The effect of Aliskiren on exercise capacity in older patients with heart failure and preserved ejection fraction: A randomized, placebo-controlled, double-blind trial.

In older patients (70 ± 7 years) with chronic well-compensated heart failure with preserved ejection and controlled blood pressure, 6 months treatment with aliskiren (direct renin inhibitor) showed non-significant trends for modest improvements in peak exercise oxygen consumption (14.9 ± 0.2 mL kg-1 min-1 versus 14.4 ± 0.2 mL kg-1 min-1; P = .10, trend) and ventilatory anaerobic threshold (888 ± 19 mL/min versus 841 ± 18 mL/min; P = .08).

Strategies for supporting intervention fidelity in the rehabilitation therapy in older acute heart failure patients (REHAB-HF) trial.

INTRODUCTION: Acute decompensated heart failure (ADHF) is the leading cause of hospitalization in older adults. Rehabilitation Therapy in Older Acute Heart Failure Patients (REHAB-HF) trial is a multi-site clinical trial to determine if physical rehabilitation intervention in older patients with ADHF improves physical function and reduces rehospitalizations. The REHAB-HF intervention aims to improve functional performance utilizing reproducible and progressive exercises that are individually tailored to the patient's physiological and physical capabilities. Fidelity of the intervention is essential to the trial's integrity and success. Maintaining fidelity is challenged by the complex, multi-domain design of the intervention implemented across multiple sites and delivered to an older, heterogeneous participant pool with severe underlying disease and multi-morbidity. METHODS/DESIGN: Given the dynamic nature of the REHAB-HF intervention, rigorous fidelity strategies were formulated. In this paper we summarize the specific strategies that REHAB-HF is using to meet the National Institutes of Health (NIH) Behavior Change Consortium Treatment Fidelity Workgroup recommendations in 5 key areas: 1) ensuring the intervention dose is consistent across participants, 2) standardizing interventionist training, 3) monitoring intervention delivery, 4) evaluating participants' understanding of information provided, and 5) ensuring that participants use the skills taught in the intervention. DISCUSSION: Effective intervention fidelity strategies are essential to the reliability and validity of physical function intervention trials. The REHAB-HF trial has developed comprehensive, specific strategies to ensure intervention fidelity despite a challenging study population and a complex intervention to meet NIH recommendations. This experience provides a strong working model for future physical function intervention trials.

Effects of supervised exercise and dietary nitrate in older adults with controlled hypertension and/or heart failure with preserved ejection fraction.

Aerobic exercise training is an effective therapy to improve peak aerobic power (peak VO2) in individuals with hypertension (HTN, AHA/ACC class A) and heart failure patients with preserved ejection fraction (HFpEF). High nitrate containing beetroot juice (BRJ) also improves sub-maximal endurance and decreases blood pressure in both HTN and HFpEF. We hypothesized that combining an aerobic exercise and dietary nitrate intervention would result in additive or even synergistic positive effects on exercise tolerance and blood pressure in HTN or HFpEF. We report results from two pilot studies examining the effects of supervised aerobic exercise combined with dietary nitrate in patients with controlled HTN (n = 26, average age 65 ± 5 years) and in patients with HFpEF (n = 20, average age 69 ± 7 years). All patients underwent an aerobic exercise training regimen; half were randomly assigned to consume a high nitrate-containing beet juice beverage (BRJ containing 6.1 mmol nitrate for the HFpEF study consumed three times a week and 8 mmol nitrate for the HTN study consumed daily) while the other half consumed a beet juice beverage with the nitrate removed (placebo). The main result was that there was no added benefit observed for any outcomes when comparing BRJ to placebo in either HTN or HFpEF patients undergoing exercise training (p ≥ 0.14). There were within-group benefits. In the pilot study in patients with HFpEF, aerobic endurance (primary outcome), defined as the exercise time to volitional exhaustion during submaximal cycling at 75% of maximal power output, improved during exercise training within each group from baseline to end of study, 369 ± 149 s vs 520 ± 257 s (p = 0.04) for the placebo group and 384 ± 129 s vs 483 ± 258 s for the BRJ group (p = 0.15). Resting systolic blood pressure in patients with HFpEF also improved during exercise training in both groups, 136 ± 16 mm Hg vs 122 ± 3 mm Hg for the placebo group (p < 0.05) and 132 ± 12 mm Hg vs 119 ± 9 mm Hg for the BRJ group (p < 0.05). In the HTN pilot study, during a treadmill graded exercise test, peak oxygen consumption (primary outcome) did not change significantly, but time to exhaustion (also a primary outcome) improved in both groups, 504 ± 32 s vs 601 ± 38 s (p < 0.05) for the placebo group and 690 ± 38 s vs 772 ± 95 s for the BRJ group (p < 0.05) which was associated with a reduction in supine resting systolic blood pressure in BRJ group. Arterial compliance also improved during aerobic exercise training in both the HFpEF and the HTN patients for both BRJ and placebo groups. Future work is needed to determine if larger nitrate doses would provide an added benefit to supervised aerobic exercise in HTN and HFpEF patients.

A Novel Rehabilitation Intervention for Older Patients With Acute Decompensated Heart Failure: The REHAB-HF Pilot Study.

OBJECTIVES: This study sought to assess a novel physical rehabilitation intervention in older patients hospitalized for acute decompensated heart failure (ADHF). BACKGROUND: After ADHF, older patients, who are frequently frail with multiple comorbidities, have prolonged and incomplete recovery of physical function and remain at high risk for poor outcomes. METHODS: The REHAB-HF (Rehabilitation Therapy in Older Acute Heart Failure Patients) pilot study was a 3-site, randomized, attention-controlled pilot study of a tailored, progressive, multidomain physical rehabilitation intervention beginning in the hospital and continuing for 12 weeks post-discharge in patients ≥60 years hospitalized with ADHF. The primary purpose was to assess the feasibility and reasonableness of the hypothesis that the novel rehabilitation intervention would improve physical function (Short Physical Performance Battery [SPPB]) over 3 months and reduce all-cause rehospitalizations over 6 months. RESULTS: The study enrolled 27 patients with ADHF (ages 60 to 98 years; 59% women; 56% African American; 41% with preserved ejection fraction [≥45%]). At baseline, participants had marked impairments in physical function, multiple comorbidities, and frailty. Study retention (89%) and intervention adherence (93%) were excellent. At 3 months, an intervention effect size was measured for the SPPB score of +1.1 U (7.4 ± 0.5 U vs. 6.3 ± 0.5 U), and at 6 months an effect size was observed for an all-cause rehospitalization rate of -0.48 (1.16 ± 0.35 vs. 1.64 ± 0.39). The change in SPPB score was strongly related to all-cause rehospitalizations, explaining 91% of change. CONCLUSIONS: These findings support the feasibility and rationale for a recently launched, National Institutes of Health-funded trial to test the safety and efficacy of this novel multidomain physical rehabilitation intervention to improve physical function and reduce rehospitalizations in older, frail patients with ADHF with multiple comorbidities. (Rehabilitation and Exercise Training After Hospitalization [REHAB-HF]; NCT01508650; A Trial of Rehabilitation Therapy in Older Acute Heart Failure Patients [REHAB-HF]; NCT02196038).

Rehabilitation Therapy in Older Acute Heart Failure Patients (REHAB-HF) trial: Design and rationale.

BACKGROUND: Acute decompensated heart failure (ADHF) is a leading cause of hospitalization in older persons in the United States. Reduced physical function and frailty are major determinants of adverse outcomes in older patients with hospitalized ADHF. However, these are not addressed by current heart failure (HF) management strategies and there has been little study of exercise training in older, frail HF patients with recent ADHF. HYPOTHESIS: Targeting physical frailty with a multi-domain structured physical rehabilitation intervention will improve physical function and reduce adverse outcomes among older patients experiencing a HF hospitalization. STUDY DESIGN: REHAB-HF is a multi-center clinical trial in which 360 patients ≥60 years hospitalized with ADHF will be randomized either to a novel 12-week multi-domain physical rehabilitation intervention or to attention control. The goal of the intervention is to improve balance, mobility, strength and endurance utilizing reproducible, targeted exercises administered by a multi-disciplinary team with specific milestones for progression. The primary study aim is to assess the efficacy of the REHAB-HF intervention on physical function measured by total Short Physical Performance Battery score. The secondary outcome is 6-month all-cause rehospitalization. Additional outcome measures include quality of life and costs. CONCLUSIONS: REHAB-HF is the first randomized trial of a physical function intervention in older patients with hospitalized ADHF designed to determine if addressing deficits in balance, mobility, strength and endurance improves physical function and reduces rehospitalizations. It will address key evidence gaps concerning the role of physical rehabilitation in the care of older patients, those with ADHF, frailty, and multiple comorbidities.

Association Between 6-Minute Walk Test Distance and Objective Variables of Functional Capacity After Exercise Training in Elderly Heart Failure Patients With Preserved Ejection Fraction: A Randomized Exercise Trial.

OBJECTIVE: To evaluate the change in the 6-minute walk test (6-MWT) distance relative to changes in key functional capacity measures after 16 weeks of exercise training in older patients (≥65y) who have heart failure with preserved ejection fraction (HFpEF). DESIGN: Prospective, randomized, single-blinded (by researchers to patient group) comparison of 2 groups of HFpEF patients. SETTING: Hospital and clinic records; ambulatory outpatients. PARTICIPANTS: Participants (N=47) randomly assigned to an attention control (AC) (n=24) or exercise training (ET) (n=23) group. INTERVENTION: The ET group performed cycling and walking at 50% to 70% of peak oxygen uptake (V˙o2peak) intensity (3d/wk, 60min each session). MAIN OUTCOME MEASURES: V˙o2peak, ventilatory threshold (VT), and 6-MWT distance were measured at baseline and after the 16-week study period. RESULTS: At follow-up, the 6-MWT distance was higher than at the baseline in both the ET (11%, P=.005) and AC (9%, P=.004) groups. In contrast, V˙o2peak and VT values increased in the ET group (19% and 11%, respectively; P=.001), but decreased in the AC group at follow-up (2% and 0%, respectively). The change in V˙o2peak versus 6-MWT distance after training was also not significantly correlated in the AC group (r=.01, P=.95) or in the ET group (r=.13, P=.57). The change in 6-MWT distance and VT (an objective submaximal exercise measure) was also not significantly correlated in the AC group (r=.08, P=.74) or in the ET group (r=.16, P=.50). CONCLUSIONS: The results of this study challenge the validity of using the 6-MWT as a serial measure of exercise tolerance in elderly HFpEF patients and suggest that submaximal and peak exercise should be determined objectively by VT and V˙o2peak in this patient population.

Comparison of Frequency of Frailty and Severely Impaired Physical Function in Patients ≥60 Years Hospitalized With Acute Decompensated Heart Failure Versus Chronic Stable Heart Failure With Reduced and Preserved Left Ventricular Ejection Fraction.

Older patients with acute decompensated heart failure (ADHF) have persistently poor outcomes including frequent rehospitalization despite guidelines-based therapy. We hypothesized that such patients have multiple, severe impairments in physical function, cognition, and mood that are not addressed by current care pathways. We prospectively examined frailty, physical function, cognition, mood, and quality of life in 27 consecutive older patients with ADHF at 3 medical centers and compared these with 197 participants in 3 age-matched cohorts: stable heart failure (HF) with preserved ejection fraction (n = 80), stable HF with reduced ejection fraction (n = 56), and healthy older adults (n = 61). Based on Fried criteria, frailty was present in 56% of patients with ADHF versus 0 for the age-matched chronic HF and health cohorts. Patients with ADHF had markedly reduced Short Physical Performance Battery score (5.3 ± 2.8) and 6-minute walk distance (178 ± 102 m) (p <0.001 vs other cohorts), with severe deficits in all domains of physical function: balance, mobility, strength, and endurance. In the patients with ADHF, cognitive impairment (78%) and depression (30%) were common, and quality of life was poor. In conclusion, older patients with ADHF are frequently frail with severe and widespread impairments in physical function, cognition, mood, and quality of life that may contribute to their persistently poor outcomes, are frequently unrecognized, are not addressed in current ADHF care paradigms, and are potentially modifiable with targeted interventions.

Skeletal Muscle Mitochondrial Content, Oxidative Capacity, and Mfn2 Expression Are Reduced in Older Patients With Heart Failure and Preserved Ejection Fraction and Are Related to Exercise Intolerance.

OBJECTIVES: The aim of this study was to examine skeletal muscle mitochondria content, oxidative capacity, and the expression of key mitochondrial dynamics proteins in patients with heart failure with preserved ejection fraction (HFpEF), as well as to determine potential relationships with measures of exercise performance. BACKGROUND: Multiple lines of evidence indicate that severely reduced peak exercise oxygen uptake (peak VO2) in older patients with HFpEF is related to abnormal skeletal muscle oxygen utilization. Mitochondria are key regulators of skeletal muscle metabolism; however, little is known about how these organelles are affected in HFpEF. METHODS: Both vastus lateralis skeletal muscle citrate synthase activity and the expression of porin and regulators of mitochondrial fusion were examined in older patients with HFpEF (n = 20) and healthy, age-matched control subjects (n = 17). RESULTS: Compared with age-matched healthy control subjects, mitochondrial content assessed by porin expression was 46% lower (p = 0.01), citrate synthase activity was 29% lower (p = 0.01), and Mfn2 (mitofusin 2) expression was 54% lower (p <0.001) in patients with HFpEF. Expression of porin was significantly positively correlated with both peak VO2 and 6-min walk distance (r = 0.48, p = 0.003 and r = 0.33, p = 0.05, respectively). Expression of Mfn2 was also significantly positively correlated with both peak VO2 and 6-min walk distance (r = 0.40, p = 0.02 and r = 0.37, p = 0.03 respectively). CONCLUSIONS: These findings suggest that skeletal muscle oxidative capacity, mitochondrial content, and mitochondrial fusion are abnormal in older patients with HFpEF and might contribute to their severe exercise intolerance.

One Week of Daily Dosing With Beetroot Juice Improves Submaximal Endurance and Blood Pressure in Older Patients With Heart Failure and Preserved Ejection Fraction.

OBJECTIVES: This study sought to determine whether a relatively low single dose or a week-long dosage of dietary inorganic nitrate could improve exercise tolerance in patients with heart failure with preserved ejection fraction (HFpEF). BACKGROUND: Exercise intolerance is the primary manifestation of HFpEF and is largely due to noncardiac factors that reduce oxygen delivery to active skeletal muscles. A recent study showed improved exercise capacity in patients with HFpEF after a single, acute dose of beetroot juice (BRJ) (12.9 mmol inorganic nitrate) while another recent study showed neutral and negative effects of an organic nitrate. METHODS: Twenty HFpEF patients (69 ± 7 years of age ) were enrolled in an initial cross-over design comparing a single, acute dose of BRJ (6.1 mmol nitrate) to a nitrate-depleted placebo BRJ. A second phase, 1 week of daily doses, used an all-treated design in which patients consumed BRJ for an average of 7 days. The primary outcome of the study was submaximal aerobic endurance, measured as cycling time to exhaustion at 75% of measured maximal power output. RESULTS: No adverse events were associated with the intervention. Submaximal aerobic endurance improved 24% after 1 week of daily BRJ dosing (p = 0.02) but was not affected by the single, acute dose of the BRJ compared to placebo. Consumption of BRJ significantly reduced resting systolic blood pressure and increased plasma nitrate and nitrite in both of the dosing schemes. CONCLUSIONS: One week of daily dosing with BRJ (6.1 mmol inorganic nitrate) significantly improves submaximal aerobic endurance and blood pressure in elderly HFpEF patients.

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.

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.

Sarcopenic obesity and the pathogenesis of exercise intolerance in heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is the most common form of heart failure (HF) in older adults. The primary chronic symptom in patients with HFpEF, even when well compensated, is severe exercise intolerance. Cardiac and peripheral functions contribute equally to exercise intolerance in HFpEF, though the latter has been the focus of fewer studies. Of note, multiple studies with exercise training have shown that exercise intolerance can improve significantly in the absence of improvements in exercise cardiac output, indicating a role of peripheral, noncardiac adaptations. In addition, clinical drug trials performed to date in HFpEF, all of which have focused on influencing cardiovascular function, have not been positive on primary clinical outcomes and most have not improved exercise capacity. Mounting evidence indicates that sarcopenic obesity, characterized by the coexistence of excess fat mass and decreased muscle mass, could contribute to the pathophysiology of exercise intolerance in older HFpEF patients and may provide avenues for novel treatments.

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.

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.

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.

Upper extremity muscle volumes and functional strength after resistance training in older adults.

Aging leads to a decline in strength and an associated loss of independence. The authors examined changes in muscle volume, maximum isometric joint moment, functional strength, and 1-repetition maximum (1RM) after resistance training (RT) in the upper extremity of older adults. They evaluated isometric joint moment and muscle volume as predictors of functional strength. Sixteen healthy older adults (average age 75 ± 4.3 yr) were randomized to a 6-wk upper extremity RT program or control group. The RT group increased 1RM significantly (p < .01 for all exercises). Compared with controls, randomization to RT led to greater functional pulling strength (p = .003), isometric shoulder-adduction moment (p = .041), elbow-flexor volume (p = .017), and shoulder-adductor volume (p = .009). Shoulder-muscle volumes and isometric moments were good predictors of functional strength. The authors conclude that shoulder strength is an important factor for performing functional reaching and pulling tasks and a key target for upper extremity RT interventions.

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.

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.

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).