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Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) was a multicenter, randomized controlled trial designed to examine the safety and efficacy of aerobic exercise training versus usual care in 2,331 patients with systolic heart failure (HF). In HF-ACTION patients with rest transthoracic echocardiographic measurements, the predictive value of 8 Doppler echocardiographic measurements-left ventricular (LV) diastolic dimension, mass, systolic (ejection fraction) and diastolic (mitral valve peak early diastolic/peak late diastolic [E/A] ratio, peak mitral valve early diastolic velocity/tissue Doppler peak early diastolic myocardial velocity [E/E'] ratio, and deceleration time) function, left atrial dimension, and mitral regurgitation severity-was examined for a primary end point of all-cause death or hospitalization and a secondary end point of cardiovascular disease death or HF hospitalization. Also compared was the prognostic value of echocardiographic variables versus peak oxygen consumption (Vo(2)). Mitral valve E/A and E/E' ratios were more powerful independent predictors of clinical end points than the LV ejection fraction but less powerful than peak Vo(2). In multivariate analyses for predicting the primary end point, adding E/A ratio to a basic demographic and clinical model increased the C-index from 0.61 to 0.62, compared with 0.64 after adding peak Vo(2). For the secondary end point, 6 echocardiographic variables, but not the LV ejection fraction or left atrial dimension, provided independent predictive power over the basic model. The addition of E/E' or E/A to the basic model increased the C-index from 0.70 to 0.72 and 0.73, respectively (all p values <0.0001). Simultaneously adding E/A ratio and peak Vo(2) to the basic model increased the C-index to 0.75 (p <0.0005). No echocardiographic variable was significantly related to the change from baseline to 3 months in exercise peak Vo(2). In conclusion, the addition of echocardiographic LV diastolic function variables improves the prognostic value of a basic demographic and clinical model for cardiovascular disease outcomes., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: Type 2 diabetes mellitus (T2DM) has been associated with reduced peak exercise capacity (VO(2peak)). The causes of this impairment are not clearly established, but evidence suggests that abnormalities in cardiac function play a significant role. We hypothesized that exercise would be associated with impaired cardiac function and hemodynamics in recently diagnosed T2DM, even in the absence of clinically evident cardiovascular complications., Methods: After baseline normal echocardiography screening, 10 premenopausal women with uncomplicated T2DM (average duration of diagnosed T2DM, 3.6 yr) and 10 healthy nondiabetic women of similar age, weight, and activity levels performed a peak cardiopulmonary exercise test while instrumented with an indwelling pulmonary artery catheter for assessing cardiac function. On separate days, technetium-99m sestamibi (cardolite) imaging was performed to assess myocardial perfusion at rest and peak exercise in seven T2DM and seven control patients., Results: Resting measures of cardiac hemodynamics were similar in T2DM and control subjects. Absolute VO(2peak) (mL x min(-1)) and peak cardiac output (L x min(-1)) tended to be lower in T2DM than in control subjects but did not reach statistical significance. However, pulmonary capillary wedge pressure (PCWP) rose significantly more during exercise in T2DM than in controls (148% vs 109% increase at peak exercise, P < 0.01). Normalized myocardial perfusion index was lower in persons with diabetes than in controls (11.0 +/- 3.5 x e(-9) vs 17.5 +/- 8.1 x e(-9), respectively, P < 0.05) and inversely related to peak exercise PCWP (R = -0.56, P < 0.05)., Conclusions: Cardiac hemodynamics during graded exercise are altered in women with recently diagnosed T2DM as demonstrated by the disproportionate increase in PCWP at peak exercise compared with controls subjects. Cardiac abnormalities observed are potentially early signs of subclinical cardiac dysfunction associated with T2DM, which may precede the more greatly impaired cardiac function at rest and with exercise observed in longer established T2DM.

Background: Peak oxygen consumption (VO(2)) is an important criterion for listing patients for cardiac transplantation. Beta-blockers improve survival without affecting peak VO(2). We questioned the value of peak VO(2) in predicting outcome in patients treated with beta-blockers., Methods and Results: We reviewed the records of 127 patients who had peak VO(2) measured at baseline and were subsequently treated with beta-blockers for at least 3 months. We divided the patients into 2 groups with peak oxygen consumption >14 (VO(2) hi) and < or =14 ml.kg.min (VO(2) lo). VO(2) hi had 109 patients and VO(2) lo had 18 patients. The combined end-point of death or cardiac transplantation was compared between groups. Mean peak VO(2) and left ventricular ejection fraction were lower in VO(2) lo versus VO(2) hi: 12.4+/-1.4 ml.kg.min versus 19.1+/-3.9 ml.kg.min and 17+/-8% versus 21+/-9%, respectively. At 30 months, the percentage of patients who did not reach the combined end-point was 94% in VO(2) lo versus 79% in VO(2) hi (P=.47). In multivariate analysis, only changes in heart rate and LVEF from baseline to follow-up were predictive of survival., Conclusions: Current peak VO(2) cutoff does not predict survival without transplantation of patients who tolerate chronic treatment with beta-blockers.

We evaluated the hypotheses that on acute exposure to hypobaric hypoxia, sympathetic stimulation leads to augmented muscle lactate production and circulating [lactate] through a beta-adrenergic mechanism and that beta-adrenergic adaptation to chronic hypoxia is responsible for the blunted exercise lactate response after acclimatization to altitude. Five control and 6 beta-blocked men were studied during rest and exercise at sea level (SL), on acute exposure to 4,300 m (A1), and after a 3-wk sojourn at altitude (A2). Exercise was by leg cycling at 49% of SL peak O2 consumption (VO2 peak) (65% of altitude VO2 peak or 87 +/- 2.6 W); beta-blockade was by propranolol (80 mg 3x daily), femoral arterial and venous blood was sampled; leg blood flow (Q) was measured by thermodilution, leg lactate net release [ = (2) (1-leg Q) venous-arterial concentrationL] was calculated, and vastus lateralis needle biopsies were obtained. Muscle [lactate] increased with exercise and acute altitude exposure but regressed to SL values with acclimatization; beta-blockade had no effect on muscle [lactate]. Arterial [lactate] rose during exercise at SL (0.9 +/- 0.1 to 1.5 +/- 0.3 mM); exercise at A1 produced the greatest arterial [lactate] (4.4 +/- 0.8 mM), and exercise at A2 an intermediate response (2.1 +/- 0.6 mM). beta-Blockade reduced circulating [lactate] approximately 45% during exercise under all altitude conditions. increased transiently at exercise onset but then declined over time under all conditions. Blood and muscle "lactate paradoxes" occurred independent of beta-adrenergic influences, and the hypotheses relating the blood lactate response at altitude to beta-adrenergic mechanisms are rejected. During exercise at altitude, arterial [lactate] is determined by factors in addition to hypoxemia, circulating epinephrine, and net lactate release from active muscle beds.

Whole body O2 uptake (VO2) during maximal and submaximal exercise has been shown to be preserved in the setting of beta-adrenergic blockade at high altitude, despite marked reductions in heart rate during exercise. An increase in stroke volume at high altitude has been suggested as the mechanism that preserves systemic O2 delivery (blood flow x arterial O2 content) and thereby maintains VO2 at sea-level values. To test this hypothesis, we studied the effects of nonselective beta-adrenergic blockade on submaximal exercise performance in 11 normal men (26 +/- 1 yr) at sea level and on arrival and after 21 days at 4,300 m. Six subjects received propranolol (240 mg/day), and five subjects received placebo. At sea level, during submaximal exercise, cardiac output and O2 delivery were significantly lower in propranolol- than in placebo-treated subjects. Increases in stroke volume and O2 extraction were responsible for the maintenance of VO2. At 4,300 m, beta-adrenergic blockade had no significant effect on VO2, ventilation, alveolar PO2, and arterial blood gases during submaximal exercise. Despite increases in stroke volume, cardiac output and thereby O2 delivery were still reduced in propranolol-treated subjects compared with subjects treated with placebo. Further reductions in already low levels of mixed venous O2 saturation were responsible for the maintenance of VO2 on arrival and after 21 days at 4,300 m in propranolol-treated subjects. Despite similar workloads and VO2, propranolol-treated subjects exercised at greater perceived intensity than subjects given placebo at 4,300 m. The values for mixed venous O2 saturation during submaximal exercise in propranolol-treated subjects at 4,300 m approached those reported at simulated altitudes >8,000 m. Thus beta-adrenergic blockade at 4,300 m results in significant reduction in O2 delivery during submaximal exercise due to incomplete compensation by stroke volume for the reduction in exercise heart rate. Total body VO2 is maintained at a constant level by an interaction between mixed venous O2 saturation, the arterial O2-carrying capacity, and hemodynamics during exercise with acute and chronic hypoxia.

Persons with type II diabetes mellitus (DM), even without cardiovascular complications have a decreased maximal oxygen consumption (VO2 max) and submaximal oxygen consumption (VO2) during graded exercise compared with healthy controls. We evaluated the hypothesis that change in the rate of VO2 in response to the onset of constant-load exercise (measured by VO2-uptake kinetics) was slowed in persons with type II DM. Ten premenopausal women with uncomplicated type II DM, 10 overweight, nondiabetic women, and 10 lean, nondiabetic women had a VO2 max test. On two separate occasions, subjects performed 7-min bouts of constant-load bicycle exercise at workloads below and above the lactate threshold to enable measurements of VO2 kinetics and heart rate kinetics (measuring rate of heart rate rise). VO2 max was reduced in subjects with type II DM compared with both lean and overweight controls (P < 0.05). Subjects with type II DM had slower VO2 and heart rate kinetics than did controls at constant workloads below the lactate threshold. The data suggest a notable abnormality in the cardiopulmonary response at the onset of exercise in people with type II DM. The findings may reflect impaired cardiac responses to exercise, although an additional defect in skeletal muscle oxygen diffusion or mitochondrial oxygen utilization is also possible.

Persons with non-insulin-dependent diabetes mellitus (NIDDM), in the absence of complications, have a decreased exercise performance compared with nondiabetic subjects. However, degree of impairment and factors associated with reduced exercise performance have not been fully characterized. Maximal exercise performance using a graded treadmill protocol was assessed in 10 sedentary persons with uncomplicated NIDDM (aged 51 +/- 7) and 10 healthy age- and activity-matched controls. Potential correlates of exercise performance measured included fasting and post-exercise glucose concentrations and fasting insulin concentration, hemoglobin A1C, hematocrit, and whole blood viscosity. At maximal exercise, diabetic persons had a 24% lower maximal walking time and 20% lower maximal VO2 than controls (both P < 0.05), while hemodynamic measures did not differ between groups. During graded exercise, at work loads below the maximal one, the relationship between VO2 and work load was significantly lower in persons with NIDDM than controls by an average of 16%. No correlations were found between peak exercise performance and any of the potential correlates of exercise performance measured. We conclude that persons with NIDDM have an impaired peak exercise performance not associated with degree of glycemic control. The reduced rate of increase in oxygen consumption during increasing submaximal work loads in NIDDM suggests that limitations in oxygen delivery may impair exercise performance in otherwise healthy persons with diabetes.

Persons with non-insulin-dependent diabetes mellitus (NIDDM), in the absence of complications, have a decreased exercise performance compared with nondiabetic subjects. However, degree of impairment and factors associated with reduced exercise performance have not been fully characterized. Maximal exercise performance using a graded treadmill protocol was assessed in 10 sedentary persons with uncomplicated NIDDM (aged 51 +/- 7) and 10 healthy age- and activity-matched controls. Potential correlates of exercise performance measured included fasting and post-exercise glucose concentrations and fasting insulin concentration, hemoglobin A1C, hematocrit, and whole blood viscosity. At maximal exercise, diabetic persons had a 24% lower maximal walking time and 20% lower maximal VO2 than controls (both P < 0.05), while hemodynamic measures did not differ between groups. During graded exercise, at work loads below the maximal one, the relationship between VO2 and work load was significantly lower in persons with NIDDM than controls by an average of 16%. No correlations were found between peak exercise performance and any of the potential correlates of exercise performance measured. We conclude that persons with NIDDM have an impaired peak exercise performance not associated with degree of glycemic control. The reduced rate of increase in oxygen consumption during increasing submaximal work loads in NIDDM suggests that limitations in oxygen delivery may impair exercise performance in otherwise healthy persons with diabetes.