Spencer H. Kubo

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.

Association of coronary artery disease in cardiac transplant recipients with cytomegalovirus infection

Coronary artery disease (CAD) is now the major limitation to long-term survival after cardiac transplantation. Its etiology remains unclear. The possible role of viral infection in the genesis of CAD stimulated the review of 102 patients transplanted since the introduction of triple drug immunosuppression (cyclosporine, azathioprine and prednisone) to assess the importance of posttransplant cytomegalovirus infection in the development of CAD in the cardiac graft. CAD occurred in 16 patients (16%). Recipient age and sex, donor age, pretransplant diagnosis, frequency of acute rejection episodes, HLA mismatch, cytomegalovirus infection, incidence of posttransplant systemic hypertension and diabetes mellitus, and mean triglyceride, cholesterol and cyclosporine levels were analyzed to assess their influence on the development of CAD. Only the occurrence of cytomegalovirus infection was found to be a significant factor (p = 0.007): infection occurred in 62% of patients with CAD and in only 25% of those without. These data support the existence of an association between cytomegalovirus infection and CAD after cardiac transplant. It is possible that the virus contributes to the initial injury to the coronary endothelium.

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

BACKGROUND Patients 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. METHODS AND RESULTS Fifteen 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). CONCLUSIONS Supplemental 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

BACKGROUND The contributions of collagen, elastin, and smooth muscle to arterial mechanical properties in the in vivo human artery are not known. METHODS AND RESULTS We 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. CONCLUSIONS This 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.

Coronary angioplasty, atherectomy and bypass surgery in cardiac transplant recipients

OBJECTIVES This study sought to analyze the outcomes of revascularization procedures in the treatment of allograft coronary disease. BACKGROUND Allograft vasculopathy is the main factor limiting survival of heart transplant recipients. Because no medical therapy prevents allograft atherosclerosis, and retransplantation is associated with suboptimal allograft survival, palliative coronary revascularization has been attempted. METHODS Thirteen medical centers retrospectively analyzed their complete experience with percutaneous transluminal coronary angioplasty, directional coronary atherectomy and coronary bypass graft surgery in allograft coronary disease. RESULTS Sixty-six patients underwent coronary angioplasty. Angiographic success (< or = 50% residual stenosis) occurred in 153 (94%) of 162 lesions. Forty patients (61%) are alive without retransplantation at 19 +/- 14 (mean +/- SD) months after angioplasty. The consequences of failed revascularization were severe. Two patients sustained periprocedural myocardial infarction and died. Angiographic restenosis occurred in 42 (55%) of 76 lesions at 8 +/- 5 months after angioplasty. Angiographic distal arteriopathy adversely affected allograft survival. Eleven patients underwent directional coronary atherectomy. Angiographic success occurred in 9 (82%) of 11 lesions. Two periprocedural deaths occurred. Nine patients are alive without transplantation at 7 +/- 4 months after atherectomy. Bypass graft surgery was performed in 12 patients. Four patients died perioperatively. Seven patients are alive without retransplantation at 9 +/- 7 months after operation. CONCLUSIONS Coronary revascularization may be an effective palliative therapy in suitable cardiac transplant recipients. Angioplasty has an acceptable survival in patients without angiographic distal arteriopathy. Because few patients underwent atherectomy and coronary bypass surgery, assessment of these procedures is limited. Angiographic distal arteriopathy is associated with decreased allograft survival in patients requiring revascularization.

Beneficial effects of pimobendan on exercise tolerance and quality of life in patients with heart failure. Results of a multicenter trial. The Pimobendan Multicenter Research Group.

BACKGROUND This multicenter trial was conducted to determine the efficacy and safety of pimobendan, an inotropic agent with calcium-sensitizing properties and activity as a phosphodiesterase inhibitor, in patients with heart failure. METHODS AND RESULTS One hundred ninety-eight ambulatory patients with symptoms of moderate to severe heart failure despite therapy with digitalis and diuretics with or without a single vasodilator were randomly assigned to receive either placebo (n = 49) or pimobendan (n = 149) in a double-blind fashion for 12 weeks. A dose range of pimobendan was used including 2.5 (n = 49), 5 (n = 51), or 10 mg/day (n = 49). One hundred fifty-eight (80%) patients were taking a converting enzyme inhibitor (CEI) and 28 (14%) patients were taking a non-CEI vasodilator. At end point, the 5-mg dose of pimobendan significantly increase exercise duration compared with placebo (121.6 +/- 19.1 seconds, p less than 0.001), whereas the 10-mg dose produced an increase of borderline significance (81.1 +/- 19.5 seconds, p = 0.05). Peak VO2 was significantly increased by 2.23 +/- 0.58 ml/kg/min in the 5-mg group (p less than 0.01 versus placebo). Furthermore, quality of life measured with the Minnesota Living With Heart Failure Questionnaire improved by 8.5 +/- 2.3 units in the 5-mg group compared with 1.3 +/- 2.2 units in the placebo group (p less than 0.01). There were a total of 23 all-cause hospitalizations in the placebo group, which was significantly greater compared with 33 in the three groups treated with pimobendan (p less than 0.01). There were no significant differences between the placebo and pimobendan groups with respect to changes in ejection fraction and plasma norepinephrine measured at baseline and at the completion of the 12-week study, proarrhythmic effect, or the number of patients with a significant adjustment in background therapy. Eleven patients died, including three (6%) on placebo and eight (5%) on pimobendan (p = NS). Among all adverse events, headache tended to be more common in the pimobendan groups compared with placebo, with the incidence increasing with dose (p less than 0.05). CONCLUSIONS These data demonstrate that pimobendan significantly increases exercise duration, peak VO2, and quality of life in patients with heart failure. Pimobendan appears to be useful adjunctive therapy when added to digitalis, diuretics, and vasodilators.

Plasma endothelin concentrations in humans with end-stage heart failure and after heart transplantation

OBJECTIVES AND BACKGROUND Endothelin is an endothelium-derived vasoconstrictor peptide that increases systemic and renal vascular resistance at pathophysiologic concentrations. Recent studies have demonstrated its presence in the circulation and its elevation in animals with congestive heart failure, suggesting that endothelin may contribute to the vasoconstrictive state of heart failure. The current study was designed with two objectives: 1) to demonstrate the elevation of circulating endothelin in patients with heart failure, and 2) to determine the short- and long-term response of endothelin levels after heart transplantation. METHODS Plasma endothelin concentrations were measured in two patient groups. Group 1 included 24 patients with end-stage heart failure who were studied during evaluation for potential heart transplantation. Group 2 included 12 patients from Group 1 who had had heart transplantation. Plasma endothelin concentrations were measured before and on days 1, 3 and 7 after heart transplantation. Eight of these patients also had levels measured 3 to 12 months later. RESULTS Plasma endothelin concentrations were significantly elevated in patients with heart failure compared with those in an age-matched control group (11.7 +/- 1.1 vs. 6.8 +/- 0.3 pg/ml). In response to heart transplantation, plasma endothelin concentrations increased further and were sustained during a long-term follow-up. These later changes were associated with a significant increase in arterial pressure and serum creatinine. CONCLUSIONS This study demonstrates that endothelin concentrations are increased in patients with heart failure and increase further after heart transplantation. It suggests a possible role for endothelin in the cardiovascular and renal adaptive responses to human heart transplantation.

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

OBJECTIVES This study was conducted to determine the relations among exercise capacity and pulmonary, peripheral vascular, cardiac and neurohormonal factors in patients with chronic heart failure. BACKGROUND The 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. METHODS Fifty 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. RESULTS The 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. CONCLUSIONS In 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.

Mechanisms of Recurrent Functional Mitral Regurgitation After Mitral Valve Repair in Nonischemic Dilated Cardiomyopathy Importance of Distal Anterior Leaflet Tethering

Background— Recurrent functional mitral regurgitation (MR) has been reported after mitral valve repair with annuloplasty in patients with dilated cardiomyopathy, but the mechanism is not understood completely. The authors sought to identify abnormalities of the mitral valve and left ventricle that are associated with recurrent MR after mitral annuloplasty. Method and Results— In 104 patients with idiopathic dilated cardiomyopathy who underwent annuloplasty for functional MR, basal mitral anterior leaflet angle, distal mitral anterior leaflet angle (ALAtip), posterior leaflet angle, coaptation depth, tenting area, mitral annular dimensions, left ventricular volumes, and MR severity were quantified by echocardiography before surgery and at 6-month intervals after it. Compared with patients without MR recurrence (n=79), patients with recurrent MR (defined as ≥2+) (n=25) had greater ALAtip (P<0.001) and basal mitral anterior leaflet angle (P<0.001), greater coaptation depth and tenting area (P<0.001), larger left ventricular volumes (P<0.001), and worse left ventricular ejection fraction (P<0.05) but similar mitral annular dimensions and postoperative exaggeration in posterior leaflet angle. Multivariable analysis identified postoperative ALAtip as the major determinant of postoperative MR. Receiver operator characteristic curves identified preoperative ALAtip as the best predictor of MR recurrence (area under curve, 0.98). For ALAtip >25°, the sensitivity, specificity, and positive and negative predictive values in predicting recurrent MR were 88%, 94%, 82%, and 93%, respectively. Three distinct patterns of anterior leaflet tethering (minimal, basal, and distal) with an increasing risk of recurrent MR were identified. Conclusions— Posterior leaflet tethering is invariable after mitral annuloplasty, rendering postoperative mitral competence highly dependent on distal anterior leaflet mobility.

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

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)