Kathryn P. Stewart

Cardiac cycle-dependent changes in aortic area and distensibility are reduced in older patients with isolated diastolic heart failure and correlate with exercise intolerance.

OBJECTIVES The goal of this study was to determine if cardiac cycle-dependent changes in proximal thoracic aortic area and distensibility are associated with exercise intolerance in elderly patients with diastolic heart failure (DHF). BACKGROUND Aortic compliance declines substantially with age. We hypothesized that a reduction in cardiac cycle-dependent changes in thoracic aortic area and distensibility (above that which occurs with aging) could be associated with the exercise intolerance that is prominent in elderly diastolic heart failure patients. METHODS Thirty subjects (20 healthy individuals [10 < 30 years of age and 10 > 60 years of age] and 10 individuals > the age of 60 years with DHF) underwent a magnetic resonance imaging (MRI) study of the heart and proximal thoracic aorta followed within 48 h by maximal exercise ergometry with expired gas analysis. RESULTS The patients with DHF had higher resting brachial pulse and systolic blood pressure, left ventricular mass, aortic wall thickness and mean aortic flow velocity, and, compared with healthy older subjects, they had a significant reduction in MRI-assessed cardiac cycle-dependent change in aortic area and distensibility (p < 0.0001) that correlated with diminished peak exercise oxygen consumption (r = 0.79). After controlling for age and gender in a multivariate analysis, thoracic aortic distensibility was a significant predictor of peak exercise oxygen consumption (p < 0.04). CONCLUSIONS Older patients with isolated DHF have reduced cardiac cycle-dependent changes in proximal thoracic aortic area and distensibility (beyond that which occurs with normal aging), and this correlates with and may contribute to their severe exercise intolerance.

Exercise Training in Older Patients with Heart Failure and Preserved Ejection Fraction: A Randomized, Controlled, Single-Blind Trial

Background—Heart failure (HF) with preserved left ventricular ejection fraction (HFPEF) is the most common form of HF in the older population. Exercise intolerance is the primary chronic symptom in patients with HFPEF and is a strong determinant of their reduced quality of life (QOL). Exercise training (ET) improves exercise intolerance and QOL in patients with HF with reduced ejection fraction (EF). However, the effect of ET in HFPEF has not been examined in a randomized controlled trial. Methods and Results—This 16-week investigation was a randomized, attention-controlled, single-blind study of medically supervised ET (3 days per week) on exercise intolerance and QOL in 53 elderly patients (mean age, 70±6 years; range, 60 to 82 years; women, 46) with isolated HFPEF (EF ≥50% and no significant coronary, valvular, or pulmonary disease). Attention controls received biweekly follow-up telephone calls. Forty-six patients completed the study (24 ET, 22 controls). Attendance at exercise sessions in the ET group was excellent (88%; range, 64% to 100%). There were no trial-related adverse events. The primary outcome of peak exercise oxygen uptake increased significantly in the ET group compared to the control group (13.8±2.5 to 16.1±2.6 mL/kg per minute [change, 2.3±2.2 mL/kg per minute] versus 12.8±2.6 to 12.5±3.4 mL/kg per minute [change, −0.3±2.1 mL/kg per minute]; P=0.0002). There were significant improvements in peak power output, exercise time, 6-minute walk distance, and ventilatory anaerobic threshold (all P<0.002). There was improvement in the physical QOL score (P=0.03) but not in the total score (P=0.11). Conclusions—ET improves peak and submaximal exercise capacity in older patients with HFPEF. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01113840.

Determinants of Exercise Intolerance in Elderly Heart Failure Patients With Preserved Ejection Fraction

OBJECTIVES The purpose of this study was to determine the mechanisms responsible for reduced aerobic capacity (peak Vo(2)) in patients with heart failure with preserved ejection fraction (HFPEF). BACKGROUND HFPEF is the predominant form of heart failure in older persons. Exercise intolerance is the primary symptom among patients with HFPEF and a major determinant of reduced quality of life. In contrast to patients with heart failure and reduced ejection fraction, the mechanism of exercise intolerance in HFPEF is less well understood. METHODS Left ventricular volumes (2-dimensional echocardiography), cardiac output, Vo(2), and calculated arterial-venous oxygen content difference (A-Vo(2) Diff) were measured at rest and during incremental, exhaustive upright cycle exercise in 48 HFPEF patients (age 69 ± 6 years) and 25 healthy age-matched controls. RESULTS In HFPEF patients compared with healthy controls, Vo(2) was reduced at peak exercise (14.3 ± 0.5 ml·kg·min(-1) vs. 20.4 ± 0.6 ml·kg·min(-1); p < 0.0001) and was associated with a reduced peak cardiac output (6.3 ± 0.2 l·min(-1) vs. 7.6 ± 0.2 l·min(-1); p < 0.0001) and A-Vo(2) Diff (17 ± 0.4 ml·dl(-1) vs. 19 ± 0.4 ml·dl(-1), p < 0.0007). The strongest independent predictor of peak Vo(2) was the change in A-Vo(2) Diff from rest to peak exercise (A-Vo(2) Diff reserve) for both HFPEF patients (partial correlate, 0.58; standardized β coefficient, 0.66; p = 0.0002) and healthy controls (partial correlate, 0.61; standardized β coefficient, 0.41; p = 0.005). CONCLUSIONS Both reduced cardiac output and A-Vo(2) Diff contribute significantly to the severe exercise intolerance in elderly HFPEF patients. The finding that A-Vo(2) Diff reserve is an independent predictor of peak Vo(2) suggests that peripheral, noncardiac factors are important contributors to exercise intolerance in these patients.

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).

A Randomized Double-Blind Trial of Enalapril in Older Patients With Heart Failure and Preserved Ejection Fraction Effects on Exercise Tolerance and Arterial Distensibility

Background—Exercise intolerance is the primary symptom in older patients with heart failure and preserved ejection fraction (HFPEF); however, little is known regarding its mechanisms and therapy. Methods and Results—Seventy-one stable elderly (70±1 years) patients (80% women) with compensated HFPEF and controlled blood pressure were randomized into a 12-month follow-up double-blind trial of enalapril 20 mg/d versus placebo. Assessments were peak exercise oxygen consumption; 6-minute walk test; Minnesota Living with HF Questionnaire; MRI; Doppler echocardiography; and vascular ultrasound. Compliance by pill count was excellent (94%). Twenty-five patients in the enalapril group versus 34 in the placebo group completed the 12-month follow-up. During follow-up, there was no difference in the primary outcome of peak exercise oxygen consumption (enalapril, 14.5±3.2 mL/kg/min; placebo, 14.3±3.4 mL/kg/min; P=0.99), or in 6-minute walk distance, aortic distensibility (the primary mechanistic outcome), left ventricle mass, or neurohormonal profile. The effect size of enalapril on peak exercise oxygen consumption was small (0.7%; 95% CI, 4.2% to 5.6%). There was a trend toward improved Minnesota Living with HF Questionnaire total score (P=0.07), a modest reduction in systolic blood pressure at peak exercise (P=0.02), and a marginal improvement in carotid arterial distensibility (P=0.04). Conclusions—In stable, older patients with compensated HFPEF and controlled blood pressure, 12 months of enalapril did not improve exercise capacity or aortic distensibility. These data, combined with those from large clinical event trials, suggest that angiotensin inhibition does not substantially improve key long-term clinical outcomes in this group of patients. This finding contrasts sharply with observations in HF with reduced EF and highlights our incomplete understanding of this important and common disorder.

Endurance Exercise Training in Older Patients with Heart Failure: Results from a Randomized, Controlled, Single‐Blind Trial

OBJECTIVES: To test the hypothesis that exercise training (ET) improves exercise capacity and other clinical outcomes in older persons with heart failure with reduced ejection fraction (HfrEF).

Effect of aldosterone antagonism on exercise tolerance, Doppler diastolic function, and quality of life in older women with diastolic heart failure.

Optimal therapy for diastolic heart failure (DHF), the most common form of heart failure in older persons, is unclear. To determine the effect of aldosterone antagonism in DHF, the authors conducted an open-label preliminary trial of spironolactone 25 mg/d in 11 women with DHF. Cardiopulmonary exercise testing, Doppler echocardiography, and a quality-of-life survey were administered at baseline and after 4 months. Peak exercise VO(2) increased by 8.3% (P=.001), the ratio of Doppler diastolic early filling velocity to mitral annulus velocity decreased by 25% (P=.02), quality-of-life score improved by 21% (P=.16 for trend), and median New York Heart Association class improved from class III to class II (P=.004). Findings from this preliminary study confirm the role of aldosterone in the pathophysiology of DHF and suggest that aldosterone antagonism may benefit such patients. These hypotheses are currently being tested in two separated National Institutes of Health-funded, randomized trials, the Spironolactone for Failure in the Elderly (SPIFFIE) and the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trials.

Decreased left ventricular distensibility in response to postural change in older patients with heart failure and preserved ejection fraction

Most elderly persons with heart failure have a preserved left ventricular (LV) ejection fraction (HFPEF). The pathophysiology of this disorder is not well understood, and there are conflicting data regarding the role of decreased LV distensibility. To assess LV distensibility over a range of preload conditions while minimizing the large, confounding changes in contractility, afterload, and heart rate characteristic of exercise, we measured LV end-diastolic volume (EDV), stroke volume (SV), and cardiac output (CO) using two-dimensional echocardiography in 48 elderly (mean age, 69 yr) HFPEF patients and 25 healthy age-matched controls during quiet supine rest, 45 degrees head-up tilt (HUT), and 45 degrees head-down tilt (HDT). As a result, when compared with controls, HFPEF patients had reduced percent changes in EDV (-7 +/- 2 vs. -17 +/- 2%; P = 0.003), SV (-7 +/- 3 vs. -27 +/- 2%; P = 0.003), and CO (-6 +/- 4 vs. -34 +/- 4%; P = 0.001) during the transition from supine to HUT. HFPEF also had reduced percent changes in EDV (8 +/- 2 vs. 15 +/- 2%; P = 0.02), SV (11 +/- 3 vs. 21 +/- 3%; P = 0.002), and CO (1 +/- 4 vs. 12 +/- 4%; P = 0.04) during the transition from HUT to HDT. In conclusion, HFNEF patients have reduced LV distensibility in response to postural change, resulting in blunted EDV, SV, and CO. This provides further support for the hypothesis that a blunted Frank-Starling mechanism may contribute to the pathophysiology of HFPEF.

Effect of Spironolactone on Exercise Tolerance and Arterial Function in Older Adults with Heart Failure with Preserved Ejection Fraction

To evaluate the effects of an aldosterone antagonist on exercise intolerance in older adults with heart failure and preserved ejection fraction (HFpEF).

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.