Clinton A. Brawner

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.

Peak aerobic capacity predicts prognosis in patients with coronary heart disease

BACKGROUND It is unknown if contemporary preventive treatments such as statins or primary percutaneous coronary intervention in patients with coronary heart disease (CHD) have rendered obsolete the use of measured exercise capacity for assessment of future risk and prognosis. Using a sample of patients from 2 clinical sites, most of whom were taking beta-blockade, antiplatelet, and statin therapy, we hypothesized that peak oxygen consumption (Vo(2)) would remain a strong and independent predictor of all-cause and cardiovascular-specific mortality in men and women with CHD. METHODS We studied 2,812 patients with CHD between 1996 and 2004. All-cause and cardiovascular disease-specific mortality served as end points. RESULTS In all men and women and in a subgroup of patients following evidence-based care, peak Vo(2) remained a strong predictor of all-cause death, with every 1 mL x kg(-1) x min(-1) increase in peak Vo(2) associated with an approximate 15% decrease in risk of death. Among men, a peak Vo(2) (mL x kg(-1) x min(-1)) below approximately 15 was associated with the highest risk, whereas a peak Vo(2) above approximately 19 was associated with a low rate and risk for annual all-cause mortality. Among women, a peak Vo(2) below approximately 12 was associated with the highest risk, whereas a peak Vo(2) above approximately 16.5 was associated with the lowest rate and risk for annual all-cause mortality. CONCLUSIONS In men and women with CHD, peak Vo(2) remains an independent predictor of all-cause and cardiovascular-specific mortality.

Effects of exercise training on chronotropic incompetence in patients with heart failure.

OBJECTIVE To describe the effects of exercise training on chronotropic incompetence in patients with stable heart failure, as measured by their inability to achieve a peak exercise heart rate greater than 85% of maximum. BACKGROUND Exercise intolerance and chronotropic incompetence are characteristic of patients with heart failure. Exercise training improves exercise capacity in these patients; however, to what extent reversal of chronotropic incompetence contributes to such a response remains uncertain. METHODS Fifty-one patients undergoing standard medical therapy were randomly assigned to a 24-week exercise training program or a no exercise control group. Twenty-one of 26 patients assigned to the exercise group and 22 of 25 control patients completed the study. Peak oxygen consumption, resting and exercise plasma norepinephrine level, and quality of life (Living With Heart Failure Questionnaire) were assessed. RESULTS A significant (P <.05) increase in peak heart rate was observed in the exercise group (9 +/- 3 beats/min) when compared with the control group (1 +/- 3 beats/min). Among exercise-trained patients with chronotropic incompetence at baseline (n = 14), the increase in peak heart rate at week 24 was 12 +/- 3 beats/min. Peak oxygen consumption was significantly (P <.05) increased in the exercise group (204 +/- 57 mL/min) versus the control group (72 +/- 33 mL/min). Health-related quality of life was not significantly changed with exercise training. Twenty-four weeks of exercise training induced a greater (P <.05) reduction in plasma norepinephrine at rest and during exercise in patients with a nonischemic cardiomyopathy versus those with ischemic cardiomyopathy. CONCLUSIONS Exercise training results in an increase in peak heart rate and partial reversal of chronotropic incompetence among patients with stable heart failure. These responses contribute, in part, to the exercise training-induced increase in exercise capacity that occurs in these patients.

Relation Between Volume of Exercise and Clinical Outcomes in Patients With Heart Failure

OBJECTIVES This study determined whether greater volumes of exercise were associated with greater reductions in clinical events. BACKGROUND The HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial showed that among patients with heart failure (HF), regular exercise confers a modest reduction in the adjusted risk for all-cause mortality or hospitalization. METHODS Patients randomized to the exercise training arm of HF-ACTION who were event-free at 3 months after randomization were included (n = 959). Median follow-up was 28.2 months. Clinical endpoints were all-cause mortality or hospitalization and cardiovascular mortality or HF hospitalization. RESULTS A reverse J-shaped association was observed between exercise volume and adjusted clinical risk. On the basis of Cox regression, exercise volume was not a significant linear predictor but was a logarithmic predictor (p = 0.03) for all-cause mortality or hospitalization. For cardiovascular mortality or HF hospitalization, exercise volume was a significant (p = 0.001) linear and logarithmic predictor. Moderate exercise volumes of 3 to <5 metabolic equivalent (MET)-h and 5 to <7 MET-h per week were associated with reductions in subsequent risk that exceeded 30%. Exercise volume was positively associated with the change in peak oxygen uptake at 3 months (r = 0.10; p = 0.005). CONCLUSIONS In patients with chronic systolic HF, volume of exercise is associated with the risk for clinical events, with only moderate levels (3 to 7 MET-h per week) of exercise needed to observe a clinical benefit. Although further study is warranted to confirm the relationship between volume of exercise completed and clinical events, our findings support the use of regular exercise in the management of these patients.

6-min walk test provides prognostic utility comparable to cardiopulmonary exercise testing in ambulatory outpatients with systolic heart failure.

OBJECTIVES The goal of this study was to compare the prognostic efficacy of the 6-min walk (6MW) and cardiopulmonary exercise (CPX) tests in stable outpatients with chronic heart failure (HF). BACKGROUND CPX and 6MW tests are commonly applied as prognostic gauges for systolic HF patients, but few direct comparisons have been conducted. METHODS Stable New York Heart Association (NYHA) functional class II and III systolic HF patients (ejection fraction ≤ 35%) from the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial were studied. 6MW distance (6MWD) and CPX indices (peak oxygen consumption [VO(2)] and ventilatory equivalents for exhaled carbon dioxide [VE/VCO(2)] slope) were compared as predictors of all-cause mortality/hospitalization and all-cause mortality over 2.5 years of mean follow-up. RESULTS A total of 2,054 HF-ACTION participants underwent both CPX and 6MW tests at baseline (median age 59 years; 71% male; 64% NYHA functional class II and 36% NYHA functional class III/IV). In unadjusted models and in models that included key clinical and demographic covariates, C-indices of 6MWD were 0.58 and 0.65 (unadjusted) and 0.62 and 0.72 (adjusted) in predicting all-cause mortality/hospitalization and all-cause mortality, respectively. C-indices for peak VO(2) were 0.61 and 0.68 (unadjusted) and 0.63 and 0.73 (adjusted). C-indices for VE/VCO(2) slope were 0.56 and 0.65 (unadjusted) and 0.61 and 0.71 (adjusted); combining peak VO(2) and VE/VCO(2) slope did not improve the C-indices. Overlapping 95% confidence intervals and modest integrated discrimination improvement values confirmed similar prognostic discrimination by 6MWD and CPX indices within adjusted models. CONCLUSIONS In systolic HF outpatients, 6MWD and CPX indices demonstrated similar utility as univariate predictors for all-cause hospitalization/mortality and all-cause mortality. However, 6MWD or CPX indices added only modest prognostic discrimination to models that included important demographic and clinical covariates.

Cardiorespiratory Fitness and Risk of Incident Atrial Fibrillation Results From the Henry Ford Exercise Testing (FIT) Project

Background— Poor cardiorespiratory fitness (CRF) is an independent risk factor for cardiovascular morbidity and mortality. However, the relationship between CRF and atrial fibrillation (AF) is less clear. The aim of this analysis was to investigate the association between CRF and incident AF in a large, multiracial cohort that underwent graded exercise treadmill testing. Methods and Results— From 1991 to 2009, a total of 64 561 adults (mean age, 54.5±12.7 years; 46% female; 64% white) without AF underwent exercise treadmill testing at a tertiary care center. Baseline demographic and clinical variables were collected. Incident AF was ascertained by use of International Classification of Diseases, Ninth Revision code 427.31 and confirmed by linkage to medical claim files. Nested, multivariable Cox proportional hazards models were used to estimate the independent association of CRF with incident AF. During a median follow-up of 5.4 years (interquartile range, 3–9 years), 4616 new cases of AF were diagnosed. After adjustment for potential confounders, 1 higher metabolic equivalent achieved during treadmill testing was associated with a 7% lower risk of incident AF (hazard ratio, 0.93; 95% confidence interval, 0.92–0.94; P<0.001). This relationship remained significant after adjustment for incident coronary artery disease (hazard ratio, 0.92; 95% confidence interval, 0.91–0.93; P<0.001). The magnitude of the inverse association between CRF and incident AF was greater among obese compared with nonobese individuals (P for interaction=0.02). Conclusions— There is a graded, inverse relationship between cardiorespiratory fitness and incident AF, especially among obese patients. Future studies should examine whether changes in fitness increase or decrease risk of atrial fibrillation. This association was stronger for obese compared with nonobese, especially among obese patients.

The relationship of heart rate reserve to VO2 reserve in patients with heart disease

UNLABELLED Recent reports indicate that among healthy adults, % heart rate reserve (HRR) is more closely related to %VO2 reserve (VO2R) than it is to %VO2max. This finding, in addition to the disparity between %HRR and %VO2max which is greater at low intensities and among low fit individuals, led the American College of Sports Medicine to adopt the use of %VO2R in place of %VO2max when prescribing exercise intensity among healthy adults and persons with heart disease. However, the relationship of %HRR to %VO2R among persons with heart disease has not been described. PURPOSE Among patients with a myocardial infarction (MI) and patients with chronic heart failure (HF), test the hypothesis that %VO2R is equivalent to %HRR, while %VO2peak is not. METHODS Using a clinical cardiology outcomes database, symptom-limited treadmill tests from 65 patients with MI and 72 patients with HF were identified. Heart rate and VO2 data were measured continuously and averaged every 15 s. For each subject, linear regression was used to calculate the slope and y-intercept of %HRR versus %VO2R (assuming rest VO2 = 3.5 mL x kg(-1) x min(-1)) and %HRR versus %VO2peak. Mean slope and y-intercept were calculated for each group and compared with the line of identity (slope = 1, y-intercept = 0). RESULTS For the MI and HF groups, the slope of %HRR versus %VO2R was 0.96 +/- 0.02 (+/-SE; P = NS, slope vs 1) and 0.97 +/- 0.02 (P = NS), respectively. And the y-intercept was -1.9 +/- 2.1% (P = NS, y-intercept vs 0) and -5.9 +/- 2.1% (P < 0.05) for MI and HF, respectively. For both patient groups, the regression of %HRR versus %VO2peak resulted in a line that differed (P < 0.001) in both slope and y-intercept from the line of identity. CONCLUSIONS In patients with heart disease, %HRR is a better estimate of %VO2R than %VO2peak. This finding does not affect the current recommended use of %HRR. However, when prescribing exercise based on VO2, relative intensity should be expressed as %VO2R.

Rationale and design of the henry ford exercise testing project (the FIT project)

Although physical fitness is a powerful prognostic marker in clinical medicine, most cardiovascular population‐based studies do not have a direct measurement of cardiorespiratory fitness. In line with the call from the National Heart Lung and Blood Institute for innovative, low‐cost, epidemiologic studies leveraging electronic medical record (EMR) data, we describe the rationale and design of the Henry Ford ExercIse Testing Project (The FIT Project). The FIT Project is unique in its combined use of directly measured clinical exercise data retrospective collection of medical history and medication treatment data at the time of the stress test, retrospective supplementation of supporting clinical data using the EMR and administrative databases and epidemiologic follow‐up for cardiovascular events and total mortality via linkage with claims files and the death registry. The FIT Project population consists of 69 885 consecutive physician‐referred patients (mean age, 54 ± 10 years; 54% males) who underwent Bruce protocol treadmill stress testing at Henry Ford Affiliated Hospitals between 1991 and 2009. Patients were followed for the primary outcomes of death, myocardial infarction, and need for coronary revascularization. The median estimated peak metabolic equivalent (MET) level was 10, with 17% of the patients having a severely reduced fitness level (METs < 6). At the end of the follow‐up duration, 15.9%, 5.6%, and 6.7% of the patients suffered all‐cause mortality, myocardial infarction, or revascularization procedures, respectively. The FIT Project is the largest study of physical fitness to date. With its use of modern electronic clinical epidemiologic techniques, it is poised to answer many clinically relevant questions related to exercise capacity and prognosis.

Caloric expenditure during cardiac rehabilitation.

PURPOSE The purpose of this study was to describe estimated caloric expenditure among patients in a maintenance cardiac rehabilitation program relative to a stated goal of approximately 300 kcal/session or 1,000 kcal/week. Additionally, we assessed the validity of several different methods for estimating caloric expenditure. METHODS The caloric expenditure for an exercise session was evaluated in 30 of 65 patients exercising in a maintenance cardiac rehabilitation program. Patients exercised using a treadmill, dual-action ergometer, upright stepper, or reclining stepper. The kilocalorie expenditure was assessed by three different techniques. The first used liquid crystal display (LCD) readings from the equipment (LCD method), the second combined both the American College of Sports Medicine metabolic equations for treadmill walking and the LCD values from the other equipment (Combined method), and the third measured oxygen consumption (VO2 method). RESULTS The caloric expenditure for the LCD, Combined, and VO2 methods were 247 +/- 83, 245 +/- 80, and 230 +/- 88 kcal, respectively. Agreement between methods using intraclass correlation analysis was r = 0.84 (0.68 to 0.92, 95% confidence intervals) for LCD versus VO2 and r = 0.88 (0.77 to 0.94, 95% confidence intervals) for Combined versus VO2 method. CONCLUSIONS Most patients (83%) in a maintenance cardiac rehabilitation program exercise below 300 kcal per session, a level believed to be necessary to illicit favorable changes in cardiovascular health. Additionally, the Combined method provides a reasonable estimate of kilocalorie expenditure. Use of kilocalorie expenditure should be considered in the cardiac rehabilitation setting as a fourth component in the exercise prescription.

Exercise training in heart failure

Patients with heart failure challenge the clinician with a constellation of difficult clinical, pathophysiologic, and psychologic issues. As a result, until recently, exercise training was not considered a safe and effective treatment strategy to be used in these patients. However, in the past 10 years, data from both randomized and nonrandomized trials showed that regular exercise training in patients with stable Class II and III heart failure can safely improve exercise tolerance, attenuate an overactivated sympathetic nervous system, partially reverse skeletal muscle abnormalities, and enhance health-related quality of life. These outcomes are achievable with a relatively moderate dose of physical activity, such as 30 to 60 minutes of walking or cycling 3 to 5 days per week at an intensity equivalent to 60% to 70% of peak oxygen consumption. Sufficiently powered trials are needed to assess morbidity, mortality, and cost-effectiveness endpoints relative to exercise training in patients with heart failure.