Normalization of acquired QT prolongation in humans by intravenous potassium.

BACKGROUND: QT interval prolongation and dispersion have been implicated in serious arrhythmias in congestive heart failure (CHF) and the congenital and drug-induced long-QT syndromes (LQTS). In a subset of the congenital LQTS, infusion of potassium can correct QT abnormalities, consistent with in vitro increases in outward currents such as I(Kr) or I(Kl) when extracellular potassium concentration ([K+]o) is increased. Furthermore, increasing [K+]o decreases the potency of I(Kr)-blocking drugs in vitro. The purpose of this study was to test the hypothesis that increasing [K+]o corrects QT abnormalities in CHF and in subjects treated with quinidine. METHODS AND RESULTS: KCl (maximum, 40 mEq) was infused into (1) 12 healthy subjects treated with quinidine sulfate (5 doses of 300 mg/5 h) or placebo and (2) 8 CHF patients and age-matched normal control subjects. Mean [K+] increased from 4 to 4.2 mEq/L to 4.7 to 5.2 mEq/L. Potassium infusion significantly reversed QTUc prolongation, especially in the precordial leads (quinidine, 590+/-79 to 479+/-35 [+/-SD] ms(1/2), P<.001; CHF, 521+/-110 to 431+/-47 ms(1/2), P<.05). There was no effect in either control group. Similarly, potassium decreased QTUc dispersion (quinidine, 210+/-62 to 130+/-75 ms(1/2), P<.01; CHF, 132+/-68 to 84+/-35 ms(1/2), P=.07) and was without effect in the control subjects. QT morphological abnormalities, including U waves and bifid T waves, were reversed by potassium. CONCLUSIONS: Potentially arrhythmogenic QT abnormalities during quinidine treatment and in CHF can be nearly normalized by modest elevation of serum potassium.

Treatment of subclinical fluid retention in patients with symptomatic heart failure: effect on exercise performance.

BACKGROUND: Patients with heart failure frequently have elevated intracardiac diastolic pressures but no clinical evidence of excess fluid retention. We speculated that such pressure elevations may indicate subclinical fluid retention and that removal of this fluid could improve exercise intolerance. METHODS: To test this hypothesis, we studied 10 patients with right atrial pressure > or = 8 mm Hg but without rales, edema, or apparent jugular venous distension. Right-sided heart catheterization was performed, after which patients underwent maximal treadmill cardiopulmonary testing. Patients were then hospitalized and underwent maximal diuresis, after which exercise was repeated. RESULTS: Before diuresis, right atrial pressure averaged 16 +/- 5 mm Hg (+/-standard deviation), pulmonary capillary wedge pressure 30 +/- 6 mm Hg, and peak exercise Vo2 11.2 +/- 2.3 ml/min/ kg. Patients underwent diuresis of 4.5 +/- 2.2 kg over 4 +/- 2 days to a resting right atrial pressure of 6 +/- 4 and wedge pressure of 19 +/- 7 mm Hg. After diuresis, all patients reported overall symptomatic improvement. Maximal exercise duration increased significantly from 9.2 +/- 4.2 to 12.5 +/- 4.7 minutes. At matched peak workloads, significant improvements were also seen in minute ventilation (45 +/- 12 to 35 +/- 9 L/min), lactate levels (42 +/- 16 to 29 +/- 9 mg/dl), and Borg dyspnea scores (15 +/- 3 to 12 +/- 4) (all p < 0.05). CONCLUSIONS: Invasive hemodynamic monitoring allows the identification of excess fluid retention in patients with heart failure when there are no clinical signs of fluid overload. Removal of this subclinical excess fluid improves exercise performance and exertional dyspnea.

Effect of sympathoinhibition on exercise performance in patients with heart failure.

BACKGROUND: In patients with heart failure, excessive sympathetic activation during exercise could interfere with exercise performance by impairing arteriolar dilation in working muscle and by adversely altering skeletal muscle metabolic behavior. To test this hypothesis, we examined the effect of sympathoinhibition with clonidine, a central sympatholytic agent, on skeletal muscle blood flow and metabolism in patients with heart failure. METHODS AND RESULTS: Swan-Ganz and femoral venous catheters were inserted in 20 patients with chronic heart failure and exercise intolerance (peak exercise VO2 = 9.3 +/- 1.4 [SEM] mL.min-1.kg-1). Central hemodynamic measurements, leg blood flow determined by thermodilution, and systemic and leg metabolic parameters were measured during maximal treadmill exercise before and 2 hours after clonidine 2 micrograms/kg IV (n = 15) or 0.9% normal saline (n = 5). During-control exercise before the administration of clonidine, leg blood flow increased from 0.3 +/- 0.1 to 1.8 +/- 0.2 L/min and plasma norepinephrine increased from 485 +/- 61 to 2155 +/- 186 pg/mL (both P < .01). Treatment with clonidine markedly suppressed norepinephrine levels during exercise (matched peak exercise workload: control, 2137 +/- 187 versus clonidine, 1430 +/- 161 pg/mL), increased leg blood flow (control, 1.8 +/- 0.2 versus clonidine, 2.3 +/- 0.4 L/min), reduced systemic oxygen consumption (control, 1002 +/- 70 versus clonidine, 966 +/- 68 mL/min), reduced pulmonary artery lactate concentration (control, 3.2 +/- 0.3 versus clonidine, 2.6 +/- 0.2 mEq/L), and decreased minute ventilation (control, 39.7 +/- 2.1 versus clonidine, 34.9 +/- 2.4 L/min) (all P < .05). CONCLUSIONS: These findings suggest that sympathetic activation during exercise reduces leg blood flow, increases muscle glycolysis, and decreases muscle efficiency in patients with heart failure.

Skeletal muscle mass and exercise performance in stable ambulatory patients with heart failure.

The purpose of this study was to determine whether skeletal muscle atrophy limits the maximal exercise capacity of stable ambulatory patients with heart failure. Body composition and maximal exercise capacity were measured in 100 stable ambulatory patients with heart failure. Body composition was assessed by using dual-energy X-ray absorption. Peak exercise oxygen consumption (VO2peak) and the anaerobic threshold were measured by using a Naughton treadmill protocol and a Medical Graphics CardioO2 System. VO2peak averaged 13.4 +/- 3.3 ml.min-1.kg-1 or 43 +/- 12% of normal. Lean body mass averaged 52.9 +/- 10.5 kg and leg lean mass 16.5 +/- 3.6 kg. Leg lean mass correlated linearly with VO2peak (r = 0.68, P < 0.01), suggesting that exercise performance is influences by skeletal muscle mass. However, lean body mass was comparable to levels noted in 1,584 normal control subjects, suggesting no decrease in muscle mass. Leg muscle mass was comparable to levels noted in 34 normal control subjects, further supporting this conclusion. These findings suggest that exercise intolerance in stable ambulatory patients with heart failure is not due to skeletal muscle atrophy.

Hemodynamic exercise testing. A valuable tool in the selection of cardiac transplantation candidates.

BACKGROUND: Peak exercise oxygen consumption (Vo2), a noninvasive index of peak exercise cardiac output (CO), is widely used to select candidates for heart transplantation. However, peak exercise Vo2 can be influenced by noncardiac factors such as deconditioning, motivation, or body composition and may yield misleading prognostic information. Direct measurement of the CO response to exercise may avoid this problem and more accurately predict prognosis. METHODS AND RESULTS: Hemodynamic and ventilatory responses to maximal treadmill exercise were measured in 185 ambulatory patients with chronic heart failure who had been referred for cardiac transplantation (mean left ventricular ejection fraction, 22 +/- 7%; mean peak Vo2, 12.9 +/- 3.0 mL. min-1.kg-1). CO response to exercise was normal in 83 patients and reduced in 102. By univariate analysis, patients with normal CO responses had a better 1-year survival rate (95%) than did those with reduced CO responses (72%) (P < .0001). Survival in patients with peak Vo2 of > 14 mL.min-1.kg-1 (88%) was not different from that of patients with peak Vo2 of < or = 14 mL.min-1.kg-1 (79%) (P = NS). However, survival was worse in patients with peak Vo2 of < or = 10 mL.min-1.kg-1 (52%) versus those with peak Vo2 of > 10 mL.min-1.kg-1 (89%) (P < .0001). By Cox regression analysis, exercise CO response was the strongest independent predictor of survival (risk ratio, 4.3), with peak Vo2 dichotomized at 10 mL. min-1.kg-1 (risk ratio, 3.3) as the only other independent predictor. Patients with reduced CO responses and peak Vo2 of < or = 10 mL.min-1.kg-1 had an extremely poor 1-year survival rate (38%). CONCLUSIONS: Both CO response to exercise and peak exercise Vo2 provide valuable independent prognostic information in ambulatory patients with heart failure. These variables should be used in combination to select potential heart transplantation candidates.

Circulatory status and response to cardiac rehabilitation in patients with heart failure.

BACKGROUND: We recently reported that some patients with heart failure and exercise intolerance exhibit severe hemodynamic dysfunction during exercise, whereas others have normal cardiac output responses to exercise. We postulated that patients with preserved cardiac output responses to exercise are limited by deconditioning and would respond to exercise training, whereas patients with reduced cardiac output responses are limited by skeletal muscle underperfusion and would not improve with exercise training. The present study was undertaken to test this hypothesis. METHODS AND RESULTS: Thirty-two patients with heart failure were studied. Hemodynamic response to maximal treadmill exercise was measured; then patients were enrolled in a standard 3-month cardiac rehabilitation program. Peak exercise VO2, lactate threshold, and quality-of-life questionnaires were assessed at 1, 2, and 3 months. Twenty-one patients had normal cardiac output responses to exercise. All 21 patients participated in the rehabilitation program without difficulty, and 9 (43%) responded to rehabilitation, defined as a > 10% increase in both peak exercise VO2 and the anaerobic threshold. Of the 11 patients with reduced cardiac output responses to exercise, 3 discontinued rehabilitation because of severe exhaustion, and only 1 qualified as a responder (9%; P < .04 versus preserved cardiac output). CONCLUSIONS: Patients with heart failure and normal cardiac output responses to exercise frequently improve with exercise training. Patients with severe hemodynamic dysfunction during exercise usually do not improve with training, which suggests that they are limited primarily by circulatory factors.

Dissociation between peak exercise oxygen consumption and hemodynamic dysfunction in potential heart transplant candidates.

OBJECTIVES: The purpose of this study was to determine how often peak exercise oxygen consumption (VO2) misclassifies the severity of cardiac dysfunction in potential heart transplant candidates. BACKGROUND: Cardiopulmonary exercise testing is being used to help select heart transplant candidates on the basis of the assumption that a low peak exercise VO2 indicates severe hemodynamic dysfunction and a poor prognosis. However, noncardiac factors, such as muscle deconditioning, can also influence exercise capacity. Therefore, peak exercise VO2 may overestimate the severity of cardiac dysfunction in some patients. METHODS: Hemodynamic and respiratory responses to maximal treadmill exercise were measured in 64 sequential patients undergoing evaluation for heart transplantation, all of whom had an ejection fraction < 35% and reduced peak exercise VO2 levels (mean [+/- SD] 13.3 +/- 2.7 ml/min per kg). RESULTS: Twenty-eight (44%) of 64 patients exhibited a reduced cardiac output response to exercise and pulmonary wedge pressure > 20 mm Hg at peak exercise, consistent with severe hemodynamic dysfunction. Twenty-three patients (36%) exhibited a normal cardiac output response to exercise but a wedge pressure > 20 mm Hg at peak exercise, suggesting moderate hemodynamic dysfunction. Thirteen patients (20%) exhibited a normal cardiac output and wedge pressure < 20 mm Hg at peak exercise, suggesting mild hemodynamic dysfunction. Despite these markedly different hemodynamic responses, all three groups exhibited similar peak exercise VO2 levels (mild dysfunction 14.2 +/- 3.5 ml/min per kg, moderate dysfunction 13.9 +/- 2.7 ml/min per kg, severe dysfunction 12.4 +/- 2.1 ml/min per kg). A peak exercise VO2 level < 14 ml/min per kg, considered to reflect severe hemodynamic dysfunction, was observed in 18 of the patients with a normal cardiac output response to exercise, whereas 7 patients with severe hemodynamic dysfunction had a peak VO2 level > 14 ml/min per kg. CONCLUSIONS: More than 50% of potential heart transplant candidates with a reduced peak exercise VO2 level exhibit only mild or moderate hemodynamic dysfunction during exercise. Hemodynamic responses to exercise should be directly measured in potential transplant candidates to confirm severe circulatory dysfunction.

Dissociation between exertional symptoms and circulatory function in patients with heart failure.

BACKGROUND: Patients with heart failure frequently report exertional dyspnea and fatigue. These symptoms are usually attributed to circulatory dysfunction and therefore are typically treated with cardiovascular medications. Serial assessment of exertional symptoms has also become the principal method used to assess drug efficacy in heart failure. Nevertheless, the relation between exertional symptoms in heart failure and circulatory dysfunction remains uncertain. METHODS AND RESULTS: This study was undertaken to investigate the relation between exertional symptoms, ventilatory and skeletal muscle dysfunction, and circulatory function in patients with heart failure. To this end, 52 ambulatory patients with heart failure underwent hemodynamic monitoring during maximal treadmill exercise testing. During exercise, the severity of dyspnea and fatigue was evaluated on a scale of 6 to 20 (Borg scale). The level of perceived exercise intolerance during daily activities was evaluated with the Minnesota Living With Heart Failure Questionnaire and the Yale Dyspnea-Fatigue Index. Maximal treadmill exercise increased the VO2 to 13.4 +/- 2.8 mL.min-1.kg-1, the dyspnea score to 15.7 +/- 2.3, the fatigue score to 14.8 +/- 3.4, the pulmonary wedge pressure to 28 +/- 11 mm Hg, and the pulmonary artery lactate concentration to 34.5 +/- 16.3 mg/dL and decreased the pulmonary artery hemoglobin oxygen saturation to 30 +/- 9%. The level of perceived dyspnea had no relation to the pulmonary wedge pressure and correlated only minimally with the level of excessive ventilation (r = 39). The level of perceived fatigue correlated only weakly with blood lactate concentration (r = .55). Eleven patients (21%) exhibited a normal cardiac output and wedge pressure < 20 mm Hg during exercise, 22 (42%) exhibited a normal cardiac output but wedge pressure > 20 mm Hg during exercise, and 19 (37%) exhibited reduced cardiac output and wedge pressure > 20 mm Hg during exercise. Despite these markedly different hemodynamic responses, all three groups exhibited similar levels of fatigue and dyspnea at comparable workloads and had comparable total scores for the Minnesota Living With Heart Failure Questionnaire and the Yale Dyspnea-Fatigue Index. There was no relation between the Living With Heart Failure Questionnaire and peak exercise VO2 and only a weak correlation between the Dyspnea-Fatigue Index and peak VO2 (r = .48). CONCLUSIONS: The level of exercise intolerance perceived by patients with heart failure has little or no relation to objective measures of circulatory, ventilatory, or metabolic dysfunction during exercise. In patients who report severe exertional symptoms, it may be desirable to directly measure hemodynamic response to exercise to ensure that these symptoms are due to circulatory dysfunction.

Allopurinol and dimethylthiourea reduce brain infarction following middle cerebral artery occlusion in rats.

Free radicals have been shown to play an important role in ischemia-reperfusion injury in several organ systems; however, the role of free radicals in central nervous system ischemia has been less well studied. Many potential free radical-generating systems exist. The primary products of these reactions, superoxide and hydrogen peroxide, may combine to produce hydroxyl radicals. Of the many potential sources of free radical generation, the enzyme xanthine oxidase has been shown to be important in ischemia in noncerebral tissue. We investigated the effect of the hydroxyl radical scavenger dimethylthiourea and the xanthine oxidase inhibitor allopurinol on infarct volume in a model of continuous partial ischemia. Male Sprague-Dawley rats were treated with dimethylthiourea or allopurinol before middle cerebral artery occlusion. Infarct volume was measured by triphenyltetrazolium chloride staining of brains removed 3 or 24 hours after occlusion. Stroke volume was reduced by 30% after dimethylthiourea treatment and by 32-35% after allopurinol treatment. At 24 hours after stroke, cortical tissue was more effectively protected than caudate tissue with both agents. Pretreatment with dimethylthiourea and allopurinol also significantly reduced cerebral edema formation and improved blood-brain barrier function as measured by fluorescein uptake. Our results imply that hydroxyl radicals are important in tissue injury secondary to partial cerebral ischemia and that xanthine oxidase may be the primary source of these radicals.