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.

Effect of angiotensin II on noradrenaline release in the human forearm.

OBJECTIVE: The aim was to test the hypothesis that in normal humans angiotensin II would stimulate local release of noradrenaline under basal conditions or during a sympathetic stimulus provided by lower body negative pressure (LBNP). METHODS: Nine healthy volunteers received intra-arterial infusions of angiotensin II, 5 ng.min-1, into the non-dominant forearm. Forearm blood flow (strain gauge plethysmography) and regional noradrenaline spillover (using the tracer methodology of Esler) were measured during angiotensin II alone, LBNP alone, and LBNP plus angiotensin II. RESULTS: Angiotensin II and LBNP decreased forearm blood flow comparably: from 3.1(SD 1.5) to 2.4 (0.9) ml.100 g-1.min-1 during angiotensin II, p < 0.05; and from 3.3(1.5) to 2.5(1.0) ml.100 g-1.min-1 during LBNP, p < 0.05 (p = NS, A-II v LBNP). Angiotensin II had no effect on forearm venous noradrenaline or regional noradrenaline spillover. LBNP increased venous noradrenaline outflow from the forearm, from 1.6(0.40) to 2.1(0.6) nmol.min-1 (p < 0.05), while regional noradrenaline spillover tended to increase, rising from 1.5(0.8) to 2.0(1.0) nmol.100 ml-1.min-1. Angiotensin II did not enhance forearm blood flow or noradrenaline responses to LBNP. CONCLUSIONS: In the human forearm, mildly vasoconstrictor infusions of angiotensin II do not increase local release of noradrenaline, either alone or during mild LBNP. At least under these conditions, angiotensin II would not appear to be a potent influence on local sympathetic activity.

Local forearm vasodilation with intra-arterial administration of enalaprilat in humans.

To determine whether converting enzyme inhibitors could produce peripheral vasodilation through a local mechanism, we infused enalaprilat, 2 micrograms/min/dl forearm volume (FAV), into the brachial artery of normal subjects and measured changes in forearm blood flow (FBF) with strain-gauge plethysmography. Enalaprilat produced a peak increase in FBF of 2.82 +/- 0.54 ml/min/dl FAV (78% increase) at 1 minute (p less than 0.01 versus vehicle) and an increase of 1.11 +/- 0.28 ml/min/dl FAV at 4 minutes (p less than 0.05 versus vehicle). Blood pressure and plasma renin activity measured at the completion of infusion did not change. Intravenous enalaprilat infusion at the same dose in seven additional normal subjects did not increase FBF. Pretreatment of seven subjects with 75 mg oral indomethacin attenuated the peak response to enalaprilat (4.13 +/- 1.52 versus 0.58 +/- 0.32 ml/min/dl; p less than 0.05). We conclude that intra-arterial enalaprilat produces an increase in FBF in normal subjects. This peripheral vasodilation is caused by a local effect independent of circulating renin-angiotensin system inhibition. This response is attenuated by indomethacin, suggesting that prostaglandins contribute to the vasodilator response.

Abnormal desmopressin-induced forearm vasodilatation in patients with heart failure: dependence on nitric oxide synthase activity.

BACKGROUND: Peripheral vasodilatation in response to muscarinic agonists has been shown to be subnormal during heart failure. However, a more recent study suggested that the abnormal muscarinic-induced vasodilatation was not due to abnormal nitric oxide synthase activity. This study was designed to show that nitric oxide synthase contributes to desmopressin-induced forearm vasodilatation and to determine whether vasodilatation mediated by nitric oxide synthase is abnormal during heart failure. METHODS: Desmopressin (10, 50, and 100 ng/min) was infused into the brachial artery of 10 healthy subjects and eight patients with heart failure, and forearm blood flow was measured by venous occlusion plethsymography. Desmopressin responses were then recorded during inhibition of nitric oxide synthase with L-monomethylarginine or after aspirin. RESULTS: In healthy subjects, desmopressin caused a significant (p < 0.001) dose-dependent increase in forearm blood flow of 0.9 +/- 0.6, 4.0 +/- 2.6, and 7.9 +/- 2.6 ml/min/dl, respectively. Desmopressin responses in heart failure of 0.8 +/- 0.6, 1.7 +/- 1.4, and 3.1 +/- 1.0 ml/min/dl were significantly less (p < 0.001) than normal. L-Monomethylarginine reduced desmopressin responses in normal subjects (p < 0.01), and this inhibitory effect was significantly (p < 0.01) greater than in patients with heart failure. Aspirin did not affect desmopressin-induced vasodilatation. CONCLUSION: Nitric oxide synthase contributes to desmopressin-induced forearm vasodilatation. In response to desmopressin, patients with heart failure have subnormal vasodilatation mediated through nitric oxide synthase.

Effects of norepinephrine on endothelium-dependent vasodilation of forearm resistance vessels.

BACKGROUND: Endothelium-dependent dilatation of forearm resistance vessels is attenuated in patients with heart failure. Activation of the sympathetic nervous system could cause this abnormality by way of vasoconstriction and chemical inactivation of nitric oxide. METHODS AND RESULTS: The effects of concurrent intra-arterial norepinephrine infusions (25, 50 and 100 ng/min) on forearm blood flow responses to equipotent doses of an endothelium-dependent vasodilator, methacholine (0.3 and 1.5 micrograms/min), and an endothelium-independent vasodilator, nitroprusside (1 and 5 micrograms/min), were studied in 12 normal subjects. Norepinephrine infusions increased the mean plasma norepinephrine from 255 pg/ml at baseline to 460, 629, and 1089 pg/ml, respectively. Basal forearm blood flow was reduced from 2.9 to 1.6 ml/min/100 ml of forearm volume at the highest dose (p < 0.01). The average response to the lowest dose of methacholine (4.5 ml/min/100 ml) was not significantly reduced by concurrent infusion of norepinephrine (4.4, 4.2, and 4.3 ml/min/100 ml, respectively), whereas the response to the higher dose of methacholine (8.9 ml/min/100 ml) tended to be lower (7.2, 6.7, and 7.4 ml/min/100 ml, respectively) but did not attain statistical significance. Methacholine induced vasodilation was not more sensitive to norepinephrine than nitroprusside responses. Lower body negative pressure (-20 mm Hg) also significantly reduced baseline forearm flow and increased plasma norepinephrine but did not effect either methacholine or nitroprusside induced vasodilation. CONCLUSION: Sympathetic stimulation induced by infusion of norepinephrine or lower body negative pressure is not a potent antagonist to endothelium-dependent vasodilation of the forearm vasculature. These data suggest that sympathetic activation does not completely explain the abnormal endothelium-dependent vasodilation seen in patients with heart failure.

Drug kinetics in burn patients.

Thermal trauma reportedly induces a spectrum of intricate physiological alterations that often involve cardiovascular, hepatic, renal, and dermatological functions. Individual responses to varying degrees of burn and secondary complications may produce unpredictable changes in the pharmacokinetics of drugs. A number of reports describing the disposition of aminoglycoside antibiotics in burn patients have demonstrated clinially significant alterations in the pharmacokinetics of this class of drugs. Several authors have found significantly reduced serum half-lives in burn patients as compared with average values in non-burned subjects. Increased aminoglycoside clearances in some burn patients have been attributed to increased glomerular filtration secondary to elevated cardiac output, prostaglandin formation, and glucagon secretion: others attribute this to enhanced elimination of drug across damaged skin tissue. Monitoring of serum aminoglycoside concentrations is recommended because of the low therapeutic index of these agents and the variable course of renal function following burn injury. Topical application of mafenide acetate, providone iodine, and gentamicin to burn wounds has resulted in varying amounts of systemic absorption. Various systemic toxicities have been attributed to these topical therapies, especially in patients with compromised renal function. The extent and area of the burn, degree of hydration, and the amount of drug applied are factors influencing transcutaneous absorption. Sulphonamide derivatives are excreted in the urine subsequent to the application of silver sulphadiazine cream, but silver ions appear to be localised on surface tissue and are thus unavailable to the subeschar space. Additional studies are needed to characterise the pharmacokinetics of medications commonly administered to burn patients. Unfortunately, the marked variability and fluctuations in pathophysiological status following burn trauma often confound the interpretation of such kinetic investigations.

Prognosis of congestive heart failure and predictors of mortality.

The interaction of physiologic variables that appear to be predictive of prognosis in patients with severe congestive heart failure was examined in a series of 139 patients referred to a heart failure service. Left ventricular ejection fraction, peak oxygen consumption during a progressive maximal exercise test and resting plasma norepinephrine concentration were identified as the strongest univariate predictors of prognosis. Examination of their interaction was accomplished by stratifying each variable into quartiles and then pooling quartiles for bivariate analysis. The data demonstrate that ejection fraction has the most profound effect on survival calculated from maximal oxygen consumption and norepinephrine concentration, but that each of the variables provides additional independent prognostic information when added to survival estimated from any of the other variables. Therefore, ventricular function, exercise tolerance and sympathetic nervous system activation appear to provide independent insight into the prognosis of patients with 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.

Impaired forearm vasodilation to hyperosmolal stimuli in patients with congestive heart failure secondary to idiopathic dilated cardiomyopathy or to ischemic cardiomyopathy.

Patients with congestive heart failure (CHF) have impaired peripheral vasodilation during exercise. Hyperosmolality is one local stimulus that produces vasodilation during exercise in normal subjects. This study addressed the hypothesis that vasodilation to hyperosmolal stimuli is impaired in patients with CHF. Forearm blood flow responses to intrabrachial artery infusions of isoosmolar (280 mosm/kg) and hyperosmolal (480 and 660 mosm/kg) solutions of saline and glucose were compared in 9 patients with CHF and 13 normal subjects. Forearm blood flow was measured by strain gauge plethysmography. In the normal subjects, hyperosmolal infusions of 480 and 660 mosm/kg increased forearm blood flow by 3.12 +/- 0.40 and 6.80 +/- 0.67 ml/min/100 ml forearm volume, respectively (both p < 0.001 compared with isoosmolal infusions). In contrast, in the patients with CHF, these infusions increased forearm blood flow by 2.19 +/- 0.44 and 4.06 +/- 0.92 ml/min/100 ml forearm volume (p < 0.05 normal vs CHF). The impaired forearm blood flow responses in heart failure occurred despite significantly greater (p < 0.05, normal vs CHF) increases in venous osmolality (17.3 +/- 6.5 vs 9.6 +/- 1.3 mosm/kg for the 660 mosm/kg infusion). There were no differences between groups in forearm venous hematocrit, calcium, and sodium or potassium changes during hyperosmolal infusions. It is concluded that peripheral vasodilation to hyperosmolal stimuli is impaired in patients with CHF.

Comparison of tilt angles and provocative agents (edrophonium and isoproterenol) to improve head-upright tilt-table testing.

Patients with syncope underwent head-up tilt testing at 60 degrees and 80 degrees followed by edrophonium or isoproterenol challenge when indicated. The 80 degrees tilt protocol and edrophonium provocation were found to be as effective or more effective in eliciting neurally mediated syncope in susceptible patients.

Lack of contribution of nitric oxide to basal vasomotor tone in heart failure.

Patients with heart failure have reduced forearm vasodilator responses when endothelial cell nitric oxide production is stimulated by muscarinic agonists. The aim of this study was to determine if activity of the nitric oxide pathway was also abnormal under basal conditions. Forearm blood flow (FBF) was measured with strain-gauge plethysmography in response to the intraarterial infusion of a subsystemic dose range of L-N-monomethylarginine (L-NMMA), a competitive inhibitor of nitric oxide synthase. In 18 normal subjects, the baseline FBF of 3.6 +/- 1.4 was decreased by 0.3 +/- 0.5 (p < 0.01), 1.0 +/- 0.7 (p < 0.01), 1.4 +/- 0.9 (p < 0.01), and 1.3 +/- 1.3 (p < 0.01) ml/min/100 ml forearm volume during infusions of 1, 4, 8, and 16 mumol/min of L-NMMA, respectively. In 10 patients with heart failure, the baseline FBF of 2.6 +/- 0.9 was decreased by 0.4 +/- 0.5 (p < 0.05), 0.4 +/- 0.5 (p < 0.05), 0.9 +/- 0.8 (p < 0.01), and 0.9 +/- 0.7 (p < 0.01) ml/min/100 ml forearm volume with the 4 doses of L-NMMA, respectively. There was no difference in the L-NMMA response between the 2 groups in terms of absolute flow, percent change, or with analysis of covariance to adjust for different baselines. The stable end products of nitric oxide (nitrite and nitrate) were measured in the forearm venous effluent. Nitrite and nitrate levels at baseline were not reduced in patients with heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of cardiac transplantation on endothelium-dependent dilation of the peripheral vasculature in congestive heart failure.

Patients with congestive heart failure demonstrate attenuated endothelium-dependent vasodilation of the peripheral vasculature, but there are no data regarding the effect of therapies on this abnormality or whether this abnormality is reversible. This study was performed to address the hypothesis that abnormalities in endothelium-dependent vasodilation in heart failure are improved by heart transplantation. Forearm blood flow responses to the intraarterial administration of a dose range of methacholine, an endothelium-dependent vasodilator, and nitroprusside, an endothelium-independent vasodilator, were examined in 2 separate protocols. In protocol 1, forearm blood flow responses to methacholine in 14 heart transplant recipients were 5.02 +/- 3.11, 11.55 +/- 7.20 and 11.61 +/- 10.24 ml/min/100 ml forearm volume. These responses were significantly greater than those in 10 patients with heart failure (2.23 +/- 1.22, 4.60 +/- 3.43 and 6.70 +/- 4.91 ml/min/100 ml forearm volume; p < 0.05). In contrast, the responses to nitroprusside were nearly identical in the 2 groups. In protocol 2, six patients were studied before and 4 months (range 1 to 11) after transplantation. Methacholine responses before transplantation were 2.5 +/- 1.3, 5.2 +/- 1.5 and 7.3 +/- 1.5 ml/min/100 ml forearm volume and were significantly improved after transplantation to 5.7 +/- 1.2, 12.1 +/- 3.0 and 14.2 +/- 2.2 ml/min/100 ml forearm volume (p < 0.05). Peak reactive hyperemia responses increased significantly from 19.0 +/- 3.7 to 44.8 +/- 6.4 ml/min/100 ml forearm volume (p < 0.01) after transplantation. These data demonstrate that heart transplantation was associated with a significant improvement in the forearm blood flow responses to methacholine.(ABSTRACT TRUNCATED AT 250 WORDS)

Health status of heart transplant recipients versus patients awaiting heart transplantation: a preliminary evaluation of the SF-36 questionnaire.

Measures of the effects of health care on patients' lives are being requested to evaluate heart transplantation programs. A relatively short, 36-item, questionnaire (SF-36) designed to measure health status is being evaluated as an outcome measure for a variety of conditions. The SF-36 was sent to all adults awaiting heart transplantation (n = 48) and heart transplant recipients (n = 177) at the University of Minnesota as a pilot study of the SF-36 applied to heart transplantation. Response rates were 88% and 81%, respectively. Heart transplant recipients had significantly (p < 0.0001) better scores for general health perceptions (70 +/- 21 versus 33 +/- 21), vitality (62 +/- 19 versus 39 +/- 2), physical function (71 +/- 22 versus 36 +/- 24), ability to perform roles without physical limitations (62 +/- 41 versus 27 +/- 35), and social function (85 +/- 18 versus 63 +/- 31) compared with patients awaiting heart transplantation. Mental function and ability to perform roles without emotional problems were good in both groups and not significantly different. Mean SF-36 scores for the heart transplant recipients were uniformly not as high as scores for a historical group with only minor medical problems. These preliminary data suggest that the SF-36 is sensitive to the effects of heart transplantation. Additional studies of the SF-36 as an outcome measure for heart transplantation are warranted and should include methods to control for extraneous variability and to provide unbiased data collection.

Retrospective risk analysis for early heart-related death after cardiomyoplasty. The Worldwide Cardiomyoplasty Group.

BACKGROUND: Dynamic cardiomyoplasty is an evolving treatment for heart failure that uses an electrically stimulated latissimus dorsi muscle wrapped around the heart to improve cardiac function. Preoperative patient characteristics and deaths after cardiomyoplasty have been recorded during the past 5 years in a cumulative database representing worldwide experience of 42 medical centers. METHODS: Statistical models of hazards (monthly death rates) were used to identify risk factors for transiently increased risk of cardiovascular mortality within 2 months after cardiomyoplasty. RESULTS: Actuarial survival (n = 261) was 88%, 80%, and 76% at 1, 3, and 6 months after cardiomyoplasty, respectively. The peak hazard of 6% dying per month occurred during the first month after the surgical procedure. Lower ejection fraction, increased number of major coronary arteries with > or = 70% stenotic lesions, and lower chronotropic responses during exercise were independent risk factors for the transient increase in early cardiovascular mortality. Early risk of cardiovascular mortality was significantly reduced as centers gained experience with more than 3 patients. CONCLUSION: Early survival after cardiomyoplasty has improved with experience and might be reduced further by preoperative assessments that identify patients at highest risk.

Effect of ACE inhibitors on the quality of life of patients with heart failure.

The physiologic effects of ACE inhibitors often result in symptomatic relief in patients with heart failure and prevention of episodes of decompensated heart failure and ischemic events in some patients. It is important to determine if these effects, in conjunction with all other aspects of ACE inhibitor treatment, favorably alter quality of life as judged by the patients. Questionnaires that allow patients to rate the effects of heart failure and treatments on their lives have been used in some controlled clinical trials. The available data suggest that symptomatic patients have a limited quality of life than can be improved by ACE inhibitors. In addition, it seems reasonable to assume that avoidance of episodes of decompensated heart failure and ischemic events would have some yet-to-be-defined effect on maintenance of patients' quality of life. However, the proportion of patients who experience these preventive effects during a few years of follow-up may be too small to document an effect on quality of life in the overall population with mild heart failure or asymptomatic left ventricular dysfunction. The high mortality rate associated with heart failure makes it difficult to study quality of life over prolonged periods of time. One investigation [18] has suggested that quality of life progressively deteriorates in survivors over 2 to 4 years despite administration of ACE inhibitors. This finding is consistent with the natural history of heart failure, although there are insufficient placebo-controlled data to determine whether ACE inhibitors can delay the long-term progressive decline in quality of life.(ABSTRACT TRUNCATED AT 250 WORDS)

Impact of mailing information about nonurgent care on emergency department visits by Medicaid beneficiaries enrolled in managed care.

CONTEXT: Emergency department services may be used more appropriately if laypeople's knowledge of managing minor medical problems could be enhanced, especially since Medicaid applies a "prudent layperson" standard for providing access to emergency care. OBJECTIVE: To investigate the effect of mailing a booklet, First Look, that informed Medicaid beneficiaries about care of common nonurgent conditions and encouraged use of alternatives to emergency care including care by office-based physicians, telephonic nursing assistance, and self-care. STUDY DESIGN: A randomized, parallel group study. PATIENTS AND METHODS: Administrative data from 2 health plans serving urban Medicaid populations were used to identify households with a history of emergency department utilization (n = 3101 and n = 3822). Within each health plan, households were randomly assigned to receive First Look. The number of emergency department visits during 6.5 months of follow-up was the primary study endpoint. RESULTS: Compared with controls, 1% fewer members of households that were mailed First Look visited an emergency department in each health plan (23% versus 24% in Plan A; 27% versus 28% in Plan B). The 95% confidence intervals on the observed differences were -3% to 1% and -4% to 1% in Plans A and B, respectively. The proportion of emergency department visits for conditions discussed in First Look was not significantly reduced in households that were mailed the booklet (62% versus 60% in Plan A and 51% versus 48% in Plan B). CONCLUSION: Mailing First Look to Medicaid beneficiaries did not have a significant effect on use of emergency departments. Medicaid programs need to evaluate other, perhaps more multifaceted, interventions to promote appropriate use of emergency departments.