Wade H. Martin

Effects of aging, sex, and physical training on cardiovascular responses to exercise.

BackgroundThe relative contributions of decreases in maximal heart rate, stroke volume, and oxygen extraction and of changes in body weight and composition to the age-related decline in maximal oxygen uptake (V˙o2max) are unclear and may be influenced by sex and level of physical activity. Methods and ResultsTo investigate mechanisms by which aging, sex, and physical activity influence V˙o2max, we quantified V˙o2, cardiac output, and heart rate during submaximal and maximal treadmill exercise and assessed weight and fat-free mass in healthy younger and older sedentary and endurance exercise-trained men and women. For results expressed in milliliters per kilogram per minute, a three-to-four-decade greater age was associated with a 40–41% lower V˙o2max in sedentary subjects and a 25–32% lower V˙o2max in trained individuals (p < 0.001). A smaller stroke volume accounted for nearly 50%o of these age-related differences, and the remainder was explained by a lower maximal heart rate and reduced oxygen extraction (all p < 0.001). Age-related effects on maximal heart rate and oxygen extraction were attenuated in trained subjects (p < 0.05). After normalization ofV˙o2max and maximal cardiac output to fat-free mass, age- and training-related differences were reduced by 24–47% but remained significant (p < 0.05). For trained but not sedentary subjects, maximal cardiac output and stroke volume normalized to fat-free mass were greater in men than in women (p < 0.05). ConclusionsA lower stroke volume, heart rate, and arteriovenous oxygen difference at maximal exercise all contribute to the age-related decline in V˙o2max. Effects of age and training on V˙o2max, maximal cardiac output, and stroke volume cannot be fully explained by differences in body composition. In sedentary subjects, however, the sex difference in maximal cardiac output and stroke volume can be accounted for by the greater percentage of body fat in women than in men.

Effect of exercise training in 60- to 69-year-old persons with essential hypertension

This study sought to determine whether 9 months of low- or moderate-intensity exercise training could decrease blood pressure (BP) in hypertensive men and women (mean age 64 +/- 3 years). Patients underwent weekly BP evaluations for 1 month to ensure that they had persistently elevated BP and then completed a maximal treadmill exercise test to exclude those with overt coronary artery disease. The low- and moderate-intensity groups trained at 53 and 73% of maximal oxygen consumption (VO2 max), respectively; however, total caloric expenditure per week was similar in both groups. VO2 max did not increase in the low-intensity group with training, but increased 28% in the moderate-intensity group. Diastolic BP decreased 11 to 12 mm Hg in both training groups. Systolic BP decreased 20 mm Hg in the low-intensity group with training, which was significantly greater than the change in the control and the moderate-intensity groups. Although systolic BP decreased 8 mm Hg in the moderate-intensity training group, this reduction was not significant. Training resulted in a somewhat lower cardiac output at rest in the low-intensity group, whereas total peripheral resistance decreased slightly in the moderate-intensity training group. Plasma and blood volumes, plasma renin levels and urinary sodium excretion did not change in either group with training. Both groups manifested lower plasma norepinephrine levels after training during standing rest, but not while supine. Thus, low-intensity training may lower BP as much or more than moderate-intensity training in older persons with essential hypertension, but the underlying mechanisms are unclear.

The effect of diabetes on outcomes of patients with advanced heart failure in the BEST trial

OBJECTIVES This was a retrospective analysis to determine the effect of diabetes on outcome in patients with advanced heart failure (HF), and to determine the effect of beta-blockade in patients with HF with and without diabetes mellitus. BACKGROUND In chronic HF the impact on clinical outcomes and therapeutic response of the prevalent comorbid condition diabetes mellitus has not been extensively investigated. METHODS We assessed the impact of diabetes on prognosis and effectiveness of beta-blocker therapy with bucindolol in patients with HF enrolled in the Beta-Blocker Evaluation of Survival Trial (BEST). We conducted a retrospective analysis to examine the prognosis of patients with advanced HF with and without diabetes, and the effect of beta-blocker therapy on mortality and HF progression or myocardial infarction (MI). The database was the 2,708 patients with advanced HF (36% with diabetes and 64% without diabetes) who were randomized to the beta-blocker bucindolol or placebo in BEST and followed for mortality, hospitalization, and MI for an average of two years. RESULTS Patients with diabetes had more severe chronic HF and more coronary risk factors than patients without diabetes. Diabetes was independently associated with increased mortality in patients with ischemic cardiomyopathy (adjusted hazard ratio 1.33, 95% confidence interval 1.12 to 1.58, p = 0.001), but not in those with a nonischemic etiology (adjusted hazard ratio 0.98, 95% confidence interval 0.74 to 1.30, p = 0.89). Compared with patients without diabetes, in diabetic patients beta-blocker therapy was at least as effective in reducing death or HF hospitalizations, total hospitalizations, HF hospitalizations, and MI. Ventricular function and physiologic responses to beta-blockade were similar in patients with and without diabetes. CONCLUSIONS Diabetes worsens prognosis in patients with advanced HF, but this worsening appears to be limited to patients with ischemic cardiomyopathy. In advanced HF beta-blockade is effective in reducing major clinical end points in patients with and without diabetes.

Effects of aging, gender, and physical training on peripheral vascular function

BackgroundBlood pressure and total peripheral resistance increase with age. However, the effect of age on vasodilatory capacity has not been characterized. Methods and ResultsTo delineate the effects of aging, gender, and physical training on peripheral vascular function, we measured blood pressure during submaximal and maximal treadmill exercise and measured blood pressure, calf blood flow, and calf conductance (blood flow/mean blood pressure) at rest and during maximal hyperemia in 58 healthy sedentary subjects (men aged 25 ± 5 and 65 ± 3 years and women aged 27 ± 5 and 65 ± 4 years) and in 52 endurance exercise-trained subjects (men aged 30 ± 3 and 65 ± 4 years and women aged 27 ± 3 and 65 ± 3 years). Systolic and mean blood pressures were higher at rest, during maximal calf hyperemia, and during submaximal exercise of the same intensity in the older than in the younger subjects of the same gender and exercise training status (p < 0.01). The magnitude of the age-related effect on blood pressure during exercise was greater in women than in men (p < 0.01). Diastolic blood pressure during submaximal exercise was also higher in the older than in the younger subjects (p < 0.05) but not in women treated with estrogen replacement. In contrast, systolic and mean blood pressures during submaximal work were lower in physically conditioned subjects than in sedentary age- and gender-matched subjects (p < 0.05) but not in older women. Increased age was associated with reduced maximal calf conductance in women (p < 0.01) but not in men. However, calf vasodilatory capacity was higher in trained than in untrained subjects (p < 0.01), regardless of age and gender. There was a significant inverse relation between maximal calf conductance and systolic, diastolic, and mean blood pressures during submaximal exercise (r = −0.31 to −0.53, p < 0.01) and a direct relation between maximal calf conductance and maximal oxygen uptake (r =0.66, p < 0.0001). ConclusionsThus, for healthy subjects between the ages of 25 and 65 years, there is an interactive effect between age and gender and an independent effect of physical -training on peripheral vascular function.

Cardiac effects of prolonged and intense exercise training in patients with coronary artery disease

The effects of intense and prolonged exercise training on the heart were studied with echocardiography in eight men with coronary artery disease with a mean age (+/- standard error of the mean) of 52 +/- 3 years. Training consisted of endurance exercise 3 times/week at 50 to 60 percent of the measured maximal oxygen uptake for 3 months followed by exercise 4 to 5 days/week at 70 to 80 percent of maximal oxygen uptake for 9 months. Maximal oxygen uptake capacity increased by 42 percent (26 +/- 1 versus 37 +/- 2 ml/kg per min; p less than 0.001). Heart rate at rest and submaximal heart rate and systolic blood pressure at a given work rate were significantly lower after training. Systolic blood pressure at the time of maximal exercise increased (145 +/- 9 before versus 166 +/- 8 mm Hg after training; probability [p] less than 0.01). Left ventricular end-diastolic diameter was increased after 12 months of training (from 47 +/- 1 to 51 +/- 1 mm; p less than 0.01). Left ventricular fractional shortening and mean velocity of circumferential shortening decreased progressively in response to graded isometric handgrip exercise before training but not after training. At comparable levels of blood pressure during static exercise, mean velocity of circumferential shortening was significantly higher after training (0.76 +/- 0.04 versus 0.98 +/- 0.07 diameter/sec, p less than 0.01). No improvement in echocardiographic or exercise variables was observed over a 12 month period in another group of five patients who did not exercise. Thus the data suggest that prolonged and vigorous exercise training in selected patients with coronary artery disease can elicit cardiac adaptations.

Effects of physical deconditioning after Intense endurance training on left ventricular dimensions and stroke volume

To determine the role of preload in maintaining the enhanced stroke volume of upright exercise-trained endurance athletes after deconditioning, six highly trained subjects undergoing upright and supine bicycle ergometry were characterized before and after 3, 8 and 12 weeks of inactivity that reduced oxygen uptake by 20%. During exercise, oxygen uptake, cardiac output by carbon dioxide rebreathing, cardiac dimensions by M-mode echocardiography, indirect arterial blood pressure and heart rate were studied simultaneously. Two months of inactivity resulted in a reduction in stroke volume, calculated as cardiac output/heart rate, during upright exercise (p less than 0.005) without a significant change during supine exercise. A concomitant decrease in the left ventricular end-diastolic dimension from the trained to the deconditioned state was observed in the upright posture (5.1 +/- 0.3 versus 4.6 +/- 0.3 cm; p = 0.02) but not with recumbency (5.4 +/- 0.2 versus 5.1 +/- 0.3 cm; p = NS). There was a strong correlation between left ventricular end-diastolic dimension and stroke volume (r greater than 0.80) in all subjects. No significant changes in percent fractional shortening or left ventricular end-systolic dimension occurred in either position after cessation of training. Estimated left ventricular mass was 20% lower after 3 and 8 weeks of inactivity than when the subjects were conditioned (p less than 0.05 for both). Thus, the endurance-trained state for upright exercise is associated with a greater stroke volume during upright exercise because of augmented preload. Despite many years of intense training, inactivity for only a few weeks results in loss of this adaptation in conjunction with regression of left ventricular hypertrophy.

Effect of hyperthyroidism of short duration on cardiac sensitivity to beta-adrenergic stimulation☆

The effect of hyperthyroidism on cardiac sensitivity to beta-adrenergic stimulation in humans is controversial. To determine whether heart rate and left ventricular contractile sensitivity to beta-adrenergic stimulation are altered by hyperthyroidism in human subjects, the frequency, velocity and extent of left ventricular shortening at rest and during a 4-stage graded dose isoproterenol infusion were characterized in eight young healthy subjects before and after 2 weeks of daily administration of 100 micrograms of triiodothyronine (T3). The rate and extent of left ventricular shortening were determined by Doppler and two-dimensionally guided M-mode echocardiography. In the hyperthyroid state, heart rate at rest was faster (57 +/- 3 vs. 68 +/- 4 beats/min; p less than 0.001) and the slope of the relation of heart rate to the rate of isoproterenol infusion was 36% steeper (1,538 +/- 126 vs. 1,131 +/- 95; p less than 0.05). The left ventricular ejection time was shorter and the mean velocity of left ventricular circumferential fiber shortening (mVcf) was greater during all stages of isoproterenol infusion in the hyperthyroid versus the euthyroid state (p less than 0.01). After adjustment for the faster heart rate after T3 administration, left ventricular ejection time and mVcf were similar in the euthyroid and hyperthyroid states at baseline and during maximal beta-adrenergic stimulation but shortened and enhanced, respectively, during stages 1 and 2 of isoproterenol infusion (p less than 0.05). There was no effect of T3 administration on left ventricular mass, dimensions, end-systolic wall stress or stroke volume at rest or during any stage of isoproterenol infusion. These results indicate that in human subjects hyperthyroidism of short duration increases the sensitivity of heart rate and left ventricular shortening velocity to beta-adrenergic stimulation in the absence of changes in left ventricular mass, loading conditions or extent of shortening.

Endurance exercise training does not alter lipolytic or adipose tissue blood flow sensitivity to epinephrine

We evaluated the relationship between lipolysis and adipose tissue blood flow (ATBF) in response to epinephrine and the effect of endurance exercise training on these responses. Five healthy untrained men underwent a four-stage incremental epinephrine infusion (0.00125, 0.005, 0.0125, and 0.025 microgram. kg fat free mass(-1). min(-1)) plus hormonal clamp before and after 16 wk of cycle ergometry exercise training. Whole body glycerol and free fatty acid (FFA) rates of appearance (R(a)) in plasma were determined by stable isotope methodology, and ATBF was assessed by (133)Xe clearance. After each training session, subjects were fed the approximate number of calories expended during exercise to prevent changes in body weight. Glycerol R(a), FFA R(a), and ATBF increased when plasma epinephrine concentration reached 0.8 nM, but at plasma epinephrine concentrations >1.6 nM ATBF plateaued, whereas lipolysis continued to increase. Exercise training increased peak oxygen uptake by 24 +/- 7% (2.9 +/- 0.2 vs. 3.6 +/- 0.1 l/min; P < 0. 05) but did not alter body weight [70.5 +/- 3.8 vs. 72.0 +/- 3.8 kg; P = nonsignificant (NS)] or percent body fat (18.4 +/- 1.6 vs. 17.8 +/- 1.9%; P = NS). Lipolytic and ATBF responses to epinephrine were also the same before and after training. We conclude that the lipolytic and ATBF responses to epinephrine are coordinated when plasma epinephrine concentration is </=1.6 nM, but that at higher epinephrine concentrations, lipolysis continues to increase while ATBF remains constant. Endurance exercise training does not change lipolytic or ATBF sensitivity to epinephrine infusion in vivo during resting conditions.We evaluated the relationship between lipolysis and adipose tissue blood flow (ATBF) in response to epinephrine and the effect of endurance exercise training on these responses. Five healthy untrained men underwent a four-stage incremental epinephrine infusion (0.00125, 0.005, 0.0125, and 0.025 μg ⋅ kg fat free mass-1 ⋅ min-1) plus hormonal clamp before and after 16 wk of cycle ergometry exercise training. Whole body glycerol and free fatty acid (FFA) rates of appearance (Ra) in plasma were determined by stable isotope methodology, and ATBF was assessed by133Xe clearance. After each training session, subjects were fed the approximate number of calories expended during exercise to prevent changes in body weight. Glycerol Ra, FFA Ra, and ATBF increased when plasma epinephrine concentration reached 0.8 nM, but at plasma epinephrine concentrations >1.6 nM ATBF plateaued, whereas lipolysis continued to increase. Exercise training increased peak oxygen uptake by 24 ± 7% (2.9 ± 0.2 vs. 3.6 ± 0.1 l/min; P < 0.05) but did not alter body weight [70.5 ± 3.8 vs. 72.0 ± 3.8 kg; P = nonsignificant (NS)] or percent body fat (18.4 ± 1.6 vs. 17.8 ± 1.9%; P = NS). Lipolytic and ATBF responses to epinephrine were also the same before and after training. We conclude that the lipolytic and ATBF responses to epinephrine are coordinated when plasma epinephrine concentration is ≤1.6 nM, but that at higher epinephrine concentrations, lipolysis continues to increase while ATBF remains constant. Endurance exercise training does not change lipolytic or ATBF sensitivity to epinephrine infusion in vivo during resting conditions.

Use of endogenous carbohydrate and fat as fuels during exercise

Carbohydrate and fat are the major fuels used by working muscles during exercise. The use of these substrates requires the mobilization of endogenous reserves present in adipose tissue, liver, and skeletal muscle and delivery to muscle mitochondria for oxidation. The integration of these processes is complex and is affected by many factors. In the present article we will review the effect of exercise duration, exercise intensity, and aerobic fitness on carbohydrate and lipid metabolism during endurance exercise in human subjects.

Triiodothyronine, β-adrenergic receptors, agonist responses, and exercise capacity☆☆☆★

Abstract Although thyroid hormone excess results in increased β-adrenergic receptor density or agonist responses in some cells of experimental animals, the role of these effects in contributing to clinical manifestations of hyperthyroidism in human subjects is unclear. To shed further light on this issue, we characterized the effect of 2 weeks of excess triiodothyronine administration on cardiac and metabolic responses to graded-dose isoproterenol infusion, skeletal muscle β-adrenergic receptor density, and physiologic determinants of exercise capacity in young healthy subjects. The slope of the heart rate response to isoproterenol was 36% greater ( p p p p p