Effects of isosorbide dinitrate and hydralazine on regional metabolic responses to arm exercise in patients with heart failure

The reduced exercise capacity of patients with heart failure is thought to be due in part to impaired skeletal muscle oxygen delivery. To determine if hydralazine and isosorbide dinitrate improve skeletal muscle oxygen delivery in such patients, the effects of these agents on regional metabolic responses to forearm exercise were examined in 16 patients with heart failure. Arm oxygen extraction and brachial venous lactate concentration were measured at rest and during 3 minutes of rhythmic handgrip and then remeasured after administration of oral hydralazine (nine patients) or sublingual isosorbide dinitrate (nine patients). Hydralazine increased mean (± standard deviation) cardiac output at rest from 3.5 ± 0.5 to 4.9 ±1.0 liters/min (p < 0.01) and decreased arm oxygen extraction from 39 ± 8 to 33 ± 10 percent (probability [p] < 0.01), suggesting improved resting limb oxygen delivery. However, hydralazine did not reduce arm oxygen extraction during exercise (control 63 ± 4, hydralazine 60 ± 12 percent; p = notsignificant[NS]) or venous lactate during exercise (control 16.6 ± 7.8, hydralazine 17.1 ± 4.8 mg/100 ml; p = NS). Isosorbide dinitrate increased the cardiac output from 3.6 ± 0.7 to 4.5 ± 0.7 liters/min (p < 0.01) but had no effect on arm oxygen extraction at rest (control 40 ± 11, isosorbide dinitrate 38 ± 11 percent; p = NS) and during exercise (control 66 ± 5, isosorbide dinitrate 64 ± 8 percent; p = NS) or on venous lactate during exercise (control 17.9 ± 6.4, isosorbide dinitrate 17.1 ± 3.9 mg/100 ml; p = NS). These data suggest that hydralazine and isosorbide dinitrate do not improve skeletal muscle oxygen delivery during exercise in patients with heart failure.     

Exercise intolerance in patients with chronic left heart failure: Relation to oxygen transport and ventilatory abnormalities

Circulatory, metabolic, and ventilatory responses to maximal and submaximal symptom-limited exercise were studied in 13 patients with chronic stable heart failure. Maximal exercise was sustained 6.5 ± 0.6 minutes (mean ± standard error of the mean) and increased minute oxygen consumption (VO₂) to 940 ± 65 ml/min, whereas submaximal exercise was sustained for 15.4 ± 2.3 minutes and increased VO₂ to 825 ± 49 ml/min (both p < 0.01 compared with maximal exercise). Both exercise protocols were terminated because of fatigue and both were associated with reduced cardiac output relative to VO₂, marked systemic oxygen extraction (80 ± 2% maximal versus 78 ± 2% submaximal) and similarly elevated blood lactate concentrations (37 ± 4 mg/dl maximal versus 36 ± 4 mg/dl submaximal), suggesting inadequate oxygen delivery to working muscle. Minute ventilation during both types of exercise was also more than twice normal relative to carbon dioxide production. However, during submaximal exercise, dyspnea was noted in only 3 patients despite these ventilatory abnormalities. During maximal exercise, dyspnea was noted in 11 patients but did not force termination of exercise or preclude achievement of marked systemic oxygen extraction and lactate production. These data suggest that patients with chronic stable cardiac failure are limited during both maximal and submaximal exercise primarily by inadequate oxygen transport to working muscle.     

Circulatory improvement after hydralazine or isosorbide dinitrate administration in patients with heart failure: Effect on metabolic responses to submaximal exercise

Hydralazine and isosorbide dinitrate can increase the cardiac output during submaximal exercise in patients with heart failure but whether this increase improves oxygen delivery to underperfused exercising muscle is uncertain. To investigate this question, we measured three systemic markers of skeletal muscle oxygen availability—exercise V?O₂, mixed venous lactate concentration and oxygen debt—during submaximal exercise in 15 patients with heart failure both before and after hydralazine (nine patients) or isosorbide dinitrate (eight patients) administration. Hydralazine increased the cardiac output during exercise from 4.9 ± 1.2 liter/min to 6.5 ± 1.8 liter/min (p < 0.01) but had no effect on exercise V?O₂ (control, 531 ± 135 ml/min; hydralazine, 489 ± 102 ml/min), peak lactate concentration (control, 18.3 ± 4.2 mg/dl; hydralazine, 17.9 ± 3.6 mg/dl) or oxygen debt (control, 474 ± 213 ml; hydralazine, 465 ± 170 ml) (all p > 0.10). Isosorbide dinitrate increased the cardiac output during exercise from 4.6 ± 0.9 liter/min to 5.3 ± 0.8 liter/min (p < 0.01) but also did not change exercise V?O₂ (control, 488 ± 62 ml/min; isosorbide, 473 ± 44 ml/min), peak lactate concentration (control, 19.2 ± 6.0 mg/dl; isosorbide, 21.4 ± 8.2 mg/dl) or oxygen debt (control, 522 ± 154 ml; isosorbide, 445 ± 147 ml) (all p > 0.10). We conclude that short-term administration of hydralazine or nitrates to patients with heart failure can substantially improve circulatory function during exercise but that this improvement probably does not enhance skeletal muscle nutritional flow.     

Effect of the renin-angiotensin system on limb circulation and metabolism during exercise in patients with heart failure

The maximal aerobic exercise capacity of patients with chronic heart failure is frequently decreased because of inadequate blood flow to working skeletal muscle. To investigate whether this reduced flow is in part due to interference by angiotensin II with arteriolar dilation in working muscle, the effect of the angiotensin-converting enzyme inhibitor captopril on leg blood flow, leg vascular resistance, leg oxygen consumption (VO2) and leg lactate release during maximal upright bicycle exercise was examined in 12 patients with heart failure (maximal VO2 10.7 +/- 3.1 ml/min per kg). Captopril decreased leg resistance at rest (258 +/- 115 to 173 +/- 67 U, p less than 0.01) and maximal exercise (68 +/- 69 to 45 +/- 29 U, p less than 0.01) associated with proportionately similar decreases in systemic vascular resistance. However, maximal exercise duration and maximal VO2 were unchanged and, at identical peak exercise work times, there was no improvement in leg blood flow (2.0 +/- 0.9 to 2.0 +/- 1.1 liters/min, p = NS), leg VO2 (261 +/- 104 to 281 +/- 157 ml/min, p = NS) or leg lactate release (269 +/- 149 to 227 +/- 151 mg/min, p = NS). These data suggest that, during exercise in patients with heart failure, angiotensin II does not interfere with blood flow to working skeletal muscle.     

Effect of chronic oral digoxin therapy on ventricular function at rest and peak exercise in patients with ischemic heart disease: Assessment with equilibrium gated blood pool imaging

The effect of chronic digoxin therapy on left ventricular ejection fraction, left ventricular volumes and cardiac output was assessed using multigated blood pool imaging both at rest and during supine exercise in 14 patients with known ischemic heart disease. Digoxin had no significant effect on ejection fraction at rest or at peak exercise. Neither exercise nor digoxin therapy had a significant influence on stroke volume index. Cardiac index was also not significantly influenced by digoxin either at rest (3.1 ± 1.15 without digoxin versus 2.9 ± 1.03 liters/min per m² during digoxin therapy) or at peak exercise (5.1 ± 2.08 versus 5.1 ± 2.04 liters/min per m², respectively), although the increase in heart rate resulted in a significant increase in cardiac index with exercise in each state (p <0.01).End-diastolic and end-systolic volume indexes both tended to be smaller at rest after digoxin therapy than before, but this difference was not significant. In the eight patients with an ejection fraction at rest of less than 0.50 (range 0.15 to 0.47), both end-diastolic and end-systolic volume indexes increased significantly with exercise (p <0.05) irrespective of therapy with digoxin. Conversely, in the six patients with a well preserved (greater than 0.50) ejection fraction at rest, digoxin prevented the exerciseinduced increase in end-diastolic and end-systolic volume indexes, and at peak exercise end-systolic volume index was significantly smaller during digoxin therapy than before it (p <0.05).It is concluded that chronic digoxin therapy in patients with stable ischemic heart disease (1) does not have a significant deleterious functional effect on the nonfailing heart, and (2) does not result in a significant change in left ventricular function at rest, but that it (3) does provide improved ventricular function at peak exercise in patients with well preserved left ventricular function at rest.     

Lidocaine disposition in obesity

Fourteen obese men (mean weight 124 ± 8 kg (± standard error of the mean), percent ideal body weight (IBW) 169 ± 10%), 11 obese women (96 ± 6 kg; 174 ± 11% IBW), 19 control men (69 ± 1 kg; 93 ± 2% IBW), and 12 control women (59 ± 2 kg; 102 ± 3% IBW), all of similar age and without clinical or laboratory evidence of cardiac or renal dysfunction, received a single 25-mg intravenous dose of lidocaine. Elimination half-life was markedly prolonged in obese compared with control men (2.69 ± 0.2 vs 1.62 ± 0.06 hour, p < 0.001) and in obese compared with control women (2.95 ± 0.1 vs 2.08 ± 0.06 hour, p <0.01). This was not the result of a change in clearance (men, obese vs control: 1,427 ± 117 vs 1,346 ± 86 ml/min, difference not significant, [NS]; women: 1,089 ± 83 vs 1,162 ± 84 ml/min, NS), but rather of an increased absolute volume of distribution (Vd) in obese men (325 ± 29 vs 186 ± 12 liters, p <0.001) and obese women (264 ± 20 vs 209 ± 15 liters, p <0.025). Vd corrected for total body weight was unchanged in obesity for both men (2.67 ± 0.22 vs 2.71 ± 0.18 1/kg, NS) and women (2.88 ± 0.31 vs 3.57 ± 0.25, NS), suggesting that lidocaine Vd increases in parallel with body weight in both sexes. Because lidocaine clearance is determined mainly by hepatic blood flow, these findings suggest that extremes of body weight do not change hepatic blood flow. However, lidocaine distribution is markedly increased in obese subjects of either sex, and is distributed to the same extent into excess body weight as into IBW. Lidocaine loading doses in obese persons should be calculated based on total body weight, but infusion rate should not be changed.     

Exercise intolerance in patients with chronic heart failure: role of pulmonary diffusing limitation

In order to test the hypothesis of pulmonary diffusing capacityinvolvement in exercise limitation in subjects with chronicheart failure (CHF), lung transfer factor (TLCO), oxygen saturation(SaO₂), cardiac output (CO) and gas exchange were studied overthe course of an incremental exercise test in 10 patients and10 controls. Tlie TLCO and transfer coefficient for carbon monoxide(TLCOIVA) were measured at rest and during recovery by the singlebreath method. Tlie SaO₂ was followed non-invasively with afinger oximeter and CO was determined according to the carbondioxide rebreathing method. Analysis of respiratory variablesat maximal effort showed significantly lower values in patientswith CHF as regards peak oxygen uptake (VO₂), minute ventilation(VE), heart rate (HR), oxygen pulse (O₂ pulse), and CO withhigher ventilatory reserve (VR) than controls. At a comparableworkload (30 W), patients with CHF demonstrated higher valuesfor VE and lower values for CO than controls. The TLCO, expressedas percent of predicted values, was significantly lower in CHFpatients than controls, respectively, at rest (90.5 ±3.75%vs 106.8 ±3.8%) and within 5 min after maximal exercise(87 ±4.4% vs 117.4 +3.81%). Hie TLCOIVA showed comparabledata between the two groups at rest (81.7 ± 3.28 vs 90.3± 2.86%). However, significantly lower values of TLCOIVAwere obtained for CHF after maximal exercise in comparison tocontrol subjects (77.5 ±3.85% vs 96.3 ±3.95%). These results confirm the alteration of the main variables inrelation to cardiopulmonary exercise limitation in CHF, andindicate a significant decrease in TLCO and TLCOIVA after maximalexercise. Due to a possible accumulation of interstitial fluid,there is a suggestion of pulmonary suboedema involvement duringexercise in these patients.     

Arm-crank ergometry: a new method for the evaluation of coronary artery disease

We have developed an electrocardiographic stress test to evaluate coronary heart disease using an arm-crank device (modified bicycle ergometer) in patients unable to perform leg exercise. With an initial work load of 200 kg-m/min at 40 revolutions/min for 3 minutes, followed by 100 kg-m/min increments every 3 minutes to a maximum of 700 kg-m/min at the same speed, a linear relation between the increase in heart rate and work load was observed. Twenty-one patients underwent both conventional treadmill exercise (modified Bruce protocol) and arm-crank exercise on separate days. Peak heart rate was slightly slower with arm-crank exercise (81 ± 4 [standard error] vs. 85 ± 3 percent of maximal predicted heart rate for age, P < 0.02) but peak systolic blood pressure and heart rate-systolic blood pressure product (double product) did not differ significantly (157 ± 7 vs. 154 ± 6 mm Hg, P > 0.5) and (22.0 ± 1.2 vs. 22.5 ± 1.2 × 10³, P > 0.1). Ten patients with documented coronary artery disease, including 7 with angina pectoris, had an ischemie S-T segment response (0.08 second depression greater than 1 mm) by both methods and 10 patients (7 with previous myocardial infarction and 3 with normal coronary arteriograms) had negative results by both techniques. One patient with normal coronary arteriograms had a negative arm-crank test and a positive treadmill test. In 26 patients unable to perform leg exercise the mean peak heart rate, systolic blood pressure and double product with arm-crank exercise were not significantly different (P > 0.05) from those achieved by the ambulatory patients (73.2 ± 1.9 vs. 81.0 ± 4.0 percent, 167 ± 8 vs. 157 ± 7 mm Hg and 22.4 ± 1.2 vs. 22.0 ± 1.4 × 10³, respectively). Six of 26 patients unable to perform leg exercise had a positive arm-crank test. Four of these six patients had angina pectoris and three had a previous myocardial infarction. We conclude that arm-crank exercise is comparable to treadmill exercise and is a reliable alternative method for the evaluation of suspected coronary artery disease in patients unable to perform leg exercise.     

Relation between central and peripheral hemodynamics during exercise in patients with chronic heart failure. Muscle blood flow is reduced with maintenance of arterial perfusion pressure

We studied the central hemodynamic, leg blood flow, and metabolic responses to maximal upright bicycle exercise in 30 patients with chronic heart failure attributable to severe left ventricular dysfunction (ejection fraction, 24 +/- 8%) and in 12 normal subjects. At peak exercise, patients demonstrated reduced oxygen consumption (15.1 +/- 4.8 vs. 32.1 +/- 9.9 ml/kg/min, p less than 0.001), cardiac output (8.7 +/- 3.2 vs. 18.6 +/- 4.4 l/min, p less than 0.001), and mean systemic arterial blood pressure (116 +/- 15 vs. 135 +/- 13 mm Hg, p less than 0.01) compared with normal subjects. Leg blood flow was decreased in patients versus normal subjects at rest and matched submaximal work rates and maximal exercise (2.1 +/- 1.9 vs. 6.4 +/- 1.4 l/min, all p less than 0.01). Mean systemic arterial blood pressure was no different in the two groups at rest or at matched submaximal work rates, whereas leg vascular resistance was higher in patients compared with normal subjects at rest, submaximal, and maximal exercise (all p less than 0.01). Although nonleg blood flow was decreased at rest in patients, it did not decrease significantly during exercise in either group. Peak exercise leg blood flow was related to peak exercise cardiac output in patients (r = 0.66, p less than 0.01) and normal subjects (r = 0.67, p less than 0.01). In patients, leg vascular resistance was not related to mean arterial blood pressure, pulmonary capillary wedge pressure, arterial catecholamines, arterial lactate, or femoral venous pH at rest or during exercise. Compared with normal subjects during submaximal exercise, patients demonstrated increased leg oxygen extraction and lactate production accompanied by decreased leg oxygen consumption. Thus, in patients with chronic heart failure compared with normal subjects, skeletal muscle perfusion is decreased at rest and during submaximal and maximal exercise, and local vascular resistance is increased. Our data indicate that nonleg blood flow and arterial blood pressure were preferentially maintained during exercise at the expense of leg hypoperfusion in our patients. This was associated with decreased leg oxygen utilization and increased leg oxygen extraction when compared to normal subjects, providing further evidence that reduced perfusion of skeletal muscle is important in causing early anaerobic skeletal muscle metabolism during exercise in subjects with this disorder.(ABSTRACT TRUNCATED AT 400 WORDS)     

Amrinone and exercise performance in patients with chronic heart failure

Whether cardiotonic agents can improve the ability of patients with chronic heart failure to exercise remains unknown. Accordingly, the circulatory and respiratory response of 11 patients with severe heart failure refractory to digitalis, diuretic drugs and vasodilators was assessed during upright treadmill exercise before, within 24 hours and after 4 weeks of therapy with amrinone. The purpose of this study was to determine the ability of amrinone therapy to improve exercise hemodynamics, effort tolerance and aerobic capacity of these patients. Acute intravenous administration of amrinone (1.8 ± 0.1 mg/kg body weight) produced the following changes (mean values ± standard error of the mean) in hemodynamic variables during supine rest; increased cardiac index (from 2.04 ± 0.39 to 2.99 ± 0.38 liters/min per m²; p <0.01) and reduced pulmonary wedge pressure (from 24 ± 6 to 14 ± 6 mm Hg; p <0.01) without altering heart rate or mean arterial pressure. Within 24 hours after administration of amrinone, wedge pressure decreased at the onset of (from 25 ± 7 to 14 ± 7 mm Hg) and throughout exercise (p <0.01), whereas the exercise response of cardiac output, arteriovenous oxygen difference, heart rate, pulmonary and systemic vascular resistances, maximal oxygen uptake and the pattern of ventilation remained similar to control values. However, after 4 weeks of amrinone therapy, exercise and aerobic capacities were increased 44 and 48 percent (p <0.03), respectively, whereas the ventilatory response was unchanged. Thus, amrinone is a potent cardiotonic agent that acutely improves the function of the failing heart at rest and during exercise; the maximal aerobic capacity was increased after 4 weeks of therapy. Amrinone therefore appears to hold promise for the management of patients with chronic heart failure.     

Brain function rescue effect of lactate following hypoglycaemia is not an adaptation process in both normal and Type I diabetic subjects

Aims/hypothesis. We have previously shown that lactate protects brain function during insulin-induced hypoglycaemia. An adaptation process could, however, not be excluded because the blood lactate increase preceded hypoglycaemia.¶Methods. We studied seven healthy volunteers and seven patients with Type I (insulin-dependent) diabetes mellitus with a hyperinsulinaemic (1.5 mU · kg^–1· min^–1) stepwise hypoglycaemic clamp (4.8 to 3.6, 3.0 and 2.8 mmo/l) with and without Na-lactate infusion (30 μmol · kg^–1· min^–1) given after initiation of hypoglycaemic symptoms.¶Results. The glucose threshold for epinephrine response was similar (control subjects 3.2 ± 0.1 vs 3.2 ± 0.1, diabetic patients = 3.5 ± 0.1 vs 3.5 ± 0.1 mmol/l) in both studies. The magnitude of the response was, however, blunted by lactate infusion (AUC; control subjects 65 ± 28 vs 314 ± 55 nmol/l/180 min, zenith = 2.6 ± 0.5 vs 4.8 ± 0.7 nmol/l, p < 0.05; diabetic patients = 102 ± 14 vs 205 ± 40 nmol/l/180 min, zenith = 1.4 ± 0.4 vs 3.2 ± 0.3 nmol/l, p < 0.01). The glucose threshold for symptoms was also similar (C = autonomic 3.0 ± 0.1 vs 3.0 ± 0.1, neuroglycopenic = 2.8 ± 0.1 vs 2.9 ± 0.1 mmol/l, D = autonomic 3.2 ± 0.1 vs 3.2 ± 0.1, neuroglycopenic 3.1 ± 0.1 vs 3.2 ± 0.1 mmol/l) but peak responses were significantly attenuated by lactate (score at 160 min C = 2.6 ± 1 vs 8.8 ± 1, and 0.4 ± 0.4 vs 4.8 ± 1, respectively; p = 0.02–0.01, D = 1.3 ± 0.5 vs 6.3 ± 1.7, and 2.3 ± 0.6 vs 5.7 ± 1.1 p = 0.07–0.02). Cognitive function deteriorated in both studies at similar glucose thresholds (C = 3.1 ± 0.1 vs 3.0 ± 0.1, D = 3.2 ± 0.1 vs 3.3 ± 0.2 mmol/l). Although in normal subjects a much smaller impairment was observed with lactate infusion (Δ four-choice reaction time at 160 min = 22 ± 12 vs 77 ± 31 ms; p = 0.02), in Type I diabetic patients lactate infusion was associated with an improvement in cognitive dysfunction (0.2 ± 0.4 vs –38 ± 0.2 Δ ms, p = 0.0001).¶Conclusion/interpretation. A blood lactate increase after the development of hypoglycaemic symptoms reduces counterregulatory and symptomatic responses to insulin-induced hypoglycaemia and favours brain function rescue both in normal and diabetic subjects. These findings confirm that lactate is an alternative substrate to glucose for cerebral metabolism under hypoglycaemic conditions. [Diabetologia (2000) 43: 733–741]     

Does dobutamine prevent the rise in left ventricular filling pressures observed during exercise after heart transplantation?

The purpose of the study was to evaluate whether infusion ofa beta-adrenergic agonist, prior to and during exercise, couldcompensate for reduced sympathetic stimulation and correct deficientacceleration of left ventricular relaxation, so preventing arise in left ventricular filling pressures during exercise aftercardiac transplantation. Abnormal left ventricular relaxationkinetics can contribute to exercise-induced diastolic dysfunctionof the cardiac allograft. This was demonstrated in transplantrecipients whose acceleration of left ventricular relaxationduring exercise was almost negligible recently and whose elevationof left ventricular end-diastolic pressure was high. Decreasedadrenergic tone due to denervation could be involved in deficientleft ventricular lusitropic response to exercise, because accelerationof left ventricular relaxation during exercise depends on adequatesympathetic stimulation. Serial supine bicycle exercise was performed at an identicalworkload in eight transplant recipients while in the controlstate and during continuous infusion of dobutamine, titratedbefore exercise to achieve a heart rate matching the heart rateat peak exercise in the control state. During control exercise,heart rate rose from 87 ± 8 to 104 ± 12 beats.min^–1 (P<0.05), left ventricular end-diastolic pressurefrom 14 ± 5 to 20 ± 4 mmHg (P<0.05), left ventriculardP/dt_max from 1374 ± 172 to 1854 ± 278 mmHg. s^–1(P<0.05), and cardiac output from 5.8 ± 0.9 to 8.5± 1.11. min^–1 P<0.05). There was a small butsignificant decrease of the time constant of left ventricularpressure decay (T) from 42 ± 6 to 38 ± 6 ms (P<0.05).During dobutamine infusion, exercise resulted in a further increasein heart rate from 108± 11 to 122 ± 17 mmHg (P<0.05),in cardiac output from 7.4 ± 0.9 to 10.3 ± 2.5l. min^–1 (P<0.05), and in left ventricular dP/dt_maxfrom2181 ± 220 to 2620 ± 214 mmHg. s^–1 (P<0.05).These values were higher than the measurements obtained at theend of the control exercise run (P<0.05). T failed to change(29 ± 4 vs 27 ± 5 mmHg, P>0.05) and left ventricularend-diastolic pressure increased from 5 ± 3 to 11 ±5 mmHg (P<0.05) but remained lower than at the end of thecontrol exercise run (11 ± 5 vs 20 ± 4 mmHg, P<0.05). Compensation for reduced sympathetic stimulation by administrationof dobutamine improves exercise haemodynamics in cardiac transplantrecipients, but cannot prevent the exercise-induced rise inleft ventricular end-diastolic pressure and correct deficientacceleration of left ventricular relaxation. Abnormal exercisehaemodynamics after heart transplantation are therefore onlypartly related to deficient sympathetic stimulation.     

Favorable effects of hydralazine on the hemodynamic response to isometric exercise in chronic severe aortic regurgitation

The hemodynamic effects of isometric exercise and the response to hydralazine therapy were evaluated in 11 patients with chronic, severe aortic regurgitation (AR). Isometric exercise produced a significant increase in heart rate (from 78 ± 11 to 93 ± 19 beats/min [mean ± standard deviation], p < 0.05), mean blood pressure (from 83 ± 8 to 104 ± 20 mm Hg, p < 0.05), mean right atrial pressure (from 3 ± 2 to 7 ± 5 mm Hg, p < 0.05) and mean pulmonary artery wedge pressure (from 12 ± 7 to 18 ± 10 mm Hg, p < 0.05). Small and insignificant changes were seen in cardiac index (from 3.4 ± 0.8 to 3.9 ± 1.0 liters/min/m²), systemic vascular resistance (from 1,097 ± 257 to 1,171 ± 284 dynes s cm^?5), pulmonary vascular resistance (from 120 ± 76 to 130 ± 89 dynes s cm^?5) and stroke volume index (from 44 ± 10 to 43 ± 12 ml/m²). After oral hydralazine administration (100 to 300 mg), hemodynamic values during isometric exercise were: Heart rate increased further, to 105 ± 14 beats/min (p < 0.05), mean blood pressure was 102 ± 16 mm Hg (difference not significant [NS]) cardiac index increased markedly, to 5.2 ± 1.4 liters/min/m² (p < 0.05), stroke volume index increased to 49 ± 12 ml/m² (p < 0.05), right atrial pressure decreased slightly, to 5 ± 5 mm Hg (NS), pulmonary artery wedge pressure decreased to 14 ± 7 mm Hg (p < 0.05), systemic vascular resistance decreased to 903 ± 288 dynes s cm^?5 (p < 0.05), and pulmonary vascular resistance changed to 100 ± 66 dynes s crrr^?5 (NS). Thus, isometric exercise in patients with chronic severe AR is associated with only a slight and insignificant increase in systemic vascular resistance, but a marked increase in pulmonary artery wedge pressure. Direct arteriolar vasodilation with hydralazine results in a significant attenuation of pulmonary artery wedge pressure increase during isometric exercise and leads concomitantly to a significant augmentation of stroke volume and cardiac output. These findings substantiate the value of hydralazine therapy in patients with chronic, severe AR.     

Exercise-induced increases in oxidized low-density lipoprotein are associated with adverse outcomes in chronic heart failure

BackgroundOxidative stress is an important pathophysiologic feature in chronic heart failure (CHF) and may in part result from the inability to counteract acute surges of circulating oxidant products. Oxidized low-density lipoprotein (oxLDL) is an emerging prognostic marker in CHF. Accordingly, we investigated the effect of exercise-induced oxidative stress on circulating levels of oxLDL and its association with clinical outcomes in CHF.Methods and ResultsPlasma levels of oxLDL and low-density lipoprotein cholesterol (LDL-c) were measured at rest and after maximal exercise in 48 subjects with CHF and 12 healthy controls. Subjects with CHF had a higher baseline oxLDL (77.7 ± 3.2 U/L vs 57.9 ± 5.0 U/L, P = .01) and a higher baseline oxLDL/LDL-c ratio (0.87 ± 0.04 vs 0.49 ± 0.04, P ≤ .001). Exercise induced an increase in oxLDL in subjects with CHF (77.7 ± 3.2 U/L to 85.3 ± 3.0 U/L, P ≤ .001) but not in controls (57.9 ± 5.0 to 61.4 ± 5.5, P = .17). In 39 subjects for whom follow-up data were available, an increase in oxLDL of more than 11.0 U/L was associated with an increased risk to meet a combined end point of death and need for ventricular assist device or heart transplant during a 19-month follow-up period (hazard ratio 8.6; 95% confidence interval 1.0–73.8, P = .05); this remained significant when adjusted for peak oxygen consumption, left ventricular ejection fraction, New York Heart Association class, sex, and age (hazard ratio 46.6, 95% confidence interval 1.5–1438.1, P = .02).ConclusionPlasma oxLDL and the oxLDL/LDL-c ratio are elevated in subjects with CHF. Whether assessment of oxLDL during maximal exercise allows early identification of subjects at highest risk for adverse outcomes should be systematically investigated.     

Surgical ablation of atrial fibrillation in patients with congestive heart failure

BackgroundCongestive heart failure (CHF) and atrial fibrillation (AF), both of which cause morbidity and mortality, are mutually promoting diseases. We aimed to evaluate surgical AF ablation in CHF.Methods and ResultsAmong 212 patients (age 69 ± 8.8 years, 87% with persistent AF) undergoing concomitant left atrial (LA) ablation, 79 (37.3%) presented CHF (n = 62 with a left ventricular ejection fraction [LVEF] 0.31–0.45, n = 17 with an LVEF ≤ 0.30). Patients with CHF were similar to controls regarding AF duration (61 ± 65.1 months vs. 54 ± 67.2 months, not significant [NS]), LA diameter (49 ± 7.5 mm vs. 50 ± 9.2 mm, NS), and heart rate (78 ± 18.4 min⁻¹ vs. 81 ± 21.3 min⁻¹, NS), but they required more circulatory support (17.7% vs. 1.5%, P < .001) and a longer intensive care unit stay (6 ± 9.5 days vs. 4 ± 10.5 days, P = .032). At follow-up after 13 ± 7.3 months, 42 patients (66%) with CHF and 81 controls (74%, NS) were in sinus rhythm (SR) (55% and 64% without antiarrhythmic drugs, respectively, NS). Univariate and logistic regression analysis revealed that AF duration and LA diameter predicted rhythm outcome but not CHF. In patients with an LVEF of 0.30 or less, SR conversion significantly improved LVEF, New York Heart Association class, and Minnesota Living with Heart Failure score. Kaplan-Meier estimates suggested superior survival of patients with stable SR (100% vs. 73%, log-rank P < .05).ConclusionsIf patients presenting with CHF and AF require cardiac surgery, concomitant AF ablation should be considered, especially if left ventricular function is severely impaired.     

Captopril versus placebo in congestive heart failure: effects on oxygen delivery to exercising skeletal muscle

The effects of captopril versus placebo on oxygen consumptionin the exercising leg have been examined Doppler measurementsof femoral flow and arteriovenous oxygen difference. Twentypatients with heart failure were randomized to captopril 25mg (N =10) or placebo (N =10). Maximal supine exercise of onewas performed before treatment and again 1 h and 4 h afterwards.Systemic haemodynamic variables were unaffected by placebo,but captopril increased stroke index at peak exercise from 26±3to 34±3 ml beat^-1 m^-2 and reduced pulmonary artery wedgepressure from 26±3 to 16±3 mmHg (P<0.05). Despitecaptopril-induced improvement in left ventricular function,exercise duration did not increase significantly peak valuesfor femoral flow (1059±178 to 938±134 ml min ^-1,P = NS), and oxygen consumption (134±26 to 111±18ml min^-1, P = NS) in the exercising leg were unaffected. Cutaneousflow, as reflected skin temperature (27.5±0.4 to 27.6±0.4°C,P = NS), was also unaffected. In the patients randomized captopril,the acute improvement in left ventricular function was abbreviatedand, after 4 h, all variables had returned towards baseline.Moreover, when the invasive studies were repeated after fourweeks chronic treatment responsiveness to converting enzymeinhibition had attenuated and there were no detectable differencesbetween the captopril and placebo groups.These data have demonstratedan acute captopril-induced improvement in left ventricular functionpatients with congestive heart failure. Nevertheless the beneficialacute response was abbreviated predicting the development ofearly tolerance. Oxygen delivery to the exercising leg showedno tendency to increase acutely when left ventricular functionwas significantly improved, or chronically when systemic responsivenesshad attenuated. Thus irrespective of its effects on left ventricularfunction, captopril does not increase nutritive flow to exercisingskeletal muscle in congestive heart failure.     

Captopril versus placebo in congestive heart failure: effects on oxygen delivery to exercising skeletal muscle

The effects of captopril versus placebo on oxygen consumptionin the exercising leg have been examined Doppler measurementsof femoral flow and arteriovenous oxygen difference. Twentypatients with heart failure were randomized to captopril 25mg (N =10) or placebo (N =10). Maximal supine exercise of onewas performed before treatment and again 1 h and 4 h afterwards.Systemic haemodynamic variables were unaffected by placebo,but captopril increased stroke index at peak exercise from 26±3to 34±3 ml beat^-1 m^-2 and reduced pulmonary artery wedgepressure from 26±3 to 16±3 mmHg (P<0.05). Despitecaptopril-induced improvement in left ventricular function,exercise duration did not increase significantly peak valuesfor femoral flow (1059±178 to 938±134 ml min ^-1,P = NS), and oxygen consumption (134±26 to 111±18ml min^-1, P = NS) in the exercising leg were unaffected. Cutaneousflow, as reflected skin temperature (27.5±0.4 to 27.6±0.4°C,P = NS), was also unaffected. In the patients randomized captopril,the acute improvement in left ventricular function was abbreviatedand, after 4 h, all variables had returned towards baseline.Moreover, when the invasive studies were repeated after fourweeks chronic treatment responsiveness to converting enzymeinhibition had attenuated and there were no detectable differencesbetween the captopril and placebo groups.These data have demonstratedan acute captopril-induced improvement in left ventricular functionpatients with congestive heart failure. Nevertheless the beneficialacute response was abbreviated predicting the development ofearly tolerance. Oxygen delivery to the exercising leg showedno tendency to increase acutely when left ventricular functionwas significantly improved, or chronically when systemic responsivenesshad attenuated. Thus irrespective of its effects on left ventricularfunction, captopril does not increase nutritive flow to exercisingskeletal muscle in congestive heart failure.     

The disposal of an intravenously administered amino acid load across the human forearm

This study was designed to examine the role of the skeletal muscle in man in the disposal of an intravenously administered L-amino acid solution. Arterio-deep venous differences of amino acids, glucose and lactate, and blood flow across the human forearm were measured in 9 healthy normal male volunteers (age = 27 ± 2 yr, weight = 79 ± 4 kg and height = 180 ± 2 cms) after an overnight fast (12 hr). Glucose and alanine turnover rates were estimated using a continuous infusion of 3-³H-glucose and U-¹⁴C-alanine isotopes. All measurements were obtained during steady state conditions, basally and two hours after the start of an L-amino acid infusion (8.5% solution). During the control period there was a significant release of total alpha amino nitrogen (AAN) equal to $\text{300 ± 97 nmole}\text{100 g}$ forearm muscle/min with alanine and glutamine accounting for over 80% of that amount ($\text{260 ± 24 nmole}\text{100 g}\text{forearm muscle/min}$). The release of the branched chain amino acids (BCAA) was only significant for valine, while the release of each of the keto acids of leucine and valine, α-ketoisocaproate and α-ketoisovalerate ($\text{37 ± 12 and 36 ± 7 nmole}\text{100 ml}\text{forearm muscle/min respectively}$) was significant from zero and exceeded the release of the corresponding amino acids ($\text{13 ± 17 and 24 ± 7 nmole}\text{100 g}\text{forearm muscle/min for leucine and valine respectively}$). The infusion of the L-amino acid solution resulted in a reversal of amino acid balance across the forearm. There was a net uptake of AAN of $\text{1195 ± 209 nmole}\text{100 g}$ forearm muscle/min with the BCAA accounting for $\text{513 ± 75 nmole}\text{100 g}$ forearm muscle/min or 49 ± 6% of the uptake. The net uptake of BCAA by skeletal muscle did not exceed 35% of the amount infused. The release of α-ketoisocaproate and α-ketoisovalerate showed no significant change from basal levels. The output of alanine and glutamine persisted in response to the infusion; while alanine output dropped by 40%, glutamine output increased by 50% ($\text{68 ± 23 and 218 ± 42 nmole}\text{100 g}\text{forearm muscle/min respectively}$), yet the combined release of alanine and glutamine did not change significantly from basal levels. Amino acid infusion resulted in a twofold increase in insulin and glucagon. Plasma glucose fell from 5.3 ± 0.05 mM basally to 5.04 ± 0.06 mM (p < 0.05), while blood lactate increased from 0.587 ± 0.03 mM to 0.639 ± 0.025 mM (p < 0.05); similarly there was a time dependent increase in glucose uptake by muscle ($\text{from}\text{0.857 ± 0.08}\text{to}\text{1.27 ± 0.07 μ}\text{mole}\text{100 g}\text{forearm muscle/min}$, p < 0.05) and lactate release ($\text{0.226 ± 0.03}\text{to}\text{0.297 ± 0.045 μ}\text{mole}\text{100 g}\text{forearm muscle/min}\text{, p < 0.05}$). These results indicate that a significant amount of the amino acids infused, and specifically the BCAA are extracted by human skeletal muscle, and mostly retained as such for later use. The data obtained under the conditions of the present study also indicate that tissues other than skeletal muscle are as important in the overall handling of these amino acids. However, it remains to be seen whether these findings can be extrapolated to other physiological conditions.     

Inefficient ventilation and reduced respiratory muscle capacity in congestive heart failure

The extent and time-course of changes in lung volumes, ventilatory efficiency at rest and during exercise, and respiratory muscle function and their influence on exercise limitation in congestive heart failure (CHF) are unclear. It is unknown whether respiratory muscle function may predict changes in exercise limitation or may be impaired in patients with poor outcome. 145 male patients (54±1 years) suffering from CHF (NYHA class I–III, mean 2.3±0.1), with a LVEF of 23±1 %, and a mean peak O₂ uptake (V_O2peak) 15.0±:0.5 mL×min⁻¹×kg⁻¹, were studied. They were grouped in Weber functional classes A to D according to their V_O2peak. Significant increases in ventilatory equivalents for O₂ and CO₂ (V_E/V_CO2peak) and in dead space ventilation at rest and during exercise were found with increasing exercise limitation. Moreover, there was a correlation of static and dynamic lung volumes (inspiratory vital capacity, IVC, r = 0.43, P < 0.01), as well as of maximal inspiratory pressure (MIP; r = 0.46, P < 0.01) with V_O2peak. Patients who died (n = 26) or were heart transplanted (n = 20) during a follow-up (mean 800 ± 10 days) had a reduced MIP (6.4 ± 0.4 kPa) as compared with survivors (n = 82; 9.3±0.7 kPa, P < 0.01). In a subgroup of 33 patients re-evaluated after six months, individual changes in IVC and V_E/V_CO2peak, but not in MIP, correlated to changes in V_O2peak (r = 0.69 and r = 0.72 respectively; P < 0.01). In CHF, exercise limitation is associated with reversible lung restriction and inefficient ventilation at rest and during exercise. Patientss with severe CHF have a significant reduction in MIP, a finding that is associated with poor outcome. Received: 12 July 1999, Returned for 1. revision: 26 August 1999, 1. Revision received: 23 November 1999, Returned for 2. Revision: 16 December 1999, 2. Revision received: 28 January 2000, Accepted: 8 February 2000     

Metformin and Exercise: no Additive Effect on Blood Lactate Levels in Healthy Volunteers

Metformin administration has been associated with substantial rises in blood lactate concentrations in individual Type 2 diabetic patients. Exercise also leads to increases in blood lactate levels. The objective of this study was to determine whether metformin administration augments the rise in plasma lactate concentrations during intermittent exercise in healthy subjects, when compared to placebo. Twelve healthy males (age 28 ± 5 years, body mass index 22.7 ± 1.3 kg m⁻²) took either 1.7 g metformin or placebo daily for 4 consecutive days before being subjected to strenuous intermittent exercise. On the morning of the fourth day exercise was performed on an upright bicycle ergometer at a work load of 200 W for 2 min alternating with 2 min rest for an overall duration of 60 min. Maximal plasma lactate levels during exercise (metformin: 4.1 ± 2.6 mmol l⁻¹, placebo: 4.5 ± 2.6 mmol l⁻¹), areas under the plasma lactate curve (207 ± 121 vs 222 ± 133 mmol l⁻¹ h⁻¹), blood pyruvate levels at the end of exercise (0.06 ± 0.04 vs 0.07 ± 0.04 mmol l⁻¹), lactate/pyruvate ratio (65 ± 41 vs 60 ± 36), serum insulin (25.4 ± 8.9 vs 32.3 ± 13.0 pmol l⁻¹), and plasma glucose (4.4 ± 0.3 vs 4.5 ± 0.3 mmol l⁻¹) did not differ significantly between metformin and placebo administration. Administration of metformin did not lead to an augmented rise in endogenous plasma lactate concentrations during intermittent exercise in healthy fasting subjects under the experimental design chosen. © 1997 by John Wiley & Sons, Ltd.