique. Smooth muscle relaxation with NTG increases isobaric compliance and decreases isobaric Einc and PWV in the human brachial artery.

Direct Effects of Smooth Muscle Relaxation and Contraction on In Vivo Human Brachial Artery Elastic Properties

OBJECTIVESnThis study was conducted to determine the relations among exercise capacity and pulmonary, peripheral vascular, cardiac and neurohormonal factors in patients with chronic heart failure.nnnBACKGROUNDnThe mechanisms of exercise intolerance in heart failure have not been fully clarified. Previous studies have indicated that peripheral factors such as regional blood flow may be more closely associated with exercise capacity than cardiac function, whereas the role of pulmonary function has received less attention.nnnMETHODSnFifty patients with stable heart failure underwent a comprehensive assessment that included a symptom-limited maximal cardiopulmonary exercise test, right heart catheterization, pulmonary function tests, neurohormonal levels, radionuclide ventriculography and forearm blood flow at rest and after 5 min of brachial artery occlusion. Univariate and stepwise linear regression analyses were used to relate peak exercise oxygen uptake to indexes of cardiac, peripheral vascular, pulmonary and neurohormonal factors both alone and in combination.nnnRESULTSnThe mean ejection fraction was 19% and peak oxygen uptake was 16.5 ml/min per kg in this group of patients. By univariate analysis, there were no significant correlations between peak oxygen uptake and rest cardiac output, pulmonary wedge pressure, ejection fraction and pulmonary or systemic vascular resistance. In contrast, even in the absence of arterial desaturation during exercise, the forced expiratory volume in 1 s (r = 0.55, p < 0.001), forced vital capacity (r = 0.46, p < 0.01) and diffusing capacity for carbon monoxide (r = 0.47, p < 0.01) were all significantly associated with peak oxygen uptake. Peak postocclusion forearm blood flow (r = 0.45, p < 0.01), the corresponding minimal forearm vascular resistance (r = -0.56; p < 0.01) and plasma norepinephrine level at rest (r = -0.45; p < 0.01) were also significantly correlated with peak oxygen uptake. By multivariate analysis, minimal forearm vascular resistance and forced expiratory volume in 1 s were shown to be independently related to peak oxygen uptake, with a combined R value of 0.71. Other two-variate models included forced expiratory volume and plasma norepinephrine (R = 0.67) and forced expiratory volume and diffusing capacity (R = 0.65). Because forced vital capacity was highly correlated with forced expiratory volume in 1 s, it could be combined with the same variables to yield similar R values. Addition of any third variable did not improve these correlations.nnnCONCLUSIONSnIn comparison with rest indexes of cardiac performance, measures of pulmonary function and peripheral vasodilator capacity were more closely associated with peak exercise oxygen uptake in patients with heart failure. Furthermore, the associations were independent of each other and together accounted for 50% of the variance in peak oxygen uptake. These data suggest that pulmonary and peripheral vascular adaptations may be important determinants of exercise intolerance in heart failure.

Smooth Muscle Relaxation: Effects on Arterial Compliance, Distensibility, Elastic Modulus, and Pulse Wave Velocity

The direct effect of smooth muscle relaxation on arterial elastic properties is controversial. Studies in animals show both a decrease and an increase in elastic modulus. In human subjects, the contribution of smooth muscle to arterial elastic mechanics has been limited by difficulty in separating the direct effects of a vasodilator drug on the arterial wall from the indirect effects due to reduced blood pressure. The purpose of the present study was to assess the direct contribution of vascular smooth muscle to brachial artery elastic mechanics in normal human subjects in vivo. We measured brachial artery compliance and incremental elastic modulus (Einc) in eight normal subjects (age, 22 to 51 years) by using intravascular ultrasound. A 3.5F 30-MHz intravascular ultrasound catheter was placed through a sheath into the brachial artery, and intraarterial pressure, cross-sectional area, and wall thickness were measured simultaneously under baseline conditions and after the administration of intra-arterial nitroglycerin (100 micrograms) and norepinephrine (1.2 micrograms). A pressurized cuff surrounding the brachial artery was inflated to reduce transmural brachial artery pressure. Using this technique, we were able to measure the following arterial characteristics for the first time in human subjects in vivo: (1) the effective unstressed arterial radius and (2) the pressure-area, stress-strain, and pressure-Einc relations over a wide pressure range (0 to 100 mm Hg). Intra-arterial nitroglycerin increased brachial artery area by 22% and intraarterial norepinephrine decreased brachial artery area by 17% at 100 mm Hg transmural pressure (P < .001 versus baseline).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of left ventricular assist devices on outcomes in patients undergoing heart transplantation

Compliance, distensibility, incremental elastic modulus (E(inc)), and pulse wave velocity are all terms used to describe the mechanical properties of arteries. Previous studies assessing the effects of smooth muscle relaxation on each of these parameters have produced conflicting results. Our laboratory has previously demonstrated that intrabrachial infusion of nitroglycerin in normal human subjects results in a large increase in brachial artery compliance without changing arterial wall stiffness as measured by E(inc). In the present study, the relationships among compliance, distensibility, E(inc), and pulse wave velocity under different levels of vascular tone are shown using data acquired by intravascular ultrasound as well as theoretical curves. We demonstrate that the effects of smooth muscle relaxation can be depicted as 2 separate steps: (1) a rightward shift to a new theoretical curve describing the relationship between 2 of the above elastic parameters that is solely due to changes in vessel geometry and (2) a shift along the new curve that is dependent on changes in wall stiffness.