Feasibility of Patient-Reported Outcomes Measurement Information System (PROMIS®) computerized adaptive tests in systemic lupus erythematosus outpatients.

Objective The aims of this study were to assess the feasibility of administering Patient-Reported Outcomes Measurement Information System (PROMIS®) computerized adaptive tests (CATs) to outpatients with systemic lupus erythematosus (SLE). Methods Adults with SLE were recruited during routine outpatient visits at an SLE Center of Excellence. Participants completed 14 PROMIS CATs and provided feedback on their experience. Differences in socio-demographic and clinical characteristics between participants and non-participants were evaluated. Results A total of 204 (86%) of 238 socioeconomically and racially diverse SLE patients completed PROMIS CATs. There were no significant differences between participants and non-participants. Time constraints were cited most frequently as reasons for non-participation. More than 75% of individuals submitted positive comments, including approval of the content and format of questions, and the survey's promotion of self-reflection. A minority of participants cited challenges, most often related to question phrasing (8%) and technical difficulties (6%). Conclusions The administration of PROMIS CATs was feasible and positively received in a diverse cohort of SLE outpatients. Neither socio-demographic nor disease characteristics were significant barriers to successful completion of PROMIS CATs. PROMIS CATs have great potential for efficiently measuring important patient-centered outcomes in routine clinical care of a wide range of SLE patients.

Assisted reproductive technology in SLE and APS.

Assisted reproductive technology (ART) procedures, which include in vitro fertilization (IVF), are performed frequently and may be considered for patients with systemic lupus erythematosus and antiphospholipid syndrome. These procedures do not appear to increase the risk of disease flare or thrombosis in these patients. In addition, the presence of antiphospholipid antibodies (aPL) does not independently predict the outcome of IVF pregnancies. As with pregnancies that are achieved naturally, candidates for ART should have quiescent disease for at least 6 months prior to attempting pregnancy for the best possible outcome for mother and child.

The efficacy and safety of bazedoxifene in postmenopausal women by baseline kidney function status.

INTRODUCTION: Two global, double-blind, placebo- and active-controlled, phase-3 studies (2-year prevention (n = 1583) and 3-year treatment (n = 7492)) have shown that bazedoxifene (BZA) is safe and effective for prevention and treatment of postmenopausal osteoporosis. OBJECTIVE: To evaluate the efficacy/safety of BZA according to baseline kidney function. METHODS: Data for the BZA 20- and 40-mg and placebo groups from both studies were integrated for assessment of bone turnover markers (BTMs), bone mineral density (BMD), and fracture incidence (treatment study only). Safety was assessed using integrated data for the BZA, placebo, and raloxifene 60-mg groups from both studies. Baseline glomerular filtration rate (GFR) was estimated by the Modification of Diet in Renal Disease Study equation; among subjects with baseline GFR, renal function categories were defined by GFR (ml/min per 1.73 m(2)): normal (GFR ≥ 90; n = 1982), mild impairment (60 ≤ GFR < 90; n = 6032), or moderate/severe impairment (GFR < 60; n = 723). RESULTS: Demographics were similar across treatment groups and within GFR subgroups. Across GFR subgroups, BZA 20 and 40 mg reduced BTM levels and improved lumbar spine and total hip BMD versus placebo. At month 24, there were significant treatment-by-GFR (p = 0.003) and treatment-by-serum creatinine (p = 0.034) interactions for the increase in lumbar spine BMD versus placebo. Fracture incidence was lower with BZA than placebo across all GFR categories, with no treatment-by-GFR interaction. There were no significant differences among treatment groups in incidences of overall, serious, or renal-related adverse events across GFR subgroups. CONCLUSIONS: Mild to moderate kidney impairment did not affect the efficacy and safety of BZA in postmenopausal women.

Safety and tolerability of bazedoxifene in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled phase 3 trial.

UNLABELLED: Findings from this 5-year phase 3 study of postmenopausal women with osteoporosis showed that bazedoxifene was associated with an overall favorable safety and tolerability profile, with no evidence of endometrial or breast stimulation. Overall, the results at 5 years were consistent with those seen at 3 years. INTRODUCTION: We report safety and tolerability findings from a 5-year randomized, double-blind, phase 3 study of bazedoxifene in postmenopausal women with osteoporosis. METHODS: In the core study, healthy postmenopausal women with osteoporosis (N=7,492; mean age, 66.4 years) were randomized to daily doses of bazedoxifene 20 or 40 mg, raloxifene 60 mg, or placebo for 3 years. During the 2-year study extension, the raloxifene 60-mg treatment arm was discontinued after the 3-year database was finalized, and subjects receiving bazedoxifene 40 mg were transitioned in a blinded manner to bazedoxifene 20 mg (bazedoxifene 40-/20-mg group) after 4 years. Safety and tolerability data are reported for subjects in the bazedoxifene 20- and 40-/20-mg and placebo groups; efficacy findings are reported elsewhere. RESULTS: A total of 3,146 subjects in the bazedoxifene 20- and 40-mg and placebo groups were enrolled in the extension study (years 4 and 5). Overall, the 5-year incidence of adverse events (AEs), serious AEs, and discontinuations due to AEs were similar among groups. The incidence of hot flushes and leg cramps was higher with bazedoxifene compared with placebo. Venous thromboembolic events, primarily deep vein thrombosis, were more frequently reported in the bazedoxifene groups compared with the placebo group. Reports of cardiac disorders and cerebrovascular events were few and evenly distributed among groups. Bazedoxifene showed a neutral effect on the breast and endometrium. CONCLUSION: Bazedoxifene was associated with an overall favorable safety and tolerability profile in postmenopausal women with osteoporosis over 5 years of therapy, consistent with findings at 3 years.

Effects of high-dose lisinopril-isosorbide dinitrate on severe mitral regurgitation and heart failure remodeling.

In long-term, 1-year follow-up, uptitration of angiotensin-converting enzyme inhibitor and nitrate therapy over established doses can further improve severe functional mitral regurgitation in patients with dilated cardiomyopathy due to a reversal of heart failure-related left ventricular remodeling. With marked left ventricular enlargement, >6.8 cm end-diastolic diameter, heart failure remodeling may be irreversible and resistant to further medical intervention.

Response of symptomatic myocardial ischemia in ischemic cardiomyopathy to intensive vasodilator therapy.

To determine the cardiovascular protective effects of angiotensin-converting enzyme inhibitors, we examined the response to intensive vasodilator therapy in patients with ischemic cardiomyopathy and ongoing angina pectoris. We found that for patients with ischemic cardiomyopathy and ongoing active angina, intensive vasodilator therapy with angiotensin-converting enzyme inhibition and nitrates improved not only heart failure-related symptoms, but also resulted in a significant improvement in symptomatic ischemia and ischemia-related morbid events.

Impact of medical therapy on pulmonary hypertension in patients with congestive heart failure awaiting cardiac transplantation.

Pulmonary artery (PA) hypertension in transplant recipients increases mortality from right heart failure following heart transplantation. We examined the impact of long-term medical therapy on the severity of PA hypertension in patients with end-stage congestive heart failure on a transplant waiting list. The initial and final, quarterly right heart catheterization data on 60 patients (50 men, aged 50 +/- 9 years, New York Heart Association class III to IV) awaiting heart transplantation were analyzed and the patients divided into 2 groups: group A, those with persistent elevated systolic PA pressures throughout the 10-month follow-up (n = 31 of 60), and group B, those who had any decrease in systolic PA pressure during that period (n = 29 of 60). Group A had no change in hemodynamics. Group B had a significant decrease( +/- SD) in right atrial (11 +/- 7 to 5 +/- 4 mm Hg), PA (57 +/- 11 to 37 +/- 11 mm Hg), and PA wedge (25 +/- 9 to 14 +/- 7 mm Hg) pressures, with increases in cardiac output (3.8 +/- 0.9 to 4.7 +/- 1.1 L/min) and ejection fraction (18 +/- 6% to 27 +/- 11%) (p < 0.05). The combined end point of transplant or death occurred in 28 of 31 patients (90%) in group A versus 14 of 29 (50%) in group B (p = 0.0004). Ischemic etiology was present in 71 % of patients in group A versus 68% with idiopathic dilated cardiomyopathy in group B (p = 0.003). The reversibility of PA hypertension rather than its initial severity is predictive of patient clinical outcome. Idiopathic, as opposed to ischemic, cardiomyopathy responds better to medical therapy.

Reinnervation of the transplanted human heart as evidenced from heart rate variability studies.

This study evaluated heart rate variability (HRV) after cardiac transplantation in humans in an attempt to test the hypothesis that cardiac reinnervation occurs in the post-transplant period. HRV was measured using 24-hour Holter recordings performed on 37 ambulant patients 1 to 122 months after cardiac transplantation. All patients were free of histologic rejection and were taking no medication likely to influence HRV. Time and frequency domain were analyzed and circadian rhythm of hourly average heart rate was calculated. HRV increased with time after the transplant. Compared with patients in the early post-transplant period, patients > 36 months after transplant had lower 24-hour heart rates (86 vs 93 beats/min), an increased average of all 5-minute SDs of NN intervals (17.6 vs 11.3), and higher low-and high-frequency power. Ten of the 27 patients > 3 years after transplantation had evidence of functional cardiac reinnervation. Compared with patients who had no reinnervation, these patients had increased circadian variability with lower nocturnal heart rates (76 vs 91 beats/min) and greater sympathetic activity during daytime (natural logarithm sympathetic power -0.36 vs -1.45) and nighttime (natural logarithm sympathetic power -0.43 vs -1.98). Despite lower nocturnal heart rates, there was no HRV evidence for an increase in parasympathetic activity. Thus, patients late after cardiac transplantation have HRV evidence for an increase in sympathetic control of the heart.

Early hospital discharge after percutaneous transluminal coronary angioplasty.

To determine the safety and efficacy of early hospital discharge after percutaneous transluminal coronary angioplasty (PTCA), 100 patients were studied prospectively. A telemetry observation unit was established to monitor patients having uncomplicated procedures. A total of 170 lesions were dilated, with a procedural success rate of 96% and a clinical success rate of 91%. There were no deaths or patients who required emergency bypass surgery. Four patients developed abrupt vessel closure in the catheterization laboratory. No major complications developed in the telemetry observation unit or after discharge. Patients with high-risk lesion morphology, based on the American College of Cardiology/American Heart Association Task Force guidelines, tended to have a lower success rate and more procedural complications. Coronary dissections were angiographically detected in 33 patients and stratified into 6 types. To reduce possible adverse sequelae, all patients with complex dissections were triaged in the catheterization laboratory to an in-patient monitored unit for additional management. Accordingly, 20 patients were admitted to an in-patient unit for extended observation. Excluding 4 patients with myocardial infarction, 75% (12 of 16) were discharged the next day. Initial experience with early discharge suggests that under proper conditions the procedure is safe and effective. Patients with complex coronary dissections who are at high risk for abrupt vessel closure can be promptly identified after dilatation and triaged to an appropriate monitoring area. Early discharge after PTCA offers more efficient use of hospital facilities and the opportunity to reduce hospital costs.

Acute reversibility of pulmonary hypertension predicts neither long-term hemodynamic response nor outcome in patients awaiting heart transplantation.

For transplant wait-list patients with end-stage congestive heart failure, reversibility of pulmonary hypertension tested with acute administration of vasodilators is a prerequisite to listing for transplantation. We have shown that the magnitude of the initial pulmonary vasodilatory response to nitroprusside predicts neither the extent of the long-term hemodynamic response nor the subsequent need for transplantation versus clinical improvement and removal from transplant consideration.

Undetected cardiogenic shock in patients with congestive heart failure presenting to the emergency department.

The purpose of this study was to examine the use of lactic acid levels and continuous central venous oxygen saturation (central venous oximetry) to stratify and treat patients with acutely decompensated end-stage chronic congestive heart failure (CHF) presenting to the emergency department. This prospective, convenience, non-outcome study was performed at an urban tertiary care hospital. Patients with end-stage CHF with an ejection fraction <30% presenting in decompensated CHF were eligible for the study. Patients were assessed using the Killip classification and New York Heart Association criteria. After lactic acid levels were obtained, patients were managed according to a standardized protocol guided by central venous oximetry. The patients were divided into high lactic acid (n = 22), low lactic acid (n = 5), and control groups (stable patients presenting to a cardiology clinic, n = 17) for comparison. There was no statistical difference in vital signs, or Killip and New York Heart Association criteria among the 3 groups. Central venous oxygen saturation was significantly lower in the high lactic acid group (32 +/- 12%) than in the normal lactic acid (51 +/- 13%) and control groups (60 +/- 6%) (p < 0.001). After treatment there was a significant decrease in lactic acid (-3.65 +/- 3.65 mM/L) and an increase in central venous oxygen saturation (32 +/- 13%) in the high lactic acid group compared with the normal lactic acid group (p < 0.001). A significant subset of patients with decompensated end-stage CHF present to the emergency department in occult shock and are clinically indistinguishable from patients with mildly decompensated CHF and stable CHF. Once identified, these patients require aggressive alternative management and disposition. Further study is necessary to identify whether this intervention impacts morbidity, mortality, and health care resource consumption.

Natural history and predictors of obesity after orthotopic heart transplantation.

Excessive weight gain resulting in obesity is commonly seen after orthotopic heart transplantation. Obesity increases the risk for the development of many significant health problems and the associated morbidity and mortality. The purpose of this study was to define the occurrence, magnitude, and predictors of overweight/obesity in this group. We followed 47 consecutive patients for 1 year after orthotopic heart transplantation for changes in weight. Weight gain from baseline was significant at months 2, 4, 6, 8, and 10, with significant weight increments between each measurement interval (p < 0.05). The mean weight gain was 10.1 kg +/- 1.6 (standard error [SE]) at 12 months. Based on entry body mass index patients were divided into two groups: group I, overweight/obese, body mass index more than 27 kg/m2 (n = 11); group II, not overweight/obese, body mass index 27 kg/m2 or less (n = 36). No significant difference was found in the amount of weight gained between the two groups (group I, 10.3 kg +/- 1.2 [SE]; group II, 10.1 kg +/- 1.4 [SE]). Only age predicted weight gain, with younger patients gaining more than older patients after transplantation (14.2 +/- 13.2 kg versus 8.8 +/- 7.9 kg; p < 0.05). We found no relationship between the observed weight gain and any of the other measured predictors, that is, history of overweight, age, diabetes, family history of overweight, sex, patient's participation in cardiac rehabilitation. The universal nature of this weight gain and the lack of markers predicting patients at greatest risk for obesity underscores the seriousness of this problem.

Reversal of end-stage heart failure is predicted by long-term therapeutic response rather than initial hemodynamic and neurohormonal profile.

BACKGROUND: Long waiting list periods for heart transplantation have led to clinical improvements for some patients resulting in their removal from the waiting list. This study sought to determine what characteristics differentiated those patients with a good clinical outcome from those who continued to need a transplant. METHODS: The initial and final serial (every 3 months) right heart catheterization data of 60 patients awaiting transplantation were retrospectively analyzed, and the patients were divided into two groups: group A, patients who were taken off the list in follow-up because of improvement (n = 18 of 60), and group B who continued to require transplantation or died (n = 42 of 60). RESULTS: For Group A, there were significant declines in right atrial pressure (9 +/- 4 to 4 +/- 3 mm Hg, initial versus final, p = 0.001), systolic pulmonary arterial pressure (51 +/- 17 to 34 +/- 6 mm Hg, p = 0.0001), with an increase in electron in ejection fraction (20% +/- 4% to 34% +/- 10%, p = 0.005). The change in cardiac output and norepinephrine level was not statistically significant. For Group B, there were no changes in the initial and final values of right atrial pressure, systolic pulmonary arterial pressure, pulmonary capillary wedge pressure, or norepinephrine levels. A significant rise in ejection fraction from 17% +/- 22% +/- 8%, p = 0.003 did occur. The majority of patients in group A (12 of 18) had idiopathic dilated cardiomyopathy. In contrast, an ischemic etiology was found in the majority of group B patients (25 of 42). CONCLUSIONS: This study shows that transplant waiting list outcome cannot be predicted from a patient's initial hemodynamic or neurohormonal presentation. Rather, those patients capable of reversing their hemodynamic derangements with therapy over time are most likely to sustain a favorable clinical outcome. It appears that patients with idiopathic rather than ischemic cardiomyopathy respond more favorably to medical interventions with improved prognosis.

Paradoxical hypertension after reversal of heart failure in patients treated with intensive vasodilator therapy.

Hypertension is a major cause of heart failure, evolving from left ventricular hypertrophy to systolic and diastolic dysfunction. Although effective heart failure therapy has been associated with a lowering or no change in systemic arterial blood pressure in long-term follow-up, this study describes the symptomatic, clinical, and left ventricular functional response of a subgroup of heart failure patients with a prior history of hypertension who demonstrated a paradoxical hypertensive response despite high-dose vasodilator therapy. We prospectively identified 45 patients with a past history of hypertension who had become normotensive with symptomatic heart failure. Of these 45 heart failure patients, 12 became hypertensive while receiving therapy in follow-up, with systolic blood pressure > or = 140 mm Hg (Group A). The remaining 33 patients did not have a hypertensive response to therapy (Group B). In the 12 Group A patients, 60+/-10 years old, with symptomatic heart failure for 6.3+/-4.3 years, vasodilator therapy was intensified in the 2.0+/-0.5 years of follow-up, achieving final doses of enalapril 78+/-19 mg and isosorbide dinitrate 293 +/-106 mg per day. New York Heart Association classification improved from 2.9+/-0.8 to 1.3+/-0.5 (P < or = .0001), with a reduction in heart-failure-related hospitalizations. Left ventricular ejection fraction increased from 17+/-6% to 40+/-10% (P < .0001). Follow-up blood pressure at 1 to 3 months was unchanged. However, both systolic and diastolic blood pressure increased at final follow-up, rising from 116+/-14 to 154+/-13 mm Hg (P = .0001) and from 71+/-9 to 85+/-14 mm Hg (P = .004), respectively. Renal function remained unchanged. Although both groups had similar clinical responses, there were more blacks and women in the hypertensive Group A. Effectively, 12 of 45 (27%) heart failure patients with an antecedent history of hypertension demonstrated a paradoxical hypertensive response to vasodilator therapy. The recurrence of hypertension in a significant portion of patients successfully treated for heart failure has important clinical implications.

Maternal renal artery Doppler velocimetry in normotensive pregnancies and pregnancies complicated by hypertensive disorders.

Hypertensive disorders in pregnancy contribute to substantial maternal and perinatal morbidity and mortality. Clinically, these disorders are characterized by hypertension and proteinuria. However, these signs appear some time after the physiologic derangements have been initiated. The primary objectives of this study were as follows: 1) to establish baseline values for the maternal renal artery systolic-diastolic ratio (S/D) as a function of gestational age in normal pregnancies, and 2) to determine whether renal artery blood flow indices can accurately identify those pregnancies complicated by, or destined to develop, hypertensive disorders. Using a pulsed Doppler scanner, maternal renal artery duplex evaluation was performed in four groups of women: normotensive nonpregnant, normotensive pregnant, chronic hypertensive pregnant, and preeclamptic. In 30 normotensive pregnant women followed longitudinally, no change was noted in the renal artery S/D as gestational age advanced, with mean (+/- SD) values of 2.5 +/- 0.20 and 2.6 +/- 0.21 for the left and right sides, respectively. No clinically meaningful discriminations were detected when the four groups were compared. We conclude that maternal renal artery Doppler waveforms are not significantly altered by either pregnancy or hypertensive complications in pregnancy.

Reliability of pleural fluid lymphocyte counts in the antenatal diagnosis of congenital chylothorax.

Two cases are presented in which fetal thoracentesis was performed to evaluate pleural effusions. In the first, a fetus with nonimmune hydrops had pleural effusions with lymphocyte counts consistent with congenital chylothorax. However, amniotic fluid cultures grew cytomegalovirus and the diagnosis of congenital cytomegalovirus infection was confirmed at autopsy. In the second, the pleural fluid lymphocyte count was lower than that considered to be diagnostic of congenital chylothorax. Nevertheless, the clinical course in this case and the patient's history of two previous infants who were presumed to have that disease suggest that this was the most likely diagnosis. These cases emphasize that pleural fluid lymphocyte counts alone are not reliable in establishing the cause of hydrothorax before birth.

Sonographic diagnosis of the large for gestational age fetus at term: does it make a difference?

We evaluated 406 women with late third-trimester ultrasound examinations to determine whether the sonographic diagnosis of a large for gestational age (LGA) fetus, defined as an estimated fetal weight at or above the 90th percentile, altered the management of labor and delivery. The sonographic prediction of LGA fetuses had a sensitivity, specificity, and positive predictive value of 50, 90, and 52%, respectively. Women without the sonographic diagnosis of an LGA fetus (N = 338) differed from those with the diagnosis (N = 68) in the frequency of diagnosed labor abnormalities (19 versus 30%, P = .03), use of epidural anesthesia (57 versus 74%, P = .01), and the incidence of cesarean deliveries (32 versus 53%, P = .004). To determine whether it was the sonographic prediction of an LGA fetus or the actual fetal weight that altered clinical management and perinatal outcomes, we stratified the study population into four groups and compared the true negatives with the false positives and the false negatives with the true positives. The incorrect sonographic diagnosis of an LGA fetus had a statistically significant effect on both the diagnosis of labor abnormalities (P = .04) and the incidence of elective cesareans (P = .04) in pregnancies with appropriate for gestational age birth weights.

Contemporary management of a potentially lethal fetal anomaly: a successful perinatal approach to epignathus.

Prenatal diagnosis of epignathus (a teratoma originating in the oropharynx) has been reported previously. However, in many of these cases the neonates succumbed to acute respiratory distress secondary to airway obstruction at the time of birth. We describe a case of antepartum diagnosis of epignathus using ultrasonography and magnetic resonance imaging as complementary techniques. The ability to accurately define the fetal anomaly permitted us to plan a unique strategy for peripartum management. After cesarean delivery of the infant from the uterus, the umbilical cord was not clamped and the fetoplacental circulation was left undisturbed. A tracheostomy was then performed, after which the umbilical cord was clamped and the infant was stabilized. Several hours later, a debulking procedure was performed in the operating room to remove the tumor from its attachment to the bony palate. Both mother and infant did well postoperatively. The ability to plan and perform a controlled tracheostomy while the infant remained oxygenated and ventilated proved to be lifesaving in this case.

Neurotoxicity produced by dibromoacetic acid in drinking water of rats.

An evaluation of potential adverse human health effects of disinfection byproducts requires study of both cancer and noncancer endpoints; however, no studies have evaluated the neurotoxic potential of a common haloacetic acid, dibromoacetic acid (DBA). This study characterized the neurotoxicity of DBA during 6-month exposure in the drinking water of rats. Adolescent male and female Fischer 344 rats were administered DBA at 0, 0.2, 0.6, and 1.5 g/l. On a mg/kg/day basis, the consumed dosages decreased greatly over the exposure period, with average intakes of 0, 20, 72, and 161 mg/kg/day. Weight gain was depressed in the high-concentration group, and concentration-related diarrhea and hair loss were observed early in exposure. Testing with a functional observational battery and motor activity took place before dosing and at 1, 2, 4, and 6 months. DBA produced concentration-related neuromuscular toxicity (mid and high concentrations) characterized by limb weakness, mild gait abnormalities, and hypotonia, as well as sensorimotor depression (all concentrations), with decreased responses to a tail-pinch and click. Other signs of toxicity at the highest concentration included decreased activity and chest clasping. Neurotoxicity was evident as early as one month, but did not progress with continued exposure. The major neuropathological finding was degeneration of spinal cord nerve fibers (mid and high concentrations). Cellular vacuolization in spinal cord gray matter (mostly) and in white matter (occasionally) tracts was also observed. No treatment-related changes were seen in brain, eyes, peripheral nerves, or peripheral ganglia. The lowest-observable effect level for neurobehavioral changes was 20 mg/kg/day (produced by 0.2 g/l, lowest concentration tested), whereas this dosage was a no-effect level for neuropathological changes. These studies suggest that neurotoxicity should be considered in the overall hazard evaluation of haloacetic acids.

Cardiovascular responses to submaximal arm and leg exercise in cardiac transplant patients.

We examined whether an increase in stroke volume (SV) contributes to the increase in cardiac output that occurs when cardiac transplant patients (CT) exercise between 50% and 75% of maximum. Upright arm and leg exercise was performed by 13 CT and 10 normal controls. Cardiac output (CO2 rebreathing), expired air, and catecholamine measures were obtained at rest and at 50% and 75% of maximum. From rest to 50% of maximum both normals and CT increased heart rate (HR) and SV during arm and leg exercise. In normals, HR (arm = +17 +/- 2 min-1; leg = +21 +/- 3 min-1) was increased further at 75% of maximum but not SV (arm = 3 +/- 4 ml; leg = +2 +/- 8 ml). In CT, further increases in both HR (arm = +9 +/- 1 min-1; leg = +13 +/- 1 min-1) and SV (arm = +12 +/- 5 ml; leg = +12 +/- 3 ml) were observed at 75% of maximum. During leg exercise plasma norepinephrine was increased more in CT than in normals. Between 50% and 75% of maximum, an increase in SV is a more important mechanism for increasing cardiac output during upright arm and leg exercise in CT than in normals.