Right Ventricular Functional Reserve in Pulmonary Arterial Hypertension.

BACKGROUND: Right ventricular (RV) functional reserve affects functional capacity and prognosis in patients with pulmonary arterial hypertension (PAH). PAH associated with systemic sclerosis (SSc-PAH) has a substantially worse prognosis than idiopathic PAH (IPAH), even though many measures of resting RV function and pulmonary vascular load are similar. We therefore tested the hypothesis that RV functional reserve is depressed in SSc-PAH patients. METHODS AND RESULTS: RV pressure-volume relations were prospectively measured in IPAH (n=9) and SSc-PAH (n=15) patients at rest and during incremental atrial pacing or supine bicycle ergometry. Systolic and lusitropic function increased at faster heart rates in IPAH patients, but were markedly blunted in SSc-PAH. The recirculation fraction, which indexes intracellular calcium recycling, was also depressed in SSc-PAH (0.32±0.05 versus 0.50±0.05; P=0.039). At matched exercise (25 W), SSc-PAH patients did not augment contractility (end-systolic elastance) whereas IPAH did (P<0.001). RV afterload assessed by effective arterial elastance rose similarly in both groups; thus, ventricular-vascular coupling declined in SSc-PAH. Both end-systolic and end-diastolic RV volumes increased in SSc-PAH patients to offset contractile deficits, whereas chamber dilation was absent in IPAH (+37±10% versus +1±8%, P=0.004, and +19±4% versus -1±6%, P<0.001, respectively). Exercise-associated RV dilation also strongly correlated with resting ventricular-vascular coupling in a larger cohort. CONCLUSIONS: RV contractile reserve is depressed in SSc-PAH versus IPAH subjects, associated with reduced calcium recycling. During exercise, this results in ventricular-pulmonary vascular uncoupling and acute RV dilation. RV dilation during exercise can predict adverse ventricular-vascular coupling in PAH patients.

Right ventricular dysfunction in systemic sclerosis-associated pulmonary arterial hypertension.

BACKGROUND: Systemic sclerosis­associated pulmonary artery hypertension (SScPAH) has a worse prognosis compared with idiopathic pulmonary arterial hypertension (IPAH), with a median survival of 3 years after diagnosis often caused by right ventricular (RV) failure. We tested whether SScPAH or systemic sclerosis­related pulmonary hypertension with interstitial lung disease imposes a greater pulmonary vascular load than IPAH and leads to worse RV contractile function. METHODS AND RESULTS: We analyzed pulmonary artery pressures and mean flow in 282 patients with pulmonary hypertension (166 SScPAH, 49 systemic sclerosis­related pulmonary hypertension with interstitial lung disease, and 67 IPAH). An inverse relation between pulmonary resistance and compliance was similar for all 3 groups, with a near constant resistance×compliance product. RV pressure­volume loops were measured in a subset, IPAH (n=5) and SScPAH (n=7), as well as SSc without PH (n=7) to derive contractile indexes (end-systolic elastance [Ees] and preload recruitable stroke work [Msw]), measures of RV load (arterial elastance [Ea]), and RV pulmonary artery coupling (Ees/Ea). RV afterload was similar in SScPAH and IPAH (pulmonary vascular resistance=7.0±4.5 versus 7.9±4.3 Wood units; Ea=0.9±0.4 versus 1.2±0.5 mm Hg/mL; pulmonary arterial compliance=2.4±1.5 versus 1.7±1.1 mL/mm Hg; P>0.3 for each). Although SScPAH did not have greater vascular stiffening compared with IPAH, RV contractility was more depressed (Ees=0.8±0.3 versus 2.3±1.1, P<0.01; Msw=21±11 versus 45±16, P=0.01), with differential RV-PA uncoupling (Ees/Ea=1.0±0.5 versus 2.1±1.0; P=0.03). This ratio was higher in SSc without PH (Ees/Ea=2.3±1.2; P=0.02 versus SScPAH). CONCLUSIONS: RV dysfunction is worse in SScPAH compared with IPAH at similar afterload, and may be because of intrinsic systolic function rather than enhanced pulmonary vascular resistive and pulsatile loading.

Sex differences in left ventricular function in older persons with mild hypertension.

BACKGROUND: Epidemiologic studies suggest that women are at increased risk of developing heart failure secondary to hypertension. Other studies have documented sex differences in left ventricular systolic and diastolic function in the presence of pressure overload states such as seen in aortic stenosis and hypertension. It is less clear if sex differences are present among older persons with mild hypertension. METHODS: One hundred seven healthy subjects, aged 55 to 75 years, with blood pressures ranging from 130 to 159 mm Hg systolic and/or 85 to 99 mm Hg diastolic, were examined by standard echocardiography and the newer modalities of tissue Doppler and color M-mode imaging. RESULTS: Women had a lower peak mitral annular systolic velocity (Sm), 8.9 (95% CI 8.4-9.5) cm/s versus 10.2 (95% CI 9.6-11.0) cm/s, (P < .01) than men. Among women, increasing age was associated with a reduction in diastolic function. For every decade of age, peak early mitral annular diastolic velocity (Em) declined by 1.6 cm/s (P < .01), mitral inflow velocity of propagation (Vp) declined by 26% (P < .01), E/Vp ratio increased by 20% (P = .03), and E/Em ratio increased by 11% (P = .04) in women. No age-associated changes were seen in men. CONCLUSIONS: As revealed by newer echocardiographic imaging modalities, women with mild hypertension showed greater reductions in systolic and diastolic function as they aged compared with men. Our findings are consistent with the increased risk older women have of developing heart failure because of hypertension.

Oxygen pulse during exercise is related to resting systolic and diastolic left ventricular function in older persons with mild hypertension.

BACKGROUND: The mechanisms responsible for impaired cardiovascular hemodynamics during exercise among persons with milder forms of hypertension are not well documented. We examined the relationship of oxygen pulse during exercise, a correlate of stroke volume, with echocardiographic indices of resting left ventricular function to determine whether abnormal contractility and relaxation are related to abnormal cardiovascular dynamics during exercise among such persons. METHODS: Subjects were 44 men and 55 women ages 55 to 75 years with mild hypertension but who were otherwise healthy. Resting left ventricular systolic and diastolic functions were assessed with 2-dimensional Doppler echocardiography and tissue Doppler imaging. Oxygen pulse (millimeters per beat) at rest and during multistage treadmill testing was derived from measurements of oxygen consumption and heart rate. The slope of oxygen pulse between successive exercise stages was calculated. RESULTS: After a steep rise in oxygen pulse from rest to stage 1 of exercise, a markedly diminished oxygen pulse slope was seen between subsequent exercise stages. In stepwise regression analysis, the increase in the slope of oxygen pulse from rest to stage 1 was explained by a greater lean body mass (57%, P < .001) and a larger left atrial size (2%, P < .001). After exercise stage 1, the increase in the slope of oxygen pulse was explained by sex (24%, P < .001), higher mitral E/A ratio (6%, P < .001), and higher mitral annular systolic velocity (6%, P < .001). CONCLUSIONS: These results suggest that a blunted oxygen pulse response to exercise among older persons with milder forms of hypertension may reflect impaired left ventricular stroke volume changes during exercise secondary to subtle abnormalities in both systolic and diastolic left ventricular functions.

Exercise effects on bone mineral density relationships to changes in fitness and fatness.

BACKGROUND: Weight loss typically reduces bone mineral density (BMD). Exercise may preserve or increase BMD even while reducing fatness. We examined the relationships among exercise-induced changes in fitness and fatness with BMD. DESIGN: Randomized controlled trial conducted between July 1999 and November 2003. PARTICIPANTS: Men and women (n =115) aged 55 to 75 years. INTERVENTION: Six months of exercise training. MAIN OUTCOME MEASURES: Fitness measured as peak oxygen uptake and muscle strength, body composition by anthropometry, dual-energy x-ray absorptiometry, and magnetic resonance imaging. RESULTS: A total of 51 men and 53 women completed the trial. Exercise increased aerobic and strength fitness and lean body mass, and reduced general and abdominal obesity. BMD did not change among men in either group. Among women exercisers, there were reductions in total skeleton BMD (p =0.02) and greater trochanter BMD (p =0.02). By bivariate correlation, among women, increased femoral neck BMD was associated with increased aerobic fitness (p =0.01) and with reduced body weight (p =0.02) and BMI (p =0.02). In the final regression model, 13% of the change in femoral neck BMD was explained by the change in aerobic fitness (p <0.01). Among the men, increased total hip BMD and femoral shaft BMD were associated with increased lean mass and lower-body strength. In the final regression models, the change in lean mass explained 9% of the variance in total hip BMD (p =0.04). The change in lean mass explained 20% of the change in femoral shaft BMD (p <0.01), and the change in lower-body strength explained an additional 6% (p <0.04). CONCLUSIONS: When examined by group assignment, 6 months of exercise had no effect on BMD among men, and reduced BMD among women. When examined by change in fitness and fatness, women who had the greatest increases in aerobic capacity and men who had the greatest increases in strength and lean mass were more likely to increase their BMD. Exercise-induced reductions in fatness did not lead to bone loss.

Effect of exercise on blood pressure in older persons: a randomized controlled trial.

BACKGROUND: Because of age-related differences in the cause of hypertension, it is uncertain whether current exercise guidelines for reducing blood pressure (BP) are applicable to older persons. Few exercise studies in older persons have evaluated BP changes in relation to changes in body composition or fitness. METHODS: This was a 6-month randomized controlled trial of combined aerobic and resistance training; controls followed usual care physical activity and diet advice. Participants (aged 55-75 years) had untreated systolic BP (SBP) of 130 to 159 mm Hg or diastolic BP (DBP) of 85 to 99 mm Hg. RESULTS: Fifty-one exercisers and 53 controls completed the trial. Exercisers significantly improved aerobic and strength fitness, increased lean mass, and reduced general and abdominal obesity. Mean decreases in SBP and DBP, respectively, were 5.3 and 3.7 mm Hg among exercisers and 4.5 and 1.5 mm Hg among controls (P < .001 for all). There were no significant group differences in mean SBP change from baseline (-0.8 mm Hg; P=.67). The mean DBP reduction was greater among exercisers (-2.2 mm Hg; P=.02). Aortic stiffness, indexed by aortofemoral pulse-wave velocity, was unchanged in both groups. Body composition improvements explained 8% of the SBP reduction (P = .006) and 17% of the DBP reduction (P<.001). CONCLUSIONS: A 6-month program of aerobic and resistance training lowered DBP but not SBP in older adults with mild hypertension more than in controls. The concomitant lack of improvement in aortic stiffness in exercisers suggests that older persons may be resistant to exercise-induced reductions in SBP. Body composition improvements were associated with BP reductions and may be a pathway by which exercise training improves cardiovascular health in older men and women.

Exercise and risk factors associated with metabolic syndrome in older adults.

BACKGROUND: Older people with elevated blood pressure (BP) often have metabolic syndrome, a clustering of central obesity, insulin resistance, dyslipidemia, and hypertension. Exercise reduces many of these risk factors. This study examined whether the benefits of exercise on cardiovascular and metabolic disease risk factors are mediated by exercise-induced changes in fitness or body composition. METHODS: Randomized controlled trial, comprising 6 months of exercise training, conducted between July 1999 and November 2003. Participants included men and women (n =115) aged 55 to 75 years with untreated systolic blood pressure (SBP) of 130 to 159 or diastolic blood pressure of (DPB) 85 to 99 mm Hg. Fitness measures included BP, lipids, lipoproteins, insulin, and glucose; peak oxygen uptake and muscle strength; and body composition measured by anthropometry, dual-energy x-ray absorptiometry, and magnetic resonance imaging. RESULTS: A total of 51 men and 53 women completed the trial. Exercise significantly increased aerobic and muscle fitness, lean mass, and high-density lipoprotein cholesterol and reduced total and abdominal fat. DBP was reduced more among exercisers. There were no associations among changes in fitness with risk factors. Reductions in total body and abdominal fat and increases in leanness, largely independent of weight loss, were associated with improved SBP, DBP, total cholesterol, very low-density lipoprotein cholesterol, triglycerides, lipoprotein(a), and insulin sensitivity. At baseline, 42.3% of participants had metabolic syndrome. At 6 months, nine exercisers (17.7%) and eight controls (15.1%) no longer had metabolic syndrome, whereas four controls (7.6%) and no exercisers developed it (p =0.06). CONCLUSIONS: Although exercise improved fitness, the reductions in total and abdominal fatness and increase in leanness were more strongly associated with favorable changes in risk factors for cardiovascular disease and diabetes, including those that constitute metabolic syndrome.

Exaggerated exercise blood pressure is related to impaired endothelial vasodilator function.

BACKGROUND: Persons with high normal blood pressure (BP) or mild hypertension who also have an exaggerated BP response to exercise are at risk for worsening hypertension. The mechanisms that explain this relationship are unknown. We examined the relationships of endothelial vasodilator function and of aortic stiffness with exercise BP. METHODS: Subjects were 38 men and 44 women, aged 55 to 75 years, with untreated high normal BP or mild hypertension but otherwise healthy. Exercise was performed on a treadmill. Endothelial vasodilator function was assessed as brachial artery flow-mediated vasodilation (FMD) during reactive hyperemia. Aortic stiffness was measured as pulse wave velocity (PWV). RESULTS: Among men, resting systolic BP explained 34% of the variance (P < .01) in maximal exercise systolic BP and FMD explained an additional 11% (P < .01); resting systolic BP explained 23% of the variance in maximal pulse pressure (PP) (P < .01), and FMD explained an additional 10% (P < .01). Among women, resting systolic BP was the only independent correlate of maximal systolic BP (R2 = 0.12, P < .03) and FMD correlated negatively with maximal PP (R2 = 0.12, P < .03). Among men, FMD was the only independent correlate of the difference between resting and maximal systolic BP (R2 = 0.20, P < .02). The FMD was the only independent correlate of the difference between resting and maximal PP among men (R2 = 0.17, P < .03) and among women (R2 = 0.12, P < .03). The PWV did not correlate with exercise BP responses. CONCLUSIONS: These results suggest that impaired endothelial vasodilator function may be a mechanism contributing to exercise hypertension and may also be one link between exaggerated exercise BP and worsening hypertension.

Relationships of insulin sensitivity with fatness and fitness and in older men and women.

PURPOSE: Increased body fatness, especially abdominal obesity, and low levels of fitness are associated with decreased insulin sensitivity. Men and women differ in obesity, body fat distribution, and fitness levels. This cross-sectional study evaluated sex differences in the relationships of insulin sensitivity with fatness and fitness and obesity. METHODS: Subjects were nonsmoking, nondiabetic, sedentary men (n = 50) and women (n = 61) aged 55-75 years with mild hypertension. Study measures were insulin sensitivity (QUICKI: 1/[log(fasting insulin) + log(fasting glucose)]), lipids and lipoproteins, total body fatness using dual energy x-ray absorptiometry (DXA), anthropometrics, abdominal obesity using magnetic resonance imaging (MRI), and aerobic fitness assessed as Vo(2) peak during treadmill testing. RESULTS: Women had a higher percentage of body fat and more abdominal subcutaneous and less visceral fat than men. Among women, QUICKI correlated negatively with body mass index (BMI), percent body fat, abdominal total fat, subcutaneous fat, and visceral fat but not with lipids. Among men, QUICKI correlated negatively with total and abdominal fatness and triglycerides. QUICKI correlated with fitness in men only. Using stepwise regression, among women, decreased total abdominal fat accounted for 33%, and postmenopausal hormone therapy accounted for an additional 5% of the variance in QUICKI. Among men, only a higher level of fitness independently correlated with insulin sensitivity, accounting for 21% of the variance (p < 0.01). CONCLUSIONS: Abdominal obesity among women and fitness among men were the strongest determinants of insulin sensitivity in this older cohort. This raises the question whether there are sex differences in the lifestyle changes that would be most effective in improving insulin sensitivity.

Usefulness of anthropometrics and dual-energy x-ray absorptiometry for estimating abdominal obesity measured by magnetic resonance imaging in older men and women.

PURPOSE: Increasing evidence suggests that abdominal obesity may be a better predictor of disease risk than total fatness. This study sought to determine how obesity and fat distribution measured by readily available anthropometric and dual-energy x-ray absorptiometry (DXA) methods is related to abdominal obesity assessed by magnetic resonance imaging (MRI). METHODS: Men (n = 43) and women (n = 47), ages 55 to 75 years, were assessed for body mass index, waist-to-hip ratio, waist circumference, and skin folds by anthropometric methods; for percentage of body fat by DXA; and for abdominal total, subcutaneous, and visceral fat by MRI. RESULTS: In stepwise regression models, the waist-to-hip ratio explained 50% of the variance in abdominal visceral fat among men (P <.01), and body mass index explained an additional 6% of the variance (P <.01). Among women, waist circumference was the only independent correlate of abdominal visceral fat, accounting for 52% of the variance (P <.01). Among men, the percentage of body fat was the only independent correlate of abdominal subcutaneous fat, explaining 65% of the variance (P <.01). Among women, the percentage of body fat explained 77% of the variance in abdominal subcutaneous fat and body mass index explained an additional 3% (P <.01). CONCLUSIONS: Obesity and body composition obtained by readily available anthropometric methods and DXA provide informative estimates of abdominal obesity assessed by MRI imaging.

Are fitness, activity, and fatness associated with health-related quality of life and mood in older persons?

PURPOSE: This study sought to determine whether levels of fitness, habitual physical activity, and fatness are associated health-related quality of life and mood in older persons. METHODS: The subjects were men (n = 38) and women (n = 44), ages 55 to 75 years, who had milder forms of hypertension, but who were otherwise healthy and not engaged in a regular exercise or diet program. Aerobic fitness was assessed by maximal oxygen uptake during treadmill testing, muscle strength by a one-repetition maximum, habitual activity by questionnaire, fatness by dual-energy x-ray absorptiometry, and body mass index. Health-related quality of life was assessed by the Medical Outcomes Study SF-36, and mood by the Profile of Mood States (POMS). Correlations were determined by bivariate and multivariate regression. RESULTS: Higher aerobic fitness was associated with more desirable outcomes, as indicated by the POMS anger and total mood disturbance scores and by the SF-36 bodily pain, physical functioning, vitality, and physical component scores. Increased fatness was associated with less desirable outcomes, as indicated by the POMS anger, depression, and total mood disturbance scores and by the SF-36 bodily pain, physical functioning, role-emotional, role-physical, social functioning, vitality, and physical component scores. Higher physical activity was associated with an increased POMS score for vigor and a decreased SF-36 score for bodily pain. Strength was not related to health-related quality of life or mood. Aerobic fitness was the strongest predictor of the SF-36 score for vitality and the POMS score for total mood disturbance, whereas fatness was the strongest predictor of the POMS anger score and the SF-36 bodily pain, physical functioning, and physical component scores. CONCLUSIONS: Even in the absence of regular exercise and a weight-loss diet, relatively small amounts of routine physical activity within a normal lifestyle, slight increases in fitness, and less body fatness are associated with a better health-related quality of life and mood.

Peripheral endothelium-dependent flow-mediated vasodilatation is associated with left ventricular mass in older persons with hypertension.

BACKGROUND: Increased left ventricular (LV) mass is associated with greater cardiovascular disease risk. Recent studies have also shown an association of increased LV mass with attenuated endothelium-dependent coronary flow reserve. Less is known about the association between LV mass and endothelium-dependent flow-mediated dilatation (FMD) in peripheral arteries, a noninvasive measure of endothelial function. METHODS: Sixty-two subjects with untreated mild hypertension, aged 55 to 75 years and otherwise healthy, were examined. Resting blood pressure was obtained by the average of 4 to 5 visits, each at least 1 week apart. LV mass was determined from magnetic resonance imaging and was indexed by body surface area, height and height(2.7). Body composition was assessed with dual energy x-ray absorptiometry. FMD was measured as the percent change of brachial artery diameter during reactive hyperemia by use of high-resolution ultrasound. RESULTS: Median LV mass index was 63 g/m2 (interquartile range, 58-73). In bivariate analysis, LV mass was correlated to lean body mass (r = 0.63, P <.001), diastolic blood pressure (r = 0.35, P <.01), and FMD (r = -0.27, P <.05). In multivariate analysis, 44% of the variance in log-LV mass was explained by lean body mass. An additional 6% of the variance was explained by FMD (P <.05). For each 1% point decrease in FMD, LV mass increased by 1.1%. CONCLUSIONS: In addition to the expected influences of body size, impairment of brachial artery FMD was independently related to LV mass in elderly subjects with mild hypertension who did not yet have LV hypertrophy. Whether mild hypertension is the common mechanism linking LV mass and endothelial function has yet to be determined.