John LaManca

Effect of Erythropoietin on Exercise Capacity in Patients With Moderate to Severe Chronic Heart Failure

Background—Patients with chronic heart failure (CHF) are frequently anemic. An increase in hemoglobin could enhance exercise performance by increasing oxygen delivery. We investigated the effect of erythropoietin (EPO) on exercise performance in anemic patients with CHF. Methods and Results—Twenty-six anemic patients aged 57±11 years were randomized to receive EPO (15 000 to 30 000 IU per week) or placebo for 3 months. Parameters measured at baseline and end therapy included blood parameters (hemoglobin, hematocrit, plasma volume), exercise parameters (peak oxygen consumption [&OV0312;o2], exercise duration, 6-minute walk), muscle aerobic metabolism (half-time of &OV0312;o2 and near infrared recovery), and forearm vasodilatory function. EPO was well tolerated by all patients. Twelve patients in the EPO group felt improvement versus 1 in the placebo group (P <0.05). There were significant increases in hemoglobin (11.0±0.5 to 14.3±1.0 g/dL, P <0.05), peak &OV0312;o2 (11.0±1.8 to 12.7±2.8 mL · min−1 · kg−1, P <0.05) and exercise duration (590±107 to 657±119 s, P <0.004) in the EPO group but no significant changes in the control group. Resting and hyperemic forearm vascular resistance and indices of the rate of muscle oxidative capacity were unchanged in both groups. Conclusion—EPO significantly enhances exercise capacity in patients with CHF. One mechanism of improvement in &OV0312;o2 is increased oxygen delivery from increased hemoglobin concentration.

Hemodilution Is Common in Patients With Advanced Heart Failure

Background—Anemia frequently occurs in chronic heart failure (CHF) patients and is associated with a poor prognosis. A low hematocrit may result from an increased plasma volume (hemodilution) or from reduced red blood cell volume (true anemia). The prevalence and clinical outcome of CHF patients with hemodilution is unknown. Methods and Results—The prevalence of anemia and its effect on outcome was examined in 196 patients with CHF. The prevalence of hemodilution was assessed in a subset of 37 ambulatory anemic patients with I131-tagged albumin to measure red blood cell and plasma volume. Clinical outcome was monitored. Sixty-one percent of the CHF patients were anemic. The prevalence of anemia increased from 33% in patients with New York Heart Association class II heart failure to 68% in class IV CHF patients. Survival was reduced in anemic patients compared with patients with a normal hematocrit (P <0.05). In the subset of 37 anemic patients, 17 patients (46%) had hemodilution and 20 patients (54%) had a true anemia. Nine patients with hemodilution died or underwent urgent transplant compared with 4 patients in the true anemia group (P <0.04). Conclusion—Hemodilution is common in CHF patients. Anemia is associated with a poor prognosis in CHF. Patients with hemodilution tend to do worse than patients with true anemia, which suggests that volume overload may be an important mechanism contributing to the poor outcome in anemic CHF patients.

Use of Rapamycin Slows Progression of Cardiac Transplantation Vasculopathy

Background Cardiac transplantation vasculopathy is the leading cause of late death in heart transplantation recipients. Rapamycin is an immunosuppressant drug with potent antiproliferative and antimigratory effects. We investigated whether rapamycin could prevent progression of graft vasculopathy in 46 patients (age, 54± 10 years; 4.3±2.3 years after transplantation) with severe disease. Methods and Results At annual cardiac catheterization, patients were randomly assigned to treatment with rapamycin (n=22) versus continued current immunosuppression (n=24). Clinical characteristics including recipient age and sex, underlying cause of congestive heart failure, donor age and sex, and ischemic time were recorded. Cardiac catheterization was graded with the use of a semiquantitative scale and repeated annually. Clinically significant adverse events were defined as death, need for angioplasty or bypass surgery, myocardial infarction, and a >25% worsening of the catheterization score. These events were monitored as primary study end points. Anti‐HLA class I and II antibody production and lymphocyte growth assays were measured with each biopsy. Patients selected for rapamycin had azathioprine or mycophenolate mofetil discontinued and were given rapamycin. Outcomes were compared by means of log‐rank analysis. There were no significant differences in baseline characteristics. Duration of follow‐up was comparable (rapamycin, 689±261; control, 630±207 days; NS). In the rapamycin group, 3 patients reached primary end points versus 14 patients in the control group (P<0.001). There was no difference in baseline or subsequent anti‐HLA class I or II antibody production. Conclusions In this patient cohort with cardiac vasculopathy, treatment with rapamycin slowed disease progression probably by its antiproliferative and antimigratory effects. (Circulation. 2003;108:48‐53.)

Metabolic and cardiovascular effects of a progressive exercise test in patients with chronic fatigue syndrome

PURPOSE To evaluate the aerobic power (as maximum volume of oxygen consumed [VO2 max]) of women with chronic fatigue syndrome (CFS). PATIENTS AND METHODS Twenty-one women with CFS and 22 sedentary healthy controls (CON) were studied at the CFS Cooperative Research Center Exercise Laboratory at the VA Medical Center, East Orange, New Jersey. Performance was measured on an incremental treadmill protocol walking to exhaustion. Expired gases were analyzed by a metabolic system, heart rate was recorded continuously, and ratings of perceived exertion (RPE) were taken at each workload. The groups were divided into those who achieved VO2 max (CFS-MAX and CON-MAX) and those who stopped at a submaximal level (CFS-NOMAX and CON-NOMAX) by using standard criteria. RESULTS Seventeen CON and 10 CFS subjects achieved VO2 max. The VO2 max (mL/kg/min) of the CFS-MAX (28.1 +/- 5.1) was lower than that of the CON-MAX (32.1 +/- 4.3, P = 0.05). The CFS-MAX achieved 98 +/- 11% of predicted VO2 max. The CFS group had a higher RPE at the same absolute workloads as controls (P < 0.01) but not the same relative workloads. CONCLUSION Compared with normal controls, women with CFS have an aerobic power indicating a low normal fitness level with no indication of cardiopulmonary abnormality. Our CFS group could withstand a maximal treadmill exercise test without a major exacerbation in either fatigue or other symptoms of their illness.

Abnormal impédance cardiography predicts symptom severity in chronic fatigue syndrome

Background: Findings indicative of a problem with circulation have been reported in patients with chronic fatigue syndrome (CFS). We examined this possibility by measuring the patient’s cardiac output and assessing its relation to presenting symptoms. Methods: Impedance cardiography and symptom data were collected from 38 patients with CFS grouped into cases with severe (n=18) and less severe (n=20) illness and compared with those from 27 matched, sedentary control subjects. Results: The patients with severe CFS had significantly lower stroke volume and cardiac output than the controls and less ill patients. Postexertional fatigue and flu‐like symptoms of infection differentiated the patients with severe CFS from those with less severe CFS (88.5% concordance) and were predictive (R2=0.46, P<0.0002) of lower cardiac output. In contrast, neuropsychiatric symptoms showed no specific association with cardiac output. Conclusions: These results provide a preliminary indication of reduced circulation in patients with severe CFS. Further research is needed to confirm this finding and to define its clinical implications and pathogenetic mechanisms.

Influence of exhaustive treadmill exercise on cognitive functioning in chronic fatigue syndrome

The purpose of this study was to determine the effect of exhaustive exercise on cognitive performance of patients with chronic fatigue syndrome (CFS) and sedentary healthy controls (CON). Subjects were 19 women with CFS and 20 CON. A test battery consisting of 4 cognitive tests (CTB) was given pre-, immediately post-, and 24 hours post-treadmill exercise to exhaustion. No differences were seen on the CTB pre-exercise. CFS patients improved at a slower rate than CON on the Symbol Digit Modalities Test (SDMT), Stroop Word Test (SWT), and Stroop Color Test (SCT). When compared with CON, a lower number of correct responses was seen for the CFS immediately postexercise on the SDMT (61 +/- 3 vs 66 +/- 2), SWT (137 +/- 6 vs 146 +/- 6), and SCT (99 +/- 4 vs 107 +/- 3), and 24 hours postexercise on the SDMT (64 +/- 3 vs 69 +/- 2), SWT (134 +/- 7 vs 148 +/- 5), and SCT (101 +/- 4 vs 106 +/- 3). We conclude that after physically demanding exercise, CFS subjects demonstrated impaired cognitive processing compared with healthy individuals.

Selective low-level leg muscle training alleviates dyspnea in patients with heart failure

OBJECTIVES The purpose of this study was to demonstrate in patients with moderate to severe heart failure that exertional dyspnea can be alleviated by improving muscle function. BACKGROUND Dyspnea is a frequent limiting symptom in patients with chronic heart failure (CHF). This sensation may originate from activation of receptors in the musculature rather than the lung. METHODS To investigate whether dyspnea could be alleviated by selective changes in leg muscle function, we performed isolated lower-limb training in 17 patients with severe CHF. Eight patients learned guided imagery relaxation techniques and served as an active control group. Exercise training consisted of three months of low-level bicycle and treadmill exercise such that minute ventilation was <25 l/min. Leg calisthenics were also performed. Maximal and submaximal exercise performance, respiratory and quadriceps muscle strength and endurance and quality-of-life and dyspnea scales were measured before and after each intervention. Metabolic stress testing (VO(2)), pulmonary function tests and isokinetic strength testing were also performed. RESULTS In the active control group, no changes in leg muscle function, pulmonary function, maximal and submaximal exercise performance or quality-of-life questionnaires were observed. In the training group, peak torque of leg flexors (pre: 39 +/- 15 ft-lb; post: 50 +/- 13 ft-lb; p < 0.002) increased and the fatigue ratio decreased, indicating improved strength and endurance of the leg muscles. Maximal inspiratory and expiratory mouth pressures and maximum voluntary ventilation were unchanged. Peak VO(2) was increased (pre:12 +/- 2.2 ml/kg/min; post: 14 +/- 2.6 ml/kg/min) as well as the duration of exercise at 70% peak VO(2) increased (pre: 11.5 +/- 3.1 min; post: 21.5 +/- 5.4 min; p < 0.003). Perceived dyspnea during the submaximal testing was decreased. Minnesota Living with Heart Failure Score, Guyatt Dyspnea Scale, and the Transitional Dyspnea Index were all improved with training (all p < 0.05). CONCLUSIONS We concluded that improvement of limb muscle function alleviates dyspnea and improves exercise performance in patients with CHF.

Immunologic parameters in chronic fatigue syndrome, major depression, and multiple sclerosis

The purpose of this study was to evaluate the immune dysfunction hypothesis of chronic fatigue syndrome (CFS) by comparing immunologic data from patients with CFS with data from patients with other fatiguing illnesses--major depression and multiple sclerosis (MS)--and with data from healthy sedentary controls. The subjects were 65 healthy sedentary controls, 71 CFS patients (41 with no axis-I diagnosis), 23 patients with mild MS, and 21 patients with major depression. Blood was sampled and assayed for the following: (1) immunologic serologic variables--circulating immune complexes (i.e., Raji cell and C1q binding), immunoglobulins A, E, G, and M, and IgG subclasses; (2) cell surface activation markers--the proportion of CD4+ cells expressing CD45RA+ and CD45RO+ and the proportion of CD8+ cells expressing CD38+, CD11b-, HLA-DR+ and CD28+; and (3) natural killer (NK) total cell count as well as the proportion of lymphocytes expressing NK cell surface markers (i.e., CD3-/CD16+ and CD56+. Of the 18 variables studied, differences between CFS patients and controls were found only for IgG1 and IgG3. When CFS patients were stratified by the presence or absence of concurrent axis-I disease, it was the group with axis-I disorder that had the lowest IgG1 values-contrary to expectation. When data from patients with MS and major depression were also evaluated, the subclass deficiency was no longer significant. The one group to show evidence for immune activation (i.e., an elevated proportion of CD4+ cells expressing the CD45RA+ activation marker) was the group with mild MS. These data support neither immune dysfunction nor immune activation in CFS or in major depression, for the variables studied. The reductions in IgG subclasses may be an epiphenomenon of patient or control subject composition. In contrast, MS, even in the mild and early stages, as in the patients studied here, is associated with immune activation.

Mouse running activity is lowered by Brucella abortus treatment : A potential model to study chronic fatigue

Chronic fatigue syndrome, which can occur after acute infection and last for years, is characterized by severe and persistent fatigue. Others have reported decreases in mouse running activity following infection and have suggested this may provide an animal model for studying chronic fatigue. Voluntary running is a highly motivated activity in mice, which will often run 5-7 mi/day in our laboratory. Following 2 weeks of acclimation to running wheels with food and water available ad lib, female BALB/c mice received 0.2-mL tail vein injections of killed Brucella abortus (BA) or saline vehicle. Subsequently the effects on voluntary running and grooming behavior were determined. Injection of BA caused an immediate large decrease in running and a lack of grooming. Vehicle injections produced no changes in behavior. After the first several days of reduced running behavior, levels of running and grooming slowly returned back to normal over the next 2-4 weeks, with substantial individual differences in the rate of recovery. The pattern of running during recovery was intriguing in that BA mice first ran at normal levels just after the lights went out, but they stopped after only 1-2 h. As recovery proceeded, they gradually increased the duration of the running bout during the night. Because this model uses voluntary exertion and the ability to run for longer periods of time characterizes recovery, the model may be a good one for studying the biologic underpinnings of chronic fatigue.

Cardiopulmonary Exercise Variables in Diastolic Versus Systolic Heart Failure

The response to cardiopulmonary exercise (CPX) in patients with heart failure (HF) with normal left ventricular (LV) ejection fractions (EFs) is not well characterized. To determine if CPX testing could distinguish between patients with HF with normal EFs (>50%; i.e., diastolic HF) and those with decreased EFs (> or =50%; i.e., systolic HF), CPX responses were compared between 185 patients with systolic HF (79% men, mean age 62.6 +/- 10.9 years) and 43 with diastolic HF (54% men, mean age 67.4 +/- 9.8 years) enrolled in a phase II multicenter clinical trial. All patients were evaluated with echocardiography and a standardized CPX test as part of the trial. CPX variables, including oxygen uptake at peak exercise (peak VO(2)) and the slope of the ventilation/carbon dioxide production ratio (VE/VCO(2)), were determined and analyzed by core laboratory personnel. Echocardiographic measurements included the LV EF, the E/A ratio, filling time, cavity volumes, right ventricular function, and mitral regurgitation. Patients in the diastolic HF group tended to be older (p <0.08), with more women (p <0.006) and with greater body mass indexes (p <0.02), than those in the systolic HF group. There was no significant difference in the use of beta blockers or the incidence of coronary artery disease. Patients with diastolic HF had decreased E/A ratios (0.9 +/- 0.4 vs 1.4 +/- 1.1, p <0.02, diastolic HF vs systolic HF) and increased filling times (30.4 +/- 3.2 vs 26.5 +/- 4.7 ms, p <0.01, diastolic HF vs systolic HF). No significant differences in peak VO(2) (14.4 +/- 1.9 vs 15.6 +/- 3.2 ml/kg/min, p = 0.06, diastolic HF vs systolic HF) were observed. The VE/VCO(2) ratios for the 2 groups were abnormal and comparable (32 2 +/- 7.5 vs 34.0 +/- 8.3, p = 0.3, diastolic HF vs systolic HF). In conclusion, the CPX response in patients with diastolic HF and systolic HF is markedly abnormal and indistinguishable with regard to peak VO(2) and ventilation despite marked differences in the LV EF.