Brian D. Duscha

Exercise and Heart Failure A Statement From the American Heart Association Committee on Exercise, Rehabilitation, and Prevention

Heart failure (HF) may be defined as the inability of the heart to meet the demands of the tissues, which results in symptoms of fatigue or dyspnea on exertion progressing to dyspnea at rest. The inability to perform exercise without discomfort may be one of the first symptoms experienced by patients with HF and is often the principal reason for seeking medical care. Therefore, exercise intolerance is inextricably linked to the diagnosis of HF. It might be expected that a tight relationship would exist between indices of resting ventricular function and exercise capacity. Data indicate, however, that indices of resting ventricular function (such as ejection fraction [EF]) are only weakly correlated to exercise tolerance.1 Exercise intolerance is defined as the reduced ability to perform activities that involve dynamic movement of large skeletal muscles because of symptoms of dyspnea or fatigue. Many investigators have sought mechanisms to explain the source of exercise intolerance. The aims of this position statement are to review (1) factors that affect exercise tolerance, with specific emphasis on chronic HF due to systolic dysfunction; (2) data that support the role of exercise training in chronic systolic HF, including the risks and benefits; (3) data on exercise training in patients with HF due to diastolic dysfunction; and finally (4) the subgroups of patients with HF for which data are lacking, and (5) the subgroups of patients who should not be included in exercise training programs. We anticipate this report will stimulate appropriate use of exercise training in patients with HF when indicated and encourage further studies in those areas in which data are lacking. ### Cardiovascular The capacity for performing aerobic exercise depends on the ability of the heart to augment its output to the exercising muscles and the ability of these muscles to utilize oxygen from the delivered …

Effects of the Amount of Exercise on Body Weight, Body Composition, and Measures of Central Obesity STRRIDE—A Randomized Controlled Study

Background Obesity is a major health problem due, in part, to physical inactivity. The amount of activity needed to prevent weight gain is unknown. Objective To determine the effects of different amounts and intensities of exercise training. Design Randomized controlled trial (February 1999–July 2002). Setting and Participants Sedentary, overweight men and women (aged 40-65 years) with mild to moderate dyslipidemia were recruited from Durham, NC, and surrounding communities. Interventions Eight-month exercise program with 3 groups: (1) high amount/vigorous intensity (calorically equivalent to approximately 20 miles [32.0 km] of jogging per week at 65%-80% peak oxygen consumption); (2) low amount/vigorous intensity (equivalent to approximately 12 miles [19.2 km] of jogging per week at 65%-80%), and (3) low amount/moderate intensity (equivalent to approximately 12 miles [19.2 km] of walking per week at 40%-55%). Subjects were counseled not to change their diet and were encouraged to maintain body weight. Main Outcome Measures Body weight, body composition (via skinfolds), and waist circumference. Results Of 302 subjects screened, 182 met criteria and were randomized and 120 completed the study. There was a significant ( P Conclusions In nondieting, overweight subjects, the controls gained weight, both low-amount exercise groups lost weight and fat, and the high-amount group lost more of each in a dose-response manner. These findings strongly suggest that, absent changes in diet, a higher amount of activity is necessary for weight maintenance and that the positive caloric imbalance observed in the overweight controls is small and can be reversed by a modest amount of exercise. Most individuals can accomplish this by walking 30 minutes every day.

Capillary density of skeletal muscle: A contributing mechanism for exercise intolerance in class II-III chronic heart failure independent of other peripheral alterations

OBJECTIVES The study was conducted to determine if the capillary density of skeletal muscle is a potential contributor to exercise intolerance in class II-III chronic heart failure (CHF). BACKGROUND Previous studies suggest that abnormalities in skeletal muscle histology, contractile protein content and enzymology contribute to exercise intolerance in CHF. METHODS The present study examined skeletal muscle biopsies from 22 male patients with CHF compared with 10 age-matched normal male control patients. Aerobic capacities, myosin heavy chain (MHC) isoforms, enzymes, and capillary density were measured. RESULTS The patients with CHF demonstrated a reduced peak oxygen consumption when compared to controls (15.0+/-2.5 vs. 19.8+/-5.0 ml x kg(-1) x min(-1), p <0.05). Using cell-specific antibodies to directly assess vascular density, there was a reduction in capillary density in CHF measured as the number of endothelial cells/fiber (1.42+/-0.28 vs. 1.74+/-0.35, p = 0.02). In CHF, capillary density was inversely related to maximal oxygen consumption (r = 0.479, p = 0.02). The MHC IIx isoform was found to be higher in patients with CHF versus normal subjects (28.5+/-13.6 vs. 19.5+/-9.4, p <0.05). CONCLUSIONS There was a significant reduction in microvascular density in patients with CHF compared with the control group, without major differences in other usual histologic and biochemical aerobic markers. The inverse relationship with peak oxygen consumption seen in the CHF group suggests that a reduction in microvascular density of skeletal muscle may precede other skeletal muscle alterations and play a critical role in the exercise intolerance characteristic of patients with CHF.

Studies of a targeted risk reduction intervention through defined exercise (STRRIDE).

PURPOSE The Studies of a Targeted Risk Reduction Intervention through Defined Exercise (STRRIDE) trial is a randomized controlled clinical trial designed to study the effects of exercise training regimens differing in dose (kcal.wk-1) and/or intensity (relative to peak VO2) on established cardiovascular risk factors and to investigate the peripheral biologic mechanisms through which chronic physical activity alters carbohydrate and lipid metabolism to result in improvements in these parameters of cardiovascular risk in humans. METHODS We will recruit 384 subjects and randomly assign them to one of three exercise training regimens or to a sedentary control group. The recruiting goal is to attain a subject population that is 50% female and 30% ethnic minority. The overall strategy is to use graded exercise training regimens in moderately overweight subjects with impairments in insulin action and mild to moderate lipid abnormalities to investigate whether there are dose or intensity effects and whether adaptations in skeletal muscle (fiber type, metabolic capacity, and/or capillary surface area) account for improvements in insulin action and parameters of lipoprotein metabolism. We will study these variables before and after exercise training, and over the course of a 2-wk detraining period. The study sample size is chosen to power the study to examine differences in responses between subjects of different gender and ethnicity to exercise training with respect to the least sensitive parameter-skeletal muscle capillary density. RESULTS The driving hypothesis is that improvements in cardiovascular risk parameters derived from habitual exercise are primarily mediated through adaptations occurring in skeletal muscle. CONCLUSION Identification that amount and intensity of exercise matter for achieving general and specific health benefits and a better understanding of the peripheral mechanisms mediating the responses in carbohydrate and lipid metabolism to chronic physical activity will lead to better informed recommendations for those undertaking an exercise program to improve cardiovascular risk.

Effect of exercise intensity and volume on persistence of insulin sensitivity during training cessation.

The purpose of this study was to determine whether exercise prescriptions differing in volume or intensity also differ in their ability to retain insulin sensitivity during an ensuing period of training cessation. Sedentary, overweight/obese subjects were assigned to one of three 8-mo exercise programs: 1) low volume/moderate intensity [equivalent of approximately 12 miles/wk, 1,200 kcal/wk at 40-55% peak O(2) consumption (Vo(2peak)), 200 min exercise/wk], 2) low volume/vigorous intensity ( approximately 12 miles/wk, 1,200 kcal/wk at 65-80% Vo(2peak), 125 min/wk), and 3) high volume/vigorous intensity ( approximately 20 miles/wk, 2,000 kcal/wk at 65-80% Vo(2peak), 200 min/wk). Insulin sensitivity (intravenous glucose tolerance test, S(I)) was measured when subjects were sedentary and at 16-24 h and 15 days after the final training bout. S(I) increased with training compared with the sedentary condition (P < or = 0.05) at 16-24 h with all of the exercise prescriptions. S(I) decreased to sedentary, pretraining values after 15 days of training cessation in the low-volume/vigorous-intensity group. In contrast, at 15 days S(I) was significantly elevated compared with sedentary (P < or = 0.05) in the prescriptions utilizing 200 min/wk (low volume/moderate intensity, high volume/vigorous intensity). In the high-volume/vigorous-intensity group, indexes of muscle mitochondrial density followed a pattern paralleling insulin action by being elevated at 15 days compared with pretraining; this trend was not evident in the low-volume/moderate-intensity group. These findings suggest that in overweight/obese subjects a relatively chronic persistence of enhanced insulin action may be obtained with endurance-oriented exercise training; this persistence, however, is dependent on the characteristics of the exercise training performed.

Altered expression of myosin heavy chain in human skeletal muscle in chronic heart failure.

To explore further alterations in skeletal muscle in chronic heart failure (CHF), we examined myosin heavy chain (MHC) isoforms from biopsies of the vastus lateralis in nine male patients with class II-III (CHF) (left ventricular ejection fraction (LVEF) 26 +/- 11%, peak oxygen consumption (peak VO2) 12.6 +/- 2 mL.kg-1.min-1) and nine age-matched sedentary normal males (NL). The relative content of MHC isoforms I, IIa, and IIx was determined by gel electrophoresis as follows: The normal sedentary group (NL) had a higher percent of MHC type I when compared with the patients (NL 48.4 +/- 7% vs CHF patients 24 +/- 21.6%, P < 0.05, no difference between MCH IIa (NL 45.1 +/- 10.5% vs CHF 56.0 +/- 12.5%), and CHF patients had a higher relative content of MHC type IIx than did the normal group (NL 6.5 +/- 9.6% vs CHF 20.0 +/- 12.9%, P < 0.05. Three of nine patients had no detectable MHC type I. In patients relative expression of MHC type I (%) was related to peak VO2 (r = 0.70, P < 0.05). Our results indicate that major alterations in MHC isoform expression are present in skeletal muscle in CHF. These alterations parallel previously reported changes in fiber typing that may affect contractile function i skeletal muscle and possibly exercise performance. The absence of MHC type I in some CHF patients suggests that skeletal muscle changes in this disorder are not solely a result of deconditioning, buy may reflect a specific skeletal muscle myopathy in this disorder.

Deconditioning fails to explain peripheral skeletal muscle alterations in men with chronic heart failure

It remains controversial whether the skeletal muscle alterations in chronic heart failure (CHF) are due to disease pathophysiology or result from chronic deconditioning. The purpose of this study was to compare the skeletal muscle of CHF patients to peak oxygen consumption (peak VO(2)) matched sedentary controls. It has been established that skeletal muscle abnormalities are related to the exercise intolerance observed in patients with CHF. We studied the skeletal muscle of sedentary controls and patients with CHF matched for age, gender and peak VO(2). Hypothesis testing for the effects of group (CHF vs. normal), gender, and the interaction group x gender were performed. For capillary density only gender (p = 0.002) and the interaction of group x gender (p = 0.007) were significantly different. For 3-hydroxyl coenzyme A (CoA) dehydrogenase only group effect (p = 0.004) was significantly different. Mean values for capillary density were 1.46 +/- 0.28 for CHF men versus 1.87 +/- 0.32 for sedentary control men, 1.40 +/- 0.32 for CHF women versus 1.15 +/- 0.35 for sedentary control women. The activities for 3-hydroxyl CoA dehydrogenase were 3.09 +/- 0.88 for CHF men versus 4.05 +/- 0.42 for sedentary control men, 2.93 +/- 0.72 for CHF women versus 3.51 +/- 0.78 for sedentary control women. This study suggests that women and men adapt to CHF differently: men develop peripheral skeletal muscle abnormalities that are not attributable to deconditioning; women do not develop the same pathologic responses in skeletal muscle when compared with normal women matched for aerobic capacity.

Angiogenesis in Skeletal Muscle Precede Improvements in Peak Oxygen Uptake in Peripheral Artery Disease Patients

Objective—Peripheral artery disease (PAD) is characterized by impaired blood flow to the lower extremities, causing claudication and exercise intolerance. The mechanism(s) by which exercise training improves functional capacity is not understood. This study tested the hypothesis that in PAD patients who undergo supervised exercise training, increases in capillary density (CD) in calf muscle take place before improvements in peak oxygen uptake (VO2). Methods and Results—Thirty-five PAD patients were randomly assigned to 12 weeks of directly supervised or home-based exercise training. Peak VO2 testing and gastrocnemius muscle biopsies were performed at baseline and after training. CD (endothelial cells/mm2) was measured using immunofluorescence staining. After 3 weeks of directly supervised training, patients had an increase in CD (216±66 versus 284±77, P<0.01) but no increase in peak VO2. However, after 12 weeks, peak VO2 increased (15.3±2.8 versus 16.8±3.8, P<0.01), whereas in muscle, CD remained increased over baseline, but there were no changes in markers of oxidative capacity. Within subjects, CD was related to peak VO2 before and after directly supervised training. Conclusion—Changes in CD in ischemic muscle with training may modulate the response to training, and those changes precede the increase in VO2.

Plasma Levels of Soluble Tie2 and Vascular Endothelial Growth Factor Distinguish Critical Limb Ischemia From Intermittent Claudication in Patients With Peripheral Arterial Disease

OBJECTIVES Our purpose was to determine whether factors that regulate angiogenesis are altered in peripheral arterial disease (PAD) and whether these factors are associated with the severity of PAD. BACKGROUND Alterations in angiogenic growth factors occur in cardiovascular disease (CVD), but whether these factors are altered in PAD or correlate with disease severity is unknown. METHODS Plasma was collected from patients with PAD (n = 46) and healthy control subjects (n = 23). Peripheral arterial disease patients included those with intermittent claudication (IC) (n = 23) and critical limb ischemia (CLI) (n = 23). Plasma angiopoietin-2 (Ang2), soluble Tie2 (sTie2), vascular endothelial growth factor (VEGF), soluble VEGF receptor 1 (sVEGFR-1), and placenta growth factor (PlGF) were measured by enzyme-linked immunoadsorbent assay. In vitro, endothelial cells (ECs) were treated with recombinant VEGF to investigate effects on sTie2 production. RESULTS Plasma concentrations of sTie2 (p < 0.01), Ang2 (p < 0.001), and VEGF (p < 0.01), but not PlGF or sVEGFR-1, were significantly greater in PAD patients compared with control subjects. Plasma Ang2 was significantly increased in both IC and CLI compared with control subjects (p < 0.0001), but there was no difference between IC and CLI. Plasma VEGF and sTie2 were similar in control subjects and IC but were significantly increased in CLI (p < 0.001 vs. control or IC). Increased sTie2 and VEGF were independent of CVD risk factors or the ankle-brachial index, and VEGF treatment of ECs in vitro significantly increased sTie2 shedding. CONCLUSIONS Levels of VEGF and sTie2 are significantly increased in CLI, and sTie2 production is induced by VEGF. These proteins may provide novel biomarkers for CLI, and sTie2 may be both a marker and a cause of CLI.

Relationship between leg muscle capillary density and peak hyperemic blood flow with endurance capacity in peripheral artery disease

The aim of this study was to determine if skeletal muscle capillary density is lower in patients with peripheral artery disease (PAD) and if capillary density relates to functional limitations. PAD patients with intermittent claudication (IC) have a decreased exercise tolerance due to exercise-induced muscle ischemia. Despite the apparent role diminished arterial flow has in this population, the degree of walking pain and functional limitation is not entirely explained by altered hemodynamics of the affected limbs. We hypothesized that skeletal muscle capillary density is lower in PAD and is related to the functional impairment observed in this population. Sixty-four patients with PAD and 56 controls underwent cardiopulmonary exercise testing and a gastrocnemius muscle biopsy. A subset of these patients (48 PAD and 47 controls) underwent peak hyperemic flow testing via plethysmography. Capillary density in PAD patients was lower compared with controls (P < 0.001). After adjustment for several baseline demographic imbalances the model relating capillary density to peak oxygen consumption (Vo(2)) remained significant (P < 0.001). In PAD subjects, capillary density correlated with peak Vo(2), peak walking time (PWT), and claudication onset time (COT). Peak hyperemic blood flow related to peak Vo(2) in both PAD and control subjects. PAD is associated with lower capillary density, and capillary density is related to the functional impairment as defined by a reduced peak Vo(2), PWT, and COT. These findings suggest that alterations in microcirculation may contribute to functional impairment capacity in PAD.