The obesity paradox in chronic heart failure: what does it mean?

Heart failure (HF) is a growing health problem, at least in part due to the concurrent obesity epidemic plaguing developed countries. However, once a patient develops HF, an elevated BMI appears to confer a survival benefit--a phenomenon termed the "obesity paradox." The exact explanation for this paradox has been difficult to ascertain. Numerous plausible mechanisms have been asserted, including the fact that obese patients tend to be younger and more symptomatic, leading them to seek medical attention earlier in the course of their HF. Obese patients may also have larger energy reserves that help to offset the catabolic changes seen with HF. Other hypotheses highlight the limitations of BMI as an obesity classifier. The purpose of this review is to examine the various theories for the obesity paradox in HF and discuss the implications for the clinical management of obese patients with HF.

Aerobic Versus Resistance Training Effects on Ventricular-Arterial Coupling and Vascular Function in the STRRIDE-AT/RT Trial.

Background: The goal was studying the differential effects of aerobic training (AT) vs. resistance training (RT) on cardiac and peripheral arterial capacity on cardiopulmonary (CP) and peripheral vascular (PV) function in sedentary and obese adults. Methods: In a prospective randomized controlled trial, we studied the effects of 6 months of AT vs. RT in 21 subjects. Testing included cardiac and vascular ultrasoundography and serial CP for ventricular-arterial coupling (Ees/Ea), strain-based variables, brachial artery flow-mediated dilation (BAFMD), and peak VO2 (pVO2; mL/kg/min) and peak O2-pulse (O2p; mL/beat). Results: Within the AT group (n = 11), there were significant increases in rVO2 of 4.2 mL/kg/min (SD 0.93) (p = 0.001); O2p of 1.9 mL/beat (SD 1.3) (p = 0.008) and the brachial artery post-hyperemia peak diameter 0.18 mm (SD 0.08) (p = 0.05). Within the RT group (n = 10) there was a significant increase in left ventricular end diastolic volume 7.0 mL (SD 9.8; p = 0.05) and percent flow-mediated dilation (1.8%) (SD 0.47) (p = 0.004). Comparing the AT and RT groups, post exercise, rVO2 2.97, (SD 1.22), (p = 0.03), O2p 0.01 (SD 1.3), (p = 0.01), peak hyperemic blood flow volume (1.77 mL) (SD 140.69) (p = 0.009), were higher in AT, but LVEDP 115 mL (SD 7.0) (p = 0.05) and Ees/Ea 0.68 mmHg/ml (SD 0.60) p = 0.03 were higher in RT. Discussion: The differential effects of AT and RT in this hypothesis generating study have important implications for exercise modality and clinical endpoints.

Safety of symptom-limited cardiopulmonary exercise testing in patients with chronic heart failure due to severe left ventricular systolic dysfunction.

BACKGROUND: To assess the safety of symptom-limited exercise testing in patients with New York Heart Association class II-IV heart failure symptoms due to left ventricular systolic dysfunction, we investigated the frequency of all-cause fatal and nonfatal major cardiovascular (CV) events among subjects enrolled in a prospective clinical trial (HF-ACTION). We hypothesized that exercise testing would be safe, as defined by a rate for all-cause death of <0.1 per 1,000 tests and a rate of nonfatal CV events <1.0 per 1,000 tests. METHODS: Before enrollment and at 3, 12, and 24 months after randomization, subjects were scheduled to complete a symptom-limited graded exercise test with open-circuit spirometry for analysis of expired gases. To ensure the accurate reporting of exercise test-related events, we report deaths and nonfatal major CV events per 1,000 tests at months 3, 12, or 24 after randomization. RESULTS: A total of 2,331 subjects were randomized into HF-ACTION. After randomization, 2,037 subjects completed 4,411 exercise tests. There were no test-related deaths, exacerbation of heart failure or angina requiring hospitalization, myocardial infarctions, strokes, or transient ischemic attacks. There was one episode each of ventricular fibrillation and sustained ventricular tachycardia. There were no exercise test-related implantable cardioverter defibrillator discharges requiring hospitalization. These findings correspond to zero deaths per 1,000 exercise tests and 0.45 nonfatal major CV events per 1,000 exercise tests (95% CI 0.11-1.81). CONCLUSIONS: In New York Heart Association class II-IV patients with severe left ventricular systolic dysfunction, we observed that symptom-limited exercise testing is safe based on no deaths and a rate of nonfatal major CV events that is <0.5 per 1,000 tests.

A sex-specific relationship between capillary density and anaerobic threshold.

Although both capillary density and peak oxygen consumption (Vo(2)) improve with exercise training, it is difficult to find a relationship between these two measures. It has been suggested that peak Vo(2) may be more related to central hemodynamics than to the oxidative potential of skeletal muscle, which may account for this observation. We hypothesized that change in a measure of submaximal performance, anaerobic threshold, might be related to change in skeletal muscle capillary density, a marker of oxidative potential in muscle, with training. Due to baseline differences among these variables, we also hypothesized that relationships might be sex specific. A group of 21 subjects completed an inactive control period, whereas 28 subjects (17 men and 11 women) participated in a 6-mo high-intensity exercise program. All subjects were sedentary, overweight, and dyslipidemic. Potential relationships were assessed between change in capillary density with both change in Vo(2) at peak and at anaerobic threshold with exercise training. All variables and relationships were assessed for sex-specific effects. Change in peak Vo(2) was not related to change in capillary density after exercise training in either sex. Men had a positive correlation between change in Vo(2) at anaerobic threshold and change in capillary density with exercise training (r = 0.635; P < 0.01), whereas women had an inverse relationship (r = -0.636; P < 0.05) between the change in these variables. These findings suggest that, although enhanced capillary density is associated with training-induced improvements in submaximal performance in men, this relationship is different in women.

Reproducibility of peak oxygen uptake and other cardiopulmonary exercise testing parameters in patients with heart failure (from the Heart Failure and A Controlled Trial Investigating Outcomes of exercise traiNing).

Peak oxygen uptake (pVo2) is an important parameter in assessing the functional capacity and prognosis of patients with heart failure. In heart failure trials, change in pVo2 was often used to assess the effectiveness of an intervention. However, the within-subject variability of pVo2 on serial testing may limit its usefulness. This study was designed to evaluate the within-subject variability of pVo2 over 2 baseline cardiopulmonary exercise tests. As a substudy of the HF-ACTION trial, 398 subjects (73% men, 27% women; mean age 59 years) with heart failure and left ventricular ejection fraction < or =35% underwent 2 baseline cardiopulmonary exercise tests within 14 days. Mean pVo2 was unchanged from test 1 to test 2 (15.16 +/- 4.97 vs 15.18 +/- 4.97 ml/kg/min; p = 0.78). However, mean within-subject absolute change was 1.3 ml/kg/min (10th, 90th percentiles 0.1, 3.0), with 46% of subjects increasing and 48% decreasing on the second test. Other parameters, including the ventilation-to-carbon-dioxide production slope and Vo2 at ventilatory threshold, also showed significant within-subject variation with minimal mean differences between tests. In conclusion, pVo2 showed substantial within-subject variability in patients with heart failure and should be taken into account in clinical applications. However, on repeated baseline cardiopulmonary exercise tests, there appears to be no familiarization effect for Vo2 in patients with HF. Therefore, in multicenter trials, there is no need to perform >1 baseline cardiopulmonary exercise test.

Improvements in signs and symptoms during hospitalization for acute heart failure follow different patterns and depend on the measurement scales used: an international, prospective registry to evaluate the evolution of measures of disease severity in acute heart failure (MEASURE-AHF).

BACKGROUND: The natural evolution of signs and symptoms during acute heart failure (AHF) is poorly characterized. METHODS AND RESULTS: We followed a prospective international cohort of 182 patients hospitalized with AHF. Patient-reported dyspnea and general well-being (GWB) were measured daily using 7-tier Likert (-3 to +3) and visual analog scales (VAS, 0-100). Physician assessments were also recorded daily. Mean age was 69 years and 68% had ejection fraction <40%. Likert measures of dyspnea initially improved rapidly (day 1, 0.22; day 2, 1.31; P <.001) with no significant improvement thereafter (day 7, 1.51; day 2 versus 7 P = .16). In contrast, VAS measure of dyspnea improved throughout hospitalization (day 1, 50.1; day 2, 64.7; day 7, 83.2; day 1 versus 2 P < .001, day 2 versus 7 P < .001). Symptoms of dyspnea and GWB tracked closely (correlation r = .813, P < .001). Physical signs resolved more completely than did symptoms (eg, from day 1 to discharge/day 7, absence of edema increased from 33% to 72% of patients, whereas significant improvements in dyspnea increased from 27% to 52% of patients; P < .001). CONCLUSIONS: Changes in patient-reported symptoms and physician-assessed signs followed different patterns during an AHF episode and are influenced by the measurement scales used. Multiple clinical measures should be considered in discharge decisions and evaluation of AHF therapies.

Relationship of depression to death or hospitalization in patients with heart failure.

BACKGROUND: Depression is widely recognized as a risk factor in patients with coronary heart disease. However, patients with heart failure (HF) have been less frequently studied, and the effect of depression on prognosis, independent of disease severity, is uncertain. METHODS: Two hundred four outpatients having a diagnosis of HF, with a ventricular ejection fraction of 40% or less, underwent baseline assessments including evaluation of depressive symptoms using the Beck Depression Inventory and of HF severity determined by plasma N-terminal pro-B-type natriuretic peptide. Cox proportional hazards regression analyses were used to examine the effects of depressive symptoms on a combined primary end point of death and hospitalizations because of cardiovascular disease (hereafter referred to as cardiovascular hospitalization) during a median follow-up of 3 years. RESULTS: Symptoms of depression (Beck Depression Inventory score) were associated with risk of death or cardiovascular hospitalization (P<.001) after controlling for established risk factors including HF disease severity, ejection fraction, HF etiology, age, and medications. Clinically significant symptoms of depression (Beck Depression Inventory score >/=10) were associated with a hazard ratio of 1.56 (95% confidence interval, 1.07-2.29) for the combined end point of death or cardiovascular hospitalization. Contrary to our expectation, antidepressant medication use was associated with increased likelihood of death or cardiovascular hospitalization (hazard ratio, 1.75; 95% confidence interval,1.14-2.68, P =.01) after controlling for severity of depressive symptoms and for established risk factors. CONCLUSIONS: Symptoms of depression were associated with an adverse prognosis in patients with HF after controlling for HF severity. The unexpected association of antidepressant medications with worse clinical outcome suggests that patients with HF requiring an antidepressant medication may need to be monitored more closely.

Effect of exercise training on ventricular function, dyssynchrony, resting myocardial perfusion, and clinical outcomes in patients with heart failure: a nuclear ancillary study of Heart Failure and A Controlled Trial Investigating Outcomes of Exercise TraiNing (HF-ACTION); design and rationale.

BACKGROUND: Technetium Tc 99m gated single photon emission computed tomography (SPECT) has become the cornerstone of noninvasive risk stratification in patients with ischemic heart disease, but its role in patients with heart failure is not as well established. STUDY DESIGN: This study is a substudy of the Heart Failure and A Controlled Trial Investigating Outcomes of Exercise TraiNing (HF-ACTION) trial--a National Institutes of Health/National Heart, Lung, and Blood Institute-funded randomized controlled trial--designed to evaluate the role of exercise training in patients with heart failure due to left ventricular dysfunction. For this substudy, a total of 300 patients distributed on an approximately 1:1 basis between the exercise training and usual care arms of HF-ACTION will undergo resting technetium Tc 99m gated SPECT at baseline and 12 months to compare changes in left ventricular function with exercise training. These changes, along with baseline data, will be correlated with changes in exercise parameters, inflammatory markers, and clinical outcomes: death, cardiovascular hospitalization, and quality of life scores. In a subset of patients, first-pass radionuclide ventriculography will be obtained to assess the relationship between ventricular dyssynchrony, ejection fraction, changes in exercise parameters, and outcomes. CONCLUSION: The role of nuclear imaging in patients with heart failure remains poorly defined. This substudy aims to harness the power of a large heart failure trial (HF-ACTION) to further delineate the utility of technetium Tc 99m gated SPECT imaging and first-pass radionuclide ventriculography for predicting important clinical outcomes in this population.

Obesity and physical activity: a review.

BACKGROUND AND METHODS: Obesity has become a problem of epidemic proportions in the U.S., with nearly two thirds of American adults being either overweight or obese. Current data suggest that this trend remains on the rise and threatens many of the gains that have been made in the prevention and treatment of heart disease. Exercise has long been considered an integral component of weight management, but available evidence suggests that exercise alone is a relatively inefficient means for losing weight. In contrast, regular exercise appears crucial in the prevention of weight gain and successful maintenance of weight loss, and in the fostering of cardiovascular health. This article reviews the available literature regarding the role of exercise in the prevention and treatment of obesity and evaluates the adequacy of current national guidelines.

Effects of exercise training amount and intensity on peak oxygen consumption in middle-age men and women at risk for cardiovascular disease.

STUDY OBJECTIVES: Although increasing aerobic fitness by exercise training is advocated as part of a healthy lifestyle, studies examining the different effects of intensity and amount on peak consumption (V(O2)) remain sparse. DESIGN: This randomized controlled trial compared the effects of three different exercise regimens differing in amount and intensity on fitness improvements. PARTICIPANTS: Overweight men and women with mild-to-moderate dyslipidemia were recruited. INTERVENTIONS: The exercise groups were as follows: (1) low amount/ moderate intensity (LAMI, n = 25), the caloric equivalent of walking 19 kilometers (km)/wk at 40 to 55% of peak V(O2); (2) low amount/high intensity (LAHI, n = 36), the equivalent of jogging 19 km/wk at 65 to 80% of peak V(O2); (3) high amount/high intensity (HAHI, n = 35), the equivalent of jogging 32 km/wk at 65 to 80% of peak V(O2); and (4) a control group (n = 37). MEASUREMENTS AND RESULTS: Peak V(O2) and time to exhaustion (TTE) were tested before and after 7 to 9 months of training. All exercise groups increased peak V(O2) and TTE compared to baseline (p < or = 0.001). Improvements in peak V(O2) were greater in the LAHI and HAHI groups compared to the control group (p < 0.02); HAHI group improvements were greater than the LAMI group (p < 0.02) and the LAHI group (p < 0.02). Increased TTE for all exercise groups was higher compared to the control group (p < 0.001) CONCLUSIONS: Exercising at a level of 19 km/wk at 40 to 55% of peak V(O2) is sufficient to increase aerobic fitness levels, and increasing either exercise intensity or the amount beyond these parameters will yield additional separate and combined effects on markers of aerobic fitness. Therefore, it is appropriate to recommend mild exercise to improve fitness and reduce cardiovascular risk yet encourage higher intensities and amounts for additional benefit.

Comparison of Estimations Versus Measured Oxygen Consumption at Rest in Patients With Heart Failure and Reduced Ejection Fraction Who Underwent Right-Sided Heart Catheterization.

Cardiac output during right-sided heart catheterization is an important variable for patient selection of advanced therapies (cardiac transplantation and left ventricular assist device implantation). The Fick method to determine cardiac output is commonly used and typically uses estimated oxygen consumption (VO2) from 1 of 3 published empirical formulas. However, these estimation equations have not been validated in patients with heart failure and reduced ejection fraction (HFrEF). The objectives of the present study were to determine the accuracy of 3 equations for estimating VO2 compared with direct measurement of VO2 and determine the extent clinically significant error occurred in calculating cardiac output of patients with HFrEF. Breath-by-breath measurements of VO2 from 44 patients who underwent cardiac catheterization (66% men; age, 65 ± 11 years, left ventricular ejection fraction, 22 ± 6%) were compared with the derived estimations of LaFarge and Miettinen, Dehmer et al, and Bergstra et al. Single-sample t tests found only the mean difference between the estimation of LaFarge and Miettinen and the measured VO2 to be nonsignificant (-10.3 ml/min ± 6.2 SE, p = 0.053). Bland-Altman plots demonstrated unacceptably large limits of agreement for all equations. The rate of ≥25% error in the equations by LaFarge and Miettinen, Dehmer et al, and Bergstra et al occurred in 11%, 23%, and 45% of patients, respectively. Misclassification of cardiac index derived from each equation for 2 clinically important classifications: cardiogenic shock-21%, 23%, and 32% and hypoperfusion-16%, 16%, and 25%; respectively. In conclusion, these findings do not support the use of these empiric formulas to estimate the VO2 at rest in patients with HFrEF who underwent right-sided heart catheterization.

Effects of respiratory exchange ratio on the prognostic value of peak oxygen consumption and ventilatory efficiency in patients with systolic heart failure.

OBJECTIVES: The purpose of this analysis was to evaluate the prognostic characteristics of peak oxygen consumption (Vo2) and the minute ventilation/carbon dioxide (VE/Vco2) slope of different peak respiratory exchange ratios (RERs) obtained from cardiopulmonary exercise testing in patients with heart failure (HF). BACKGROUND: For patients with HF, peak Vo2 and the VE/Vco2 slope are used for assessing prognosis. Peak Vo2 is assessed in association with peak RER ≥1.10, indicating maximal effort and prognostic sensitivity. Conversely, the VE/Vco2 slope provides effort-independent prognostic discrimination. METHODS: Patients with HF scheduled to undergo cardiopulmonary exercise testing were enrolled. Patients were subclassified by peak RER (RER <1.00, RER 1.00 to 1.04, RER 1.05 to 1.09, RER ≥1.10) and followed for up to 3 years for major cardiac-related events (death, left ventricular assist device implantation, or cardiac transplantation). RESULTS: Included were 1,728 patients with HF (75% males; 40% ischemic etiology; age: 55 ± 14 years; left ventricular ejection fraction: 28 ± 10%). Two hundred seventy major events occurred, with no proportional differences across the RER subgroups. Multivariate Cox regression analysis indicated that the VE/Vco2 slope and peak Vo2 remained prognostic within each subgroup; the VE/Vco2 slope remained the strongest predictor. Receiver-operating characteristic analysis demonstrated equitable prognostic cutoffs for the VE/Vco2 slope (range: 34.9 to 35.7; area under the curve [AUC] range: 0.69 to 0.75) and peak Vo2 (range: 13.8 to 14.0 ml·kg(-1)·min(-1); AUC range: 0.68 to 0.75). CONCLUSIONS: Peak Vo2 provided a sensitive assessment of prognosis in patients with HF in all RER subgroups. The VE/Vco2 slope provided greater prognostic discrimination in all RER subgroups. Clinical consideration may be warranted for patients with low RER, low peak Vo2, and an elevated VE/Vco2 slope.

Worsening depressive symptoms are associated with adverse clinical outcomes in patients with heart failure.

OBJECTIVES: The purpose of this study was to assess the impact of changes in symptoms of depression over a 1-year period on subsequent clinical outcomes in heart failure (HF) patients. BACKGROUND: Emerging evidence shows that clinical depression, which is prevalent among patients with HF, is associated with a poor prognosis. However, it is uncertain how changes in depression symptoms over time may relate to clinical outcomes. METHODS: One-hundred forty-seven HF outpatients with ejection fraction of less than 40% were assessed for depressive symptoms using the Beck Depression Inventory (BDI) at baseline and again 1 year later. Cox proportional hazards regression analyses, controlling for established risk factors, were used to evaluate how changes in depressive symptoms were related to a combined primary end point of death or cardiovascular hospitalization over a median follow-up period of 5 years (with a range of 4 to 7 years and no losses to follow-up). RESULTS: The 1-year change in symptoms of depression, as indicated by higher BDI scores over a 1-year interval (1-point BDI change hazard ratio [HR]: 1.07, 95% confidence interval [CI]: 1.02 to 1.12, p = 0.007), was associated with death or cardiovascular hospitalization after controlling for baseline depression (baseline BDI HR: 1.1, 95% CI: 1.06 to 1.14, p < 0.001) and established risk factors, including HF cause, age, ejection fraction, plasma N-terminal pro-B-type natriuretic peptide level, and prior hospitalizations. CONCLUSIONS: Worsening symptoms of depression are associated with a poorer prognosis in HF patients. Routine assessment of symptoms of depression in HF patients may help to guide appropriate medical management of these patients who are at increased risk for adverse clinical outcomes.

Increased levels of apoptosis in gastrocnemius skeletal muscle in patients with peripheral arterial disease.

Intermittent claudication (IC) is the major clinical manifestation of peripheral arterial disease (PAD). Apoptosis has been linked to skeletal muscle pathophysiology in other chronic diseases such as congestive heart failure. This study tested the hypothesis that there would be increased levels of apoptosis in the skeletal muscle of patients with PAD compared with control individuals. In total, 26 individuals with PAD and 28 age-appropriate controls underwent studies of peak oxygen consumption (peak VO2) and a gastrocnemius muscle biopsy in the most symptomatic leg. Muscle biopsies were analyzed for apoptosis and caspase-3 activity. Patients with PAD had a reduced peak VO2 compared with controls. Apoptosis was increased in those with PAD compared with age-appropriate controls (3.83% +/- 2.6 vs 1.53% +/- 0.96; p < 0.001). In conclusion, PAD is associated with increased levels of apoptosis in the peripheral skeletal muscle. Further study is required to ascertain whether apoptosis plays a role in decreased functional capacity.