The effect of gender on outcome in digitalis-treated heart failure patients.

BACKGROUND: The use of digitalis is recommended for the treatment of heart failure to reduce hospitalization. Recent data suggest that digitalis treatment may adversely affect survival in women but not in men. We studied patients with left ventricular dysfunction enrolled in the Studies of Left Ventricular Dysfunction (SOLVD) to determine whether there was a gender-based survival difference in patients treated with digitalis. METHODS AND RESULTS: Symptomatic (n = 2569) and asymptomatic (n = 4228) patients with left ventricular ejection fraction < or = 0.35 were studied. Digitalis use was assessed at baseline and baseline demographic variables were catalogued and compared. A multivariate analysis, incorporating known covariates of risk for adverse cardiovascular events, was used to examine the association of digitalis with all-cause mortality, cardiovascular death, death from heart failure, and arrhythmic death, with, or without, worsening heart failure in women compared with men. Analysis for an interaction between digitalis and gender on mortality was also performed. No interaction between gender and digitalis treatment on survival was found, and there was no significant difference in the hazard ratios for men and women on digitalis either with respect to all-cause mortality, cardiovascular mortality, heart failure mortality, or arrhythmic death with worsening heart failure. When mortality for arrhythmic death without worsening heart failure was adjusted for the probability of being treated with digitalis (propensity analysis), women fared better than men. CONCLUSION: Data from the SOLVD trials suggest that digitalis treatment of heart failure does not result in a difference in survival between men and women. Because a randomized trial to definitively answer the question is unlikely, and perhaps inappropriate, examination of other heart failure populations for a gender-digitalis interaction is indicated.

IGF2 genotype and obesity in men and women across the adult age span.

We studied a previously reported association between the IGF2 gene's ApaI polymorphism and obesity in 500 healthy men and women (19-90 y). We hypothesized that individuals homozygous for the IGF2 A allele (A/A) would exhibit lower body mass, BMI and DEXA-measured fat mass compared to G/G homozygotes. Subjects were categorized as exhibiting the G/G (n = 241), G/A (n = 197) or A/A (n = 62) genotype. Contrary to our hypothesis, no difference was observed in body mass, body mass index (BMI) or fat mass between the G/G and A/A genotype groups in the entire cohort. Surprisingly, Caucasian A/A individuals (n = 427) exhibited significantly higher fat mass compared to Caucasian G/G individuals (P < 0.05). In summary, individuals homozygous for the IGF2 G allele do not exhibit higher body mass, BMI or fat mass compared to A/A individuals; however, Caucasians with the A/A genotype exhibit higher fat mass than G/G individuals.

Does age, sex, or ACE genotype affect glucose and insulin responses to strength training?

The purpose of the present study was to determine whether age, sex, or angiotensin I-converting enzyme (ACE) genotype influences the effects of strength training (ST) on glucose homeostasis. Nineteen sedentary young (age = 20-30 yr) men (n = 10) and women (n = 9) were studied and compared with 21 sedentary older (age = 65-75 yr) men (n = 12) and women (n = 9) before and after a 6-mo total body ST program. Fasting insulin concentrations were reduced in young men and in older men with ST (P < 0.05 in both). In addition, total insulin area under the curve decreased by 21% in young men (P < 0.05), and there was a trend for a decrease (11%) in older men (P = 0.06). No improvements in insulin responses were observed in young or older women. The ACE deletion/deletion genotype group had the lowest fasting insulin and insulin areas under the oral glucose tolerance test (OGTT) curve before training (all P < 0.05), but those with at least one insertion allele had a trend for a greater reduction in total insulin area than deletion homozygotes (P = 0.07). These results indicate that ST has a more favorable effect on insulin response to an OGTT in men than in women and offer some support for the hypothesis that ACE genotype may influence insulin responses to ST.

The effect of anthropometric and socioeconomic factors on the racial difference in lung function.

African-Americans have lower lung function than whites. However, the relative contributions of body habitus and socioeconomic factors are unknown. To address this question, we analyzed data from 1242 white (806 women, 436 men) and 1084 African-American (696 women, 388 men) asymptomatic, nonsmoking adult participants of the third National Health and Nutrition Examination Survey (NHANES III). African-Americans were poorer, had larger FEV(1)/FVC and body mass index (BMI), but lower sitting height, FEV(1) and FVC than whites. Cross-sectional regression analyses using spirometric, anthropometric, and socioeconomic data were performed separately by sex to investigate racial differences in lung function. Sitting height accounted for 35-39% of the race difference in both sexes. Poverty index accounted for about 7.5% and 2.5% of the racial difference in women and men, respectively, whereas the effect of education accounted for about 2% in women and 4.7% in men. With further adjustment for BMI, we could account for only about half of the racial difference in FEV(1) and FVC. We conclude that the racial difference in lung function is only partially explained by a shorter upper body segment in African-Americans. Although low socioeconomic indicators are related to lower lung function, they explain only a small proportion of this racial difference.

Stress testing in the elderly.

The ever-increasing number of older patients requiring diagnostic and prognostic assessment for coronary artery disease has necessitated accurate, noninvasive techniques applicable to this age group. Exercise testing, either alone or with radionuclide or echocardiographic imaging, remains a useful tool in elderly patients capable of performing vigorous treadmill or cycle exercise. Fortunately, for the large elderly subset incapable of such exercise, pharmacologic stress testing with dipyridamole, adenosine, or dobutamine offers an excellent alternative. Choosing the most appropriate stress testing modality for a given patient from among the many choices available remains the clinician's challenge.

Associations of aortic Windkessel function with age, gender and cardiovascular risk factors.

Aortic Windkessel function is thought to represent a potential cardiovascular risk factor. As an indicator for the function, we have recently introduced the decay index (DI). DI is the coefficient of an exponential function applied to the postpeak portion of internal carotid artery Doppler waveform, and is inversely associated with the function. This study compares DI with age, gender and traditional cardiovascular risk factors in 220 apparently healthy volunteers (59 +/- 16 years). DI increased linearly with age (r = 0.51, p < 0.001), and was higher in women than in men at all ages (p < 0.001). Also, DI was positively associated with systolic blood pressure (beta = 0.17, p < 0.01) and diabetic medication (beta = 0.14, p < 0.05), independent of age (beta = 0.49, p < 0.0001), gender (beta = 0.27, p < 0.0001) and other traditional cardiovascular risk factors (model r(2) = 0.36). Based on the present results, the Windkessel function as assessed by DI declines with age and is lower in women. However, the associations with cardiovascular risk factors need to be established on a larger sample at higher cardiovascular risk.

Hormone replacement therapy and longitudinal changes in blood pressure in postmenopausal women.

BACKGROUND: The incidence of hypertension in postmenopausal women exceeds that in age-matched men. Longitudinal studies relating hormone replacement therapy (HRT) to blood pressure changes are sparse. OBJECTIVE: To investigate the association between HRT and longitudinal changes in blood pressure in postmenopausal women. DESIGN: Longitudinal observational study. SETTING: Community-dwelling volunteers. PATIENTS: 226 healthy, normotensive postmenopausal women from the Baltimore Longitudinal Study of Aging with a mean (+/-SD) age of 64 +/- 10 years were followed for 5.7 +/- 5.3 years. Seventy-seven women used both estrogen and progestin, and 149 used neither. MEASUREMENTS: Lifestyle variables, blood pressure, and traditional cardiovascular risk factors were measured at baseline and approximately every 2 years thereafter. RESULTS: Systolic blood pressure at baseline was similar in HRT users and nonusers (133.9 +/- 16.0 mm Hg vs. 132.4 +/- 14.8 mm Hg). Over time, average systolic blood pressure increased less in HRT users than nonusers, independent of other cardiovascular risk factors, physical activity, and alcohol use. For example, HRT users who were 55 years of age at their first Baltimore Longitudinal Study of Aging visit experienced a 7.6-mm Hg average increase in systolic blood pressure over 10 years; in contrast, the average increase in nonusers was 18.7 mm Hg. The lesser increase in systolic blood pressure in HRT users was more evident at older age. Diastolic blood pressure, which did not change statistically over time in either group, was not associated with HRT. CONCLUSION: Postmenopausal women taking HRT have a smaller increase in systolic blood pressure over time than those not taking HRT. This difference is intensified at older ages.

Effect of estrogen and progestin replacement on arterial stiffness indices in postmenopausal women.

Our objectives were to investigate whether long-term estrogen replacement therapy (ERT) is associated with a reduction in age-associated increases in arterial stiffness and blood pressure (BP), and whether the addition of progestin modifies the effects of estrogen. ERT has been found to have beneficial effects on cardiovascular risk. There are few data, however, delineating the effects of ERT on BP and arterial stiffness, and their age-associated changes. BP and aorto-femoral pulse wave velocity (PWV) were measured in 134 postmenopausal volunteers, aged 51 to 90 years, from the Baltimore Longitudinal Study of Aging, screened to exclude clinical and occult cardiovascular disease, and classified as ERT non-users (N=57) or ERT users (N=77). The latter group was further substratified according to the use of estrogen alone (N=32) or a combination of estrogen and progestins (N=45). ERT users showed similar body habitus, physical activity, and plasma lipids compared to non-ERT users. ERT was associated with an average 9.8 mmHg lower systolic BP (p<0.001), and a 6.3 mmHg lower pulse pressure (p<0.01) than in non-users. Multiple regression analysis showed that ERT was an independent predictor of lower SBP and PP (p<0.05). By analysis of covariance, ERT predicted a reduced age-associated increase in SBP, PP, and PWV (p<0.05). When systolic BP was >130 mmHg, the combination of ERT and progestins predicted a higher PWV than ERT alone. In conclusion, ERT in postmenopausal women can beneficially affect the vascular system, by reducing BP and the age-associated increase in arterial stiffness. The addition of progestins to ERT may reduce these beneficial effects.

Effect of strength training on resting metabolic rate and physical activity: age and gender comparisons.

PURPOSE: The purpose of this study was to compare age and gender effects of strength training (ST) on resting metabolic rate (RMR), energy expenditure of physical activity (EEPA), and body composition. METHODS: RMR and EEPA were measured before and after 24 wk of ST in 10 young men (20-30 yr), 9 young women (20-30 yr), 11 older men (65-75 yr), and 10 older women (65-75 yr). RESULTS: When all subjects were pooled together, absolute RMR significantly increased by 7% (5928 +/- 1225 vs 6328 +/- 1336 kJ.d-1, P < 0.001). Furthermore, ST increased absolute RMR by 7% in both young (6302 +/- 1458 vs 6719 +/- 1617 kJ x d(-1), P < 0.01) and older (5614 +/- 916 vs 5999 +/- 973 kJ x d(-1), P < 0.05) subjects, with no significant interaction between the two age groups. In contrast, there was a significant gender x time interaction (P < 0.05) for absolute RMR with men increasing RMR by 9% (6645 +/- 1073 vs 7237 +/- 1150 kJ x d(-1), P < 0.001), whereas women showed no significant increase (5170 +/- 884 vs 5366 +/- 692 kJ x d(-1), P = 0.108). When RMR was adjusted for fat-free mass (FFM) using ANCOVA, with all subjects pooled together, there was still a significant increase in RMR with ST. Additionally, there was still a gender effect (P < 0.05) and no significant age effect (P = NS), with only the men still showing a significant elevation in RMR. Moreover, EEPA and TEE estimated with a Tritrac accelerometer and TEE estimated by the Stanford Seven-Day Physical Activity Recall Questionnaire did not change in response to ST for any group. CONCLUSIONS: In conclusion, changes in absolute and relative RMR in response to ST are influenced by gender but not age. In contrast to what has been suggested previously, changes in body composition in response to ST are not due to changes in physical activity outside of training.

The effect of gender on the relationship between body fat distribution and lung function.

Although abdominal obesity, as measured by waist-to-hip ratio (WHR), has long been recognized as a risk factor for metabolic and cardiovascular diseases, little is known about the effect of WHR on pulmonary function, especially in women. In this study of 1094 men and 540 women (18-102 years) from the Baltimore Longitudinal Study of Aging (BLSA), we examined the effect of WHR on forced expiratory volume in 1 s (FEV(1)). Cross-sectional analyses, after accounting for body mass index (BMI) and other variables, showed a strong inverse association of WHR with FEV(1) in men (beta = -1.338, P=.0001) but not in women. Furthermore, larger values of WHR were associated with greater reductions of forced vital capacity (FVC) in men (beta = -1.383, P =.0005) compared to women (beta = -0.679, P =.02). Thus, body fat distribution has independent effects on lung function that are more prominent in men than women.

Insulin action after resistive training in insulin resistant older men and women.

OBJECTIVES: To determine the effects of resistive training (RT) on insulin action and assess the determinants of the changes in insulin action. DESIGN: Longitudinal study. SETTING: Outpatient setting. PARTICIPANTS: Eighteen older men and older postmenopausal women (65-74 years) with normal (6 men and 5 women) or impaired glucose tolerance (4 men and 3 women). INTERVENTION: Six months of progressive whole-body RT. MEASUREMENTS: Upper and lower body strength was assessed by the one repetition maximum test. Total body fat and fat-free mass (FFM) were determined by dual-energy x-ray absorptiometry before and after 6 months of RT. Insulin sensitivity was estimated from the relationship of glucose utilization (M) to the concentration of insulin (I) during the last 30 minutes of 3-hour hyperinsulinemic-euglycenic clamps (240 pmol x min(-2) x min(-1)) (M/I) before and after RT. RESULTS: RT significantly improved upper- and lower-body muscular strength (P < .005). FFM increased after RT in the entire group (P < .01) with no significant change in body fat. Although the change in M was larger in men (13%) than women (3%), the difference was not significant. The change in M was a function of initial M (r = -0.53, P < .05). There was a trend (0.060+/-0.006 vs 0.066+/-0.006 micromol x kg(-1) x min(-1)/pmol/l, n = 18) for M/I to increase after RT in the combined group of men and women (P = .06). There were no significant relationships between changes in M or M/I with changes in body composition or strength. CONCLUSION: A 6-month RT program tends to improve insulin action in insulin-resistant older adults. These results suggest that RT may be useful in ameliorating insulin resistance that often occurs with physical inactivity, obesity, and loss of muscular strength in older insulin resistant men and women.

Is the apoE4 allele an independent predictor of coronary events?

PURPOSE: Although the apolipoprotein E genotype epsilon4 (apoE4) has been associated with high cholesterol levels, whether it is an independent predictor of coronary events is not certain. SUBJECTS AND METHODS: We measured apoE genotypes in 730 participants in the Baltimore Longitudinal Study of Aging (421 men and 309 women, mean [+/- SD] age of 52+/-17 years) who were free of preexisting coronary heart disease. A proportional hazards regression model was used to study the association between risk factors and the occurrence of coronary events, defined as angina pectoris, documented myocardial infarction by history or major Q waves on the electrocardiogram (Minnesota Code 1:1 or 1:2), or coronary death, adjusted for other risk factors, including total plasma cholesterol level. RESULTS: The apoE4 allele was observed in 200 subjects (27%), including 183 heterozygotes and 17 homozygotes. Coronary risk factor profiles were similar in those with and without apoE4. Coronary events developed in 104 (14%) of the 730 subjects, including 77 (18%) of the 421 men during a mean follow-up of 20 years and 27 (9%) of the 309 women during a mean follow-up of 13 years. Coronary events occurred significantly more frequently in subjects with apoE4 (n = 40, 20%) than in those without this allele (64, 12%, P <0.05). In a multivariate model, apoE4 was an independent predictor of coronary events in men (risk ratio [RR]= 2.9, 95% confidence interval [CI]: 1.8 to 4.5, P<0.0001) but not in women (RR = 0.9, 95% CI: 0.4 to 1.9, P = 0.62). CONCLUSION: The apoE4 genotype is a strong independent risk factor for coronary events in men, but not women. The association does not appear to be mediated by differences in total cholesterol levels.

Muscle size responses to strength training in young and older men and women.

OBJECTIVES: To examine the possible influences of age and gender on muscle volume responses to strength training (ST). DESIGN: Prospective intervention study. SETTING: University of Maryland Exercise Science and Wellness Research Laboratories. PARTICIPANTS: Eight young men (age 20-30 years), six young women (age 20-30 years), nine older men (age 65-75 years), and ten older women (age 65-75 years). INTERVENTION: A 6-month whole-body ST program that exercised all major muscle groups of the upper and lower body 3 days/week. MEASUREMENTS: Thigh and quadriceps muscle volumes and mid-thigh muscle cross-sectional area (CSA) were assessed by magnetic resonance imaging before and after the ST program. RESULTS: Thigh and quadriceps muscle volume increased significantly in all age and gender groups as a result of ST (P < .001), with no significant differences between the groups. Modest correlations were observed between both the change in quadriceps versus the change in total thigh muscle volume (r = 0.65; P < .001) and the change in thigh muscle volume versus the change in mid-thigh CSA (r = 0.76, P < .001). CONCLUSIONS: The results indicate that neither age nor gender affects muscle volume response to whole-body ST. Muscle volume, rather than muscle CSA, is recommended for studying muscle mass responses to ST.

A comparison of longitudinal changes in aerobic fitness in older endurance athletes and sedentary men.

OBJECTIVES: To compare the longitudinal changes in maximal aerobic capacity (VO2max) in healthy middle aged and older athletes and sedentary men. DESIGN: A cohort study with mean follow-up of 8.7 years (range 4.0-12.8). SETTING: Outpatient research at a tertiary hospital. PARTICIPANTS: Forty-two healthy, middle aged, and older athletes (initial age 64 +/- 1 year) and 47 healthy sedentary men of comparable age recruited for research studies. MEASUREMENTS: VO2max during a maximal treadmill test. RESULTS: At baseline, the cross-sectional rates of decline in VO2max with age (slope) were virtually identical in the athletes and sedentary men (-0.42 versus -0.43 mL x kg(-1) x min(-1) x year(-1)). At follow-up, the VO2max had declined by 11.9 +/- 1.1 mL x kg(-1) x min(-1) (22%) in the athletes, a crude average rate of -1.4 +/- 0.14 mL x kg(-1)x min(-1) x year(-1). By comparison, the VO2max declined by 4.4 +/- 0.6 mL x kg(-1) x min(-1) (14%) in the sedentary men, a crude average rate of change of -0.48 +/- 0.07 mL x kg(-1) x min(-1) x year(-1). Therefore, the observed absolute rate of longitudinal decline in VO2max in the athletes was triple that of the sedentary men (P= .001) and significantly greater than the decline predicted by their baseline cross-sectional data (P= .001). Post hoc analyses of the longitudinal data in the athletes based on the training regimens over the follow-up period demonstrated that the seven individuals who continued to train vigorously ("high training") had no significant decline in VO2max (0.28% change in VO2max per year). By contrast, the VO2max declined by 2.6% per year in the "moderate training" group (N=21), 4.6% per year in the "low training" group (N=13), and 4.7% per year in the two individuals who developed cardiovascular disease. CONCLUSION: The longitudinal decline in VO2max in older male endurance athletes is highly dependent upon the continued magnitude of the training stimulus. The majority of the athletes reduced their training levels over time, resulting in longitudinal reductions in VO2max two to three times as large as those predicted by cross-sectional analyses or those observed longitudinally in their sedentary peers.

Effects of age, gender, and myostatin genotype on the hypertrophic response to heavy resistance strength training.

BACKGROUND: Because of the scarcity of data available from direct comparisons of age and gender groups using the same relative training stimulus, it is unknown whether older individuals can increase their muscle mass as much as young individuals and whether women can increase as much as men in response to strength training (ST). In addition, little is known about whether the hypertrophic response to ST is affected by myostatin genotype, a candidate gene for muscle hypertrophy. METHODS: Eleven young men (25 +/- 3 years, range 21-29 years), 11 young women (26 +/- 2 years, range 23-28 years), 12 older men (69 +/- 3 years, range 65-75 years), and 11 older women (68 +/- 2 years, range 65-73 years) had bilateral quadriceps muscle volume measurements performed using magnetic resonance imaging (MRI) before and after ST and detraining. Training consisted of knee extension exercises of the dominant leg three times per week for 9 weeks. The contralateral limb was left untrained throughout the ST program. Following the unilateral training period, the subjects underwent 31 weeks of detraining during which no regular exercise was performed. Myostatin genotype was determined in a subgroup of 32 subjects, of which five female subjects were carriers of a myostatin gene variant. RESULTS: A significantly greater absolute increase in muscle volume was observed in men than in women (204 +/- 20 vs 101 +/- 13 cm3, p < .01), but there was no significant difference in muscle volume response to ST between young and older individuals. The gender effect remained after adjusting for baseline muscle volume. In addition, there was a significantly greater loss of absolute muscle volume after 31 weeks of detraining in men than in women (151 +/- 13 vs 88 +/- 7 cm3, p < .05), but no significant difference between young and older individuals. Myostatin genotype did not explain the hypertrophic response to ST when all 32 subjects were assessed. However, when only women were analyzed, those with the less common myostatin allele exhibited a 68% larger increase in muscle volume in response to ST (p = .056). CONCLUSIONS: Aging does not affect the muscle mass response to either ST or detraining, whereas gender does, as men increased their muscle volume about twice as much in response to ST as did women and experienced larger losses in response to detraining than women. Young men were the only group that maintained muscle volume adaptation after 31 weeks of detraining. Although myostatin genotype may not explain the observed gender difference in the hypertrophic response to ST, a role for myostatin genotype may be indicated in this regard for women, but future studies are needed with larger subject numbers in each genotype group to confirm this observation.

Incidence, predictive factors, and prognostic significance of supraventricular tachyarrhythmias in congestive heart failure.

BACKGROUND: The incidence, predictive factors, morbidity, and mortality associated with the development of supraventricular tachyarrhythmias (SVTs) in patients with congestive heart failure (CHF) are poorly defined. METHODS: In the Digitalis Investigation Group trial, patients with CHF who were in sinus rhythm were randomly assigned to digoxin (n = 3,889) or placebo (n = 3,899) and followed up for a mean of 37 months. Baseline factors that predicted the occurrence of SVT and the effects of SVT on total mortality, stroke, and hospitalization for worsening CHF were determined. RESULTS: Eight hundred sixty-six patients (11.1%) had SVT during the study period. Older age (odds ratio [OR], 1.029 for each year increase in age; p = 0.0001), male sex (OR, 1.270; p = 0.0075), increasing duration of CHF (OR, 1.003 for each month increase in duration of CHF; p = 0.0021), and a cardiothoracic ratio of > 0.50 (OR, 1.403; p = 0.0001) predicted an increased risk of experiencing SVT. Left ventricular ejection fraction, New York Heart Association functional class, and treatment with digoxin vs placebo were not related to the occurrence of SVT. After adjustment for other risk factors, development of SVT predicted a greater risk of subsequent total mortality (risk ratio [RR] = 2.451; p = 0.0001), stroke (RR = 2.352; p = 0.0001), and hospitalization for worsening CHF (RR = 3. 004; p = 0.0001). CONCLUSION: In CHF patients in sinus rhythm, older age, male sex, longer duration of CHF, and increased cardiothoracic ratio predict an increased risk for experiencing SVT. Development of SVT is a strong independent predictor of mortality, stroke, and hospitalization for CHF in this population. Prevention of SVT may prolong survival and reduce morbidity in CHF patients.