Timothy M. Morgan

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.

Magnetic Resonance Imaging Determination of Cardiac Prognosis

Background—Regional assessments of left ventricular (LV) wall motion obtained during MRI cardiac stress tests can be used to identify myocardial injury and ischemia, but the utility of MRI stress test results for the assessment of cardiac prognosis is not known. Methods and Results—Two hundred seventy-nine patients referred (because of poor LV endocardial visualization with echocardiography) for dobutamine/atropine MRI for the detection of inducible ischemia were followed for an average of 20 months. After MRI stress testing, the occurrence of myocardial infarction, cardiac death, death attributable to any cause, coronary arterial revascularization, and unstable angina or congestive heart failure requiring hospitalization was determined. In a multivariate analysis, the presence of inducible ischemia (hazard ratio 3.3, CI 1.1 to 9.7) or an LV ejection fraction <40% (hazard ratio 4.2, CI 1.3 to 13.9) was associated with future MI or cardiac death independent of the presence of risk factors for coronary arteriosclerosis. Conclusions—In patients with poor echocardiograms, the results of cardiac MRI stress tests can be used to forecast myocardial infarction or cardiac death.

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.

Demonstration of an association among dietary cholesterol, central serotonergic activity, and social behavior in monkeys.

&NA; Epidemiologic studies link plasma cholesterol reduction to increased mortality rates as a result of suicide, violence, and accidents. Deficient central serotonergic activity is similarly associated with violence and suicidal behavior. We investigated the relationship among dietary and plasma cholesterol, social behavior, and the serotonin system as a possible explanation for these findings. Juvenile cynomolgus monkeys (eight female and nine male) were fed a diet high in fat and either high or low in cholesterol. We then evaluated their behavior over an 8‐month period. Plasma lipids and cerebrospinal fluid metabolites of serotonin, norepinephrine, and dopamine were assessed on two occasions, at 4 and 5.5 months after the initiation of behavioral observations. Animals that consumed a low‐cholesterol diet were more aggressive, less affiliative, and had lower cerebrospinal fluid concentrations of 5‐hydroxyindoleacetic acid than did their high‐cholesterol counterparts (p < .05 for each). The association among dietary cholesterol, serotonergic activity, and social behavior was consistent with data from other species and experiments and suggested that dietary lipids can influence brain neurochemistry and behavior; this phenomenon could be relevant to our understanding of the increase in suicide and violence‐related death observed in cholesterol‐lowering trials.

Regression of Atherosclerosis in Female Monkeys

The objective of this study was to determine the structural and functional changes that occur in the artery wall in response to plasma lipid lowering and hormone replacement in surgically postmenopausal monkeys with established coronary artery atherosclerosis. Eighty-eight surgically postmenopausal cynomolgus monkeys were fed an atherogenic diet for 24 months and were then allocated into 4 groups: group 1 (n = 20), a baseline necropsy group; group 2 (n = 25), a lipid-lowering diet only; group 3 (n = 22), lipid lowering plus conjugated equine estrogen treatment equivalent to 0.625 mg/d for a woman; and group 4 (n = 21), lipid lowering plus conjugated equine estrogen and medroxyprogesterone acetate treatment (equivalent to 2.5 mg/d for a woman). Treatment was for 30 months. Histomorphometric analysis of perfusion-fixed coronary arteries revealed that plaque size did not change significantly in any of the groups compared with group 1 (P > .20). Plasma lipid lowering permitted coronary artery remodeling to occur (coronary artery and lumen size doubled compared with group 1) (P < .05); however, hormone therapy did not augment remodeling. Quantitative angiographic analysis of coronary artery reactivity revealed that lipid lowering improved dilator responses to acetylcholine by 22 +/- 4% (P = .01) but not to nitroglycerin (P = .23). Hormone replacement did not further affect vascular reactivity to the agonists tested (P > .4), but addition of medroxyprogesterone acetate diminished the beneficial effects of conjugated estrogens on coronary flow reserve (P = .03). In summary, the major arterial sequelae of lipid lowering in female monkeys were artery and lumen enlargement and improved reactivity of large epicardial coronary arteries. Addition of hormone replacement to the dietary modification did not further augment these improvements, except for the dilator capacity of the coronary microcirculation.

Endothelial-dependent coronary vasomotor responsiveness in postmenopausal women with and without estrogen replacement therapy.

Recently, Williams et al’ reported that acute administration of estrogen attenuates the coronary vasoconstrictor response to acetylcholine in atherosclerotic cynomolgus monkeys. These observations suggest that estrogen plays a fundamentally important role in the relationship between coronary vascular endothelium and vascular smooth muscle. This study examines the influence of current estrogen replacement therapy in postmenopausal women on endothelial-dependent and independent vasomotor responsiveness to acetylcholine. Ten postmenopausal women with exertional angina undergoing routine diagnostic coronary angiography or percutaneous transluminal coronary angioplasty were studied. The protocol was approved by the Clinical Research Practices Committee and each subject gave informed consent before the study, Four women were taking estrogen replacement therapy (PremarinB 0.625 to 1.25 mglday or topical estradiol 0.1 mg). None of the women were taking progesterone. All of the women had minimal coronary artery narrowings in the proximal portion of the left anterior descending or a nondominant circumflex coronary artery. Vasoactive medications were withheld for 12-24 hours before the procedure. A 3Fr infusion catheter was positioned in the proximal left anterior descending or proximal circumflex artery through the guiding catheter. After the baseline angiogram was recorded, 3 consecutive 2-minute infusions of acetylcholine were administered into the proximal coronary artery. The

Brachial flow-mediated vasodilator responses in population-based research: methods, reproducibility and effects of age, gender and baseline diameter.

ow rate (0.8 mllmin) was calculated to deliver a final estimated blood concentration of 10s, 10m7 and 10m6 M. After each acetylcholine infusion, repeat angiography was performed in an identical fashion to baseline. After the third acetylcholine in& sion and angiogram, a 50 pg bolus of nitroglycerin was administered and a final coronary angiogram was recorded. Heart rate, blood pressure and appropriate electrocardiographic leads were monitored during the infusions to verify the absence of any changes in hemodynamic status or evidence of &hernia. Proximal and midvessel segments of the coronary artery distal to the tip of the infusion catheter were analyzed without knowledge of the estrogen status using a quantitative coronary angiography method (Gammasonits, Chicago, Illinois). When possible, coronary segments from the noninfused half of the left coronary distribution

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

Background Brachial artery ultrasound has been proposed as an inexpensive, accurate way to assess cardiovascular risk in populations. However, analysis and interpretation of these data are not uniform. Methods We analysed the relationship between relative and absolute changes in brachial artery diameter in response to flow-mediated dilation and age, gender and baseline diameter among 4040 ultrasound examinations from subjects aged 14 to 98 years. Results Reproducibility studies demonstrated intra- and interreader and intrasubject correlations from 0.67 to 0.84 for repeated measures of per cent change in diameter. Per cent change in diameter after flow stimulus was 3.58 ± 0.10% (mean ± standard deviation). Corresponding values for baseline diameter and absolute change in diameter were 4.43 ± 0.87 mm and 0.15 ± 0.01 mm, respectively. Baseline diameter and its variance were inversely related to per cent change in diameter (P < 0.001). In contrast, absolute change in diameter was more uniform throughout the range of baseline diameters. Baseline diameter was directly related, and per cent change in diameter inversely related, to age (P < 0.001 for all three measures). Time to maximum vasodilator response increased with age (P < 0.001). Women (n=2315) had significantly larger per cent change in diameter than men (n=1725) (P < 0.001). However, after adjustment for age and baseline diameter, per cent and absolute change were 5% smaller in women than men (P < 0.05 for both). In multivariate analysis, age was overwhelmingly the most important determinant of absolute change in diameter (P < 0.001). Conclusions Automated analysis of brachial flow-mediated vasodilator responses is both feasible and reproducible in large-scale clinical and population-based research.

One-Year Results of a Community-Based Translation of the Diabetes Prevention Program Healthy-Living Partnerships to Prevent Diabetes (HELP PD) Project

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).