Joel Eggebeen

Effect of endurance training on the determinants of peak exercise oxygen consumption in elderly patients with stable compensated heart failure and preserved ejection fraction.

OBJECTIVES The purpose of this study was to evaluate the mechanisms for improved exercise capacity after endurance exercise training (ET) in elderly patients with heart failure and preserved ejection fraction (HFPEF). BACKGROUND Exercise intolerance, measured objectively by reduced peak oxygen consumption (VO(2)), is the primary chronic symptom in HFPEF and is improved by ET. However, the mechanisms are unknown. METHODS Forty stable, compensated HFPEF outpatients (mean age 69 ± 6 years) were examined at baseline and after 4 months of ET (n = 22) or attention control (n = 18). The VO(2) and its determinants were assessed during rest and peak upright cycle exercise. RESULTS After ET, peak VO(2) in those patients was higher than in control patients (16.3 ± 2.6 ml/kg/min vs. 13.1 ± 3.4 ml/kg/min; p = 0.002). That was associated with higher peak heart rate (139 ± 16 beats/min vs. 131 ± 20 beats/min; p = 0.03), but no difference in peak end-diastolic volume (77 ± 18 ml vs. 77 ± 17 ml; p = 0.51), stroke volume (48 ± 9 ml vs. 46 ± 9 ml; p = 0.83), or cardiac output (6.6 ± 1.3 l/min vs. 5.9 ± 1.5 l/min; p = 0.32). However, estimated peak arterial-venous oxygen difference was significantly higher in ET patients (19.8 ± 4.0 ml/dl vs. 17.3 ± 3.7 ml/dl; p = 0.03). The effect of ET on cardiac output was responsible for only 16% of the improvement in peak VO(2). CONCLUSIONS In elderly stable compensated HFPEF patients, peak arterial-venous oxygen difference was higher after ET and was the primary contributor to improved peak VO(2). This finding suggests that peripheral mechanisms (improved microvascular and/or skeletal muscle function) contribute to the improved exercise capacity after ET in HFPEF. (Prospective Aerobic Reconditioning Intervention Study [PARIS]; NCT01113840).

Effect of Caloric Restriction or Aerobic Exercise Training on Peak Oxygen Consumption and Quality of Life in Obese Older Patients With Heart Failure With Preserved Ejection Fraction: A Randomized Clinical Trial

IMPORTANCE More than 80% of patients with heart failure with preserved ejection fraction (HFPEF), the most common form of heart failure among older persons, are overweight or obese. Exercise intolerance is the primary symptom of chronic HFPEF and a major determinant of reduced quality of life (QOL). OBJECTIVE To determine whether caloric restriction (diet) or aerobic exercise training (exercise) improves exercise capacity and QOL in obese older patients with HFPEF. DESIGN, SETTING, AND PARTICIPANTS Randomized, attention-controlled, 2 × 2 factorial trial conducted from February 2009 through November 2014 in an urban academic medical center. Of 577 initially screened participants, 100 older obese participants (mean [SD]: age, 67 years [5]; body mass index, 39.3 [5.6]) with chronic, stable HFPEF were enrolled (366 excluded by inclusion and exclusion criteria, 31 for other reasons, and 80 declined participation). INTERVENTIONS Twenty weeks of diet, exercise, or both; attention control consisted of telephone calls every 2 weeks. MAIN OUTCOMES AND MEASURES Exercise capacity measured as peak oxygen consumption (V̇O2, mL/kg/min; co-primary outcome) and QOL measured by the Minnesota Living with Heart Failure (MLHF) Questionnaire (score range: 0-105, higher scores indicate worse heart failure-related QOL; co-primary outcome). RESULTS Of the 100 enrolled participants, 26 participants were randomized to exercise; 24 to diet; 25 to exercise + diet; 25 to control. Of these, 92 participants completed the trial. Exercise attendance was 84% (SD, 14%) and diet adherence was 99% (SD, 1%). By main effects analysis, peak V̇O2 was increased significantly by both interventions: exercise, 1.2 mL/kg body mass/min (95% CI, 0.7 to 1.7), P < .001; diet, 1.3 mL/kg body mass/min (95% CI, 0.8 to 1.8), P < .001. The combination of exercise + diet was additive (complementary) for peak V̇O2 (joint effect, 2.5 mL/kg/min). There was no statistically significant change in MLHF total score with exercise and with diet (main effect: exercise, -1 unit [95% CI, -8 to 5], P = .70; diet, -6 units [95% CI, -12 to 1], P = .08). The change in peak V̇O2 was positively correlated with the change in percent lean body mass (r = 0.32; P = .003) and the change in thigh muscle:intermuscular fat ratio (r = 0.27; P = .02). There were no study-related serious adverse events. Body weight decreased by 7% (7 kg [SD, 1]) in the diet group, 3% (4 kg [SD, 1]) in the exercise group, 10% (11 kg [SD, 1] in the exercise + diet group, and 1% (1 kg [SD, 1]) in the control group. CONCLUSIONS AND RELEVANCE Among obese older patients with clinically stable HFPEF, caloric restriction or aerobic exercise training increased peak V̇O2, and the effects may be additive. Neither intervention had a significant effect on quality of life as measured by the MLHF Questionnaire. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00959660.

Skeletal muscle abnormalities and exercise intolerance in older patients with heart failure and preserved ejection fraction

Heart failure (HF) with preserved ejection fraction (HFPEF) is the most common form of HF in older persons. The primary chronic symptom in HFPEF is severe exercise intolerance, and its pathophysiology is poorly understood. To determine whether skeletal muscle abnormalities contribute to their severely reduced peak exercise O2 consumption (Vo2), we examined 22 older HFPEF patients (70 ± 7 yr) compared with 43 age-matched healthy control (HC) subjects using needle biopsy of the vastus lateralis muscle and cardiopulmonary exercise testing to assess muscle fiber type distribution and capillarity and peak Vo2. In HFPEF versus HC patients, peak Vo2 (14.7 ± 2.1 vs. 22.9 ± 6.6 ml·kg(-1)·min(-1), P < 0.001) and 6-min walk distance (454 ± 72 vs. 573 ± 71 m, P < 0.001) were reduced. In HFPEF versus HC patients, the percentage of type I fibers (39.0 ± 11.4% vs. 53.7 ± 12.4%, P < 0.001), type I-to-type II fiber ratio (0.72 ± 0.39 vs. 1.36 ± 0.85, P = 0.001), and capillary-to-fiber ratio (1.35 ± 0.32 vs. 2.53 ± 1.37, P = 0.006) were reduced, whereas the percentage of type II fibers was greater (61 ± 11.4% vs. 46.3 ± 12.4%, P < 0.001). In univariate analyses, the percentage of type I fibers (r = 0.39, P = 0.003), type I-to-type II fiber ratio (r = 0.33, P = 0.02), and capillary-to-fiber ratio (r = 0.59, P < 0.0001) were positively related to peak Vo2. In multivariate analyses, type I fibers and the capillary-to-fiber ratio remained significantly related to peak Vo2. We conclude that older HFPEF patients have significant abnormalities in skeletal muscle, characterized by a shift in muscle fiber type distribution with reduced type I oxidative muscle fibers and a reduced capillary-to-fiber ratio, and these may contribute to their severe exercise intolerance. This suggests potential new therapeutic targets in this difficult to treat disorder.

Impaired Aerobic Capacity and Physical Functional Performance in Older Heart Failure Patients With Preserved Ejection Fraction: Role of Lean Body Mass

BACKGROUND Exercise intolerance is the primary chronic symptom in patients with heart failure and preserved ejection fraction (HFPEF), the most common form of heart failure in older persons, and can result from abnormalities in cardiac, vascular, and skeletal muscle, which can be further worsened by physical deconditioning. However, it is unknown whether skeletal muscle abnormalities contribute to exercise intolerance in HFPEF patients. METHODS This study evaluated lean body mass, peak exercise oxygen consumption (VO2), and the short physical performance battery in 60 older (69 ± 7 years) HFPEF patients and 40 age-matched healthy controls. RESULTS In HFPEF versus healthy controls, peak percent total lean mass (60.1 ± 0.8% vs. 66.6 ± 1.0%, p < .0001) and leg lean mass (57.9 ± 0.9% vs. 63.7 ± 1.1%, p = .0001) were significantly reduced. Peak VO2 was severely reduced including when indexed to leg lean mass (79.3 ± 18.5 vs. 104.3 ± 20.4 ml/kg/min, p < .0001). Peak VO2 was correlated with percent total (r = .51) and leg lean mass (.52, both p < .0001). The slope of the relationship of peak VO2 with percent leg lean mass was markedly reduced in HFPEF (11 ± 5 ml/min) versus healthy controls (36 ± 5 ml/min; p < .001). Short physical performance battery was reduced (9.9 ± 1.4 vs. 11.3 ± 0.8) and correlated with peak VO2 and total and leg lean mass (all p < .001). CONCLUSION Older HFPEF patients have significantly reduced percent total and leg lean mass and physical functional performance compared with healthy controls. The markedly decreased peak VO2 indexed to lean body mass in HFPEF versus healthy controls suggests that abnormalities in skeletal muscle perfusion and/or metabolism contribute to the severe exercise intolerance in older HFPEF patients.

Skeletal muscle composition and its relation to exercise intolerance in older patients with heart failure and preserved ejection fraction.

Exercise intolerance is the primary chronic symptom in heart failure with preserved ejection fraction (HFpEF), the most common form of heart failure in older patients; however its pathophysiology is not well understood. Recent data suggest that peripheral factors such as skeletal muscle (SM) dysfunction may be important contributors. Therefore, 38 participants, 23 patients with HFpEF (69±7 years) and 15 age-matched healthy controls (HCs), underwent magnetic resonance imaging and cardiopulmonary exercise testing to assess for SM, intermuscular fat (IMF), subcutaneous fat, total thigh, and thigh compartment (TC) areas and peak exercise oxygen consumption (peak VO2). There were no significant intergroup differences in total thigh area, TC, subcutaneous fat, or SM. However, in the HFpEF versus HC group, IMF area (35.6±11.5 vs 22.3±7.6 cm2, p=0.01), percent IMF/TC (26±5 vs 20±5%, p=0.005), and the ratio of IMF/SM (0.38±0.10 vs 0.28±0.09, p=0.007) were significantly increased, whereas percent SM/TC was significantly reduced (70±5 vs 75±5, p=0.009). In multivariate analyses, IMF area (partial r=-0.51, p=0.002) and IMF/SM ratio (partial r=-0.45, p=0.006) were independent predictors of peak VO2 whereas SM area was not (partial r = -0.14, p=0.43). Thus, older patients with HFpEF have greater thigh IMF and IMF/SM ratio compared with HCs, and these are significantly related to their severely reduced peak VO2. These data suggest that abnormalities in SM composition may contribute to the severely reduced exercise capacity in older patients with HFpEF. This implicates potential targets for novel therapeutic strategies in this common debilitating disorder of older persons.

Carotid Arterial Stiffness and Its Relationship to Exercise Intolerance in Older Patients With Heart Failure and Preserved Ejection Fraction

Heart failure with a preserved ejection fraction (HFpEF) is the dominant form of heart failure in the older population. The primary chronic symptom in HFpEF is severe exercise intolerance; however, its pathophysiology and therapy are not well understood. We tested the hypothesis that older patients with HFpEF have increased arterial stiffness beyond what occurs with normal aging and that this contributes to their severe exercise intolerance. Sixty-nine patients ≥60 years of age with HFpEF and 62 healthy volunteers (24 young healthy subjects ⩽30 years and 38 older healthy subjects ≥60 years old) were examined. Carotid arterial stiffness was assessed using high-resolution ultrasound, and peak exercise oxygen consumption was measured using expired gas analysis. Peak exercise oxygen consumption was severely reduced in the HFpEF patients compared with older healthy subjects (14.1±2.9 versus 19.7±3.7 mL/kg per minute; P<0.001) and in both was reduced compared with young healthy subjects (32.0±7.2 mL/kg per minute; both P<0.001). In HFpEF compared with older healthy subjects, carotid arterial distensibility was reduced (0.97±0.45 versus 1.33±0.55×10–3 mm Hg−1; P=0.008) and Young’s elastic modulus was increased (1320±884 versus 925±530 kPa; P<0.02). Carotid arterial distensibility was directly (0.28; P=0.02) and Young’s elastic modulus was inversely (–0.32; P=0.01) related to peak exercise oxygen consumption. Carotid arterial distensibility is decreased in HFpEF beyond the changes attributed to normal aging and is related to peak exercise oxygen consumption. This supports the hypothesis that increased arterial stiffness contributes to exercise intolerance in HFpEF and is a potential therapeutic target.

Exercise intolerance in heart failure with preserved ejection fraction: more than a heart problem

Heart failure (HF) with preserved ejection fraction (HFpEF) is the most common form of HF in older adults, and is increasing in prevalence as the population ages. Furthermore, HFpEF is increasing out of proportion to HF with reduced EF (HFrEF), and its prognosis is worsening while that of HFrEF is improving. Despite the importance of HFpEF, our understanding of its pathophysiology is incomplete, and optimal treatment remains largely undefined. A cardinal feature of HFpEF is reduced exercise tolerance, which correlates with symptoms as well as reduced quality of life. The traditional concepts of exercise limitations have focused on central dysfunction related to poor cardiac pump function. However, the mechanisms are not exclusive to the heart and lungs, and the understanding of the pathophysiology of this disease has evolved. Substantial attention has focused on defining the central versus peripheral mechanisms underlying the reduced functional capacity and exercise tolerance among patients with HF. In fact, physical training can improve exercise tolerance via peripheral adaptive mechanisms even in the absence of favorable central hemodynamic function. In addition, the drug trials performed to date in HFpEF that have focused on influencing cardiovascular function have not improved exercise capacity. This suggests that peripheral limitations may play a significant role in HF limiting exercise tolerance, a hallmark feature of HFpEF.

Exercise Training Improves Heart Rate Variability in Older Patients With Heart Failure: A Randomized, Controlled, Single-Blinded Trial

Reduced heart rate variability (HRV) in older patients with heart failure (HF) is common and indicates poor prognosis. Exercise training (ET) has been shown to improve HRV in younger patients with HF. However, the effect of ET on HRV in older patients with HF is not known. Sixty-six participants (36% men), aged 69±5 years, with HF and both preserved ejection fraction (HFPEF) and reduced ejection fraction (HFREF), were randomly assigned to 16 weeks of supervised ET (ET group) vs attention-control (AC group). Two HRV parameters (the standard deviation of all normal RR intervals [SDNN] and the root mean square of successive differences in normal RR intervals [RMSSD]) were measured at baseline and after completion of the study. When compared with the AC group, the ET group had a significantly greater increase in both SDNN (15.46±5.02 ms in ET vs 2.37±2.13 ms in AC, P=.016) and RMSSD (17.53±7.83 ms in ET vs 1.69±2.63 ms in AC, P=.003). This increase was seen in both sexes and HF categories. ET improved HRV in older patients with both HFREF and HFPEF.

Kinematics of gait in golden retriever muscular dystrophy.

The goal of this study was to quantify the two-dimensional kinematics of pathologic gait during over-ground walking at a self-selected speed at the stifle (knee) and hock (ankle) joints in six Golden Retriever Muscular Dystrophy (GRMD) dogs and six carrier littermates (controls). We found that GRMD dogs walked significantly slower than controls (p<0.01). At the stifle joint, both groups displayed similar ROM (range of motion), but compared to controls, GRMD dogs walked with the stifle joint relatively more extended. At the hock joint, GRMD dogs displayed less ROM (range of motion) and walked with the joint relatively less flexed compared to controls. We controlled for gait speed in all analyses, so the differences we observed in joint kinematics between groups cannot be attributed solely to the slower walking speed of the GRMD dogs. This is the first kinematic study of gait in the GRMD dog, an important step in using this model in pre-clinical trials.

Reliability of Peak Exercise Testing in Patients with Heart Failure with Preserved Ejection Fraction

Exercise intolerance is the primary symptom in patients with heart failure and preserved ejection fraction (HFpEF), a major determinant of their decreased quality of life, and an important outcome in clinical trials. Although cardiopulmonary exercise testing (CPET) provides peak and submaximal diagnostic indexes, the reliability of peak treadmill CPET in patients >55 years of age with HFpEF has not been examined. Two CPETs were performed in 52 patients with HFpEF (70 ± 7 years old). The 2 tests were separated by an average of 23 ± 13 days (median 22) and performed under identical conditions, with no intervention or change in status between visits except for initiation of a placebo run-in. A multistep protocol for patient screening, education, and quality control was used. Mean peak oxygen consumption was similar on tests 1 and 2 (14.4 ± 2.4 vs 14.3 ± 2.3 ml/kg/min). Correlation coefficients and intraclass correlations from the testing days were determined (oxygen consumption, r = 0.85, p <0.001, intraclass correlation 0.855; ventilatory anaerobic threshold, r = 0.79, p <0.001, intraclass correlation 0.790; ventilation per carbon dioxide slope, r = 0.87, p <0.001, intraclass correlation 0.864; heart rate, r = 0.94, p <0.001, intraclass correlation 0.938). These results challenge conventional wisdom that serial baseline testing is required in clinical trials with exercise-capacity outcomes. In conclusion, in women and men with HFpEF and severe physical dysfunction, key submaximal and peak ET variables exhibited good reliability and were not significantly altered by a learning effect or placebo administration.