Common genetic variation near the connexin-43 gene is associated with resting heart rate in African Americans: a genome-wide association study of 13,372 participants.

BACKGROUND: Genome-wide association studies have identified several genetic loci associated with variation in resting heart rate in European and Asian populations. No study has evaluated genetic variants associated with heart rate in African Americans. OBJECTIVE: To identify novel genetic variants associated with resting heart rate in African Americans. METHODS: Ten cohort studies participating in the Candidate-gene Association Resource and Continental Origins and Genetic Epidemiology Network consortia performed genome-wide genotyping of single nucleotide polymorphisms (SNPs) and imputed 2,954,965 SNPs using HapMap YRI and CEU panels in 13,372 participants of African ancestry. Each study measured the RR interval (ms) from 10-second resting 12-lead electrocardiograms and estimated RR-SNP associations using covariate-adjusted linear regression. Random-effects meta-analysis was used to combine cohort-specific measures of association and identify genome-wide significant loci (P≤2.5×10(-8)). RESULTS: Fourteen SNPs on chromosome 6q22 exceeded the genome-wide significance threshold. The most significant association was for rs9320841 (+13 ms per minor allele; P = 4.98×10(-15)). This SNP was approximately 350 kb downstream of GJA1, a locus previously identified as harboring SNPs associated with heart rate in Europeans. Adjustment for rs9320841 also attenuated the association between the remaining 13 SNPs in this region and heart rate. In addition, SNPs in MYH6, which have been identified in European genome-wide association study, were associated with similar changes in the resting heart rate as this population of African Americans. CONCLUSIONS: An intergenic region downstream of GJA1 (the gene encoding connexin 43, the major protein of the human myocardial gap junction) and an intragenic region within MYH6 are associated with variation in resting heart rate in African Americans as well as in populations of European and Asian origin.

The effect of conjugated equine oestrogen on diabetes incidence: the Women's Health Initiative randomised trial.

AIMS/HYPOTHESIS: Recent clinical trials have found that the combination of conjugated equine oestrogen (CEO) and medroxyprogesterone has a protective effect on the incidence of type 2 diabetes. To determine the effect of CEO alone on the incidence of diabetes mellitus in postmenopausal women, we analysed the results of the Women's Health Initiative oestrogen-alone trial. METHODS: The Women's Health Initiative is a randomised, double-masked trial comparing the effect of daily 0.625 mg CEO with placebo during 7.1 years of follow-up of 10,739 postmenopausal women who were aged 50-79 years and had previously had a hysterectomy. Diabetes incidence was ascertained by self-report of treatment with insulin or oral hypoglycaemic medication. Fasting glucose, insulin and lipoproteins were measured in an 8.6% random sample of study participants, at baseline and at 1, 3 and 6 years. RESULTS: The cumulative incidence of treated diabetes was 8.3% in the oestrogen-alone group and 9.3% in the placebo group (hazard ratio 0.88, 95% CI 0.77-1.01, p=0.072). During the first year of follow-up, a significant fall in insulin resistance (homeostasis model assessment of insulin resistance) in actively treated women compared with the control subjects (Year 1 baseline between-group difference -0.53) was seen. However, there was no difference in insulin resistance at the 3- or 6-year follow-up. CONCLUSIONS/INTERPRETATION: Postmenopausal therapy with oestrogen alone may reduce the incidence of treated diabetes. The effect is smaller than that seen with oestrogen plus progestin. CEO should not, however, be used with the intention of preventing diabetes, as its well-described adverse effects preclude long-term use for primary prevention.

Can sedentary adults accurately recall the intensity of their physical activity?

BACKGROUND: Physical activity, in particular vigorous activity (i.e., > or =6 METs), lowers mortality from chronic diseases such as cardiovascular disease (CVD). The 7-Day Physical Activity Recall (PAR), a self-administered activity log (LOG), and heart rate monitoring (HR) were used to quantify activity patterns among sedentary adults. We hypothesized that individuals in this population could accurately estimate the duration, but not the intensity, of their activity. METHODS: Sedentary adults (n = 94, 47.8 +/- 7.1 years) completed two PARs 1 week apart and underwent HR monitoring while completing a LOG for 1 day during the PAR assessment interval. RESULTS: The relationship between PARs (kcal. kg(-1). day(-1) ) was significant (r = 0.80, 95% CI 0.68-0.87) among individuals (n = 63) reporting "typical" activity patterns and among all individuals (n = 94) reporting "typical" and "not typical" activity patterns combined (r = 0.44, 95% CI 0.26-0.59). Quantity of moderate activity was greater (P = 0.0001) on PAR and LOG compared to that measured by HR. Quantity of hard (vigorous) activity was also greater (P = 0.019) on LOG compared to that measured by HR. CONCLUSIONS: Sedentary adults tend to overestimate the intensity of their activity, specifically for moderate activity. Furthermore, the aerobic capacity of our sedentary adult sample (about 7.3 METs) suggests that the definition of a threshold intensity level of activity necessary to reduce mortality from CVD should be reexamined, because a value of > or =6 METs appears to be too high in this population.

Risk factors for kidney stones in older women in the southern United States.

BACKGROUND: The occurrence of kidney stones is disproportionate in the southern region of the United States. Risk factors for the occurrence of kidney stones in this geographic area have not been reported previously. METHODS: The Women's Health Initiative (WHI) is an ongoing multicenter clinical investigation of strategies for the prevention of common causes of morbidity and mortality among postmenopausal women. A case-control ancillary study was conducted on 27,410 (white or black) women enrolled in the 9 southern WHI clinical centers. There were 1,179 cases (4.3%) of kidney stones at the baseline evaluation. Risk factors for stone formation were assessed in cases versus age- and race-matched control subjects. RESULTS: Risk factors (univariate) included low dietary potassium (2,404 versus 2,500 mg/day, P = 0.006), magnesium (243 versus 253 mg/day, P = 0.003) and oxalate (330 versus 345 mg/day, P = 0.02) intake, as well as increased body mass index (28.5 versus 27.7 kg/m2, P = 0.001) and a history of hypertension (42% versus 34%, P = 0.001). A slightly lower dietary calcium intake (683 versus 711 mg/day, P = 0.04) was noted in case subjects versus control subjects, but interpretation was confounded by the study of prevalent rather than incident cases. Supplemental calcium intake >500 mg/day was inversely associated with stone occurrence. CONCLUSION: Multivariate risk factors for the occurrence of kidney stones in postmenopausal women include a history of hypertension, a low dietary intake of magnesium, and low use of calcium supplements.

Echocardiographic predictors of clinical outcome in patients with left ventricular dysfunction enrolled in the SOLVD registry and trials: significance of left ventricular hypertrophy. Studies of Left Ventricular Dysfunction.

OBJECTIVES: To assess the relation of left ventricular (LV) and left atrial (LA) dimensions, ejection fraction (EF) and LV mass to subsequent clinical outcome of patients with LV dysfunction enrolled in the Studies of Left Ventricular Dysfunction (SOLVD) Registry and Trials. BACKGROUND: Data are lacking on the relation of LV mass to prognosis in patients with LV dysfunction and on the interaction of LV mass with other measurements of LV size and function as they relate to clinical outcome. METHODS: A cohort of 1,172 patients enrolled in the SOLVD Trials (n = 577) and Registry (n = 595) had baseline echocardiographic measurements and follow-up for 1 year. RESULTS: After adjusting for age, New York Heart Association (NYHA) functional class, Trial vs. Registry and ischemic etiology, a 1-SD difference in EF was inversely associated with an increased risk of death (risk ratio, 1.62; p = 0.0008) and cardiovascular (CV) hospitalization (risk ratio, 1.59; p = 0.0001). Consequently, the other echo parameters were adjusted for EF in addition to age, NYHA functional class, Trial vs. Registry and ischemic etiology. A 1-SD difference in LV mass was associated with increased risk of death (risk ratio of 1.3, p = 0.012) and CV hospitalization (risk ratio of 1.17, p = 0.018). Similar results were observed with the LA dimension (mortality risk ratio, 1.32; p < 0.02; CV hospitalizations risk ratio, 1.18; p < 0.04). Likewise, LV mass > or =298 g and LA dimension > or =4.17 cm were associated with increased risk of death and CV hospitalization. An end-systolic dimension >5.0 cm was associated with increased mortality only. A protective effect of EF was noted in patients with LV mass > or =298 g (those in the group with EF >35% had lower mortality) but not in the group with LV mass <298 g. CONCLUSIONS: In patients with LV dysfunction enrolled in the SOLVD Registry and Trials, increasing levels of hypertrophy are associated with adverse events. A protective effect of EF was noted in patients with LV mass > or =298 g (those in the group with EF >35% fared better) but not in the group with LV mass <298 g. These data support the development and use of drugs that can inhibit hypertrophy or alter its characteristics.

The ACC professional life survey: career decisions of women and men in cardiology. A report of the Committee on Women in Cardiology. American College of Cardiology.

OBJECTIVES: This survey was conducted to learn how the career decisions of women and men in cardiology influenced their professional and personal lives. BACKGROUND: Women represent only 5% of practicing adult cardiologists and 10% of trainees. Yet, women and men now enter medical school at nearly equal numbers. The factors that contribute to career satisfaction in cardiology should be identified to permit the development of future strategies to ensure that the best possible candidates are attracted to the profession. METHODS: A questionnaire developed by the Ad Hoc Committee on Women in Cardiology of the American College of Cardiology (ACC) was mailed in March 1996 to all 964 female ACC members and an age-matched sample of 1,199 male members who had completed cardiovascular training. RESULTS: Women were more likely to describe their primary or secondary role as a clinical/noninvasive than invasive cardiologist (p < 0.0001 women vs. men). Men and women both reported a high level of satisfaction with family life, but women were less satisfied with their work as cardiologists (88% vs. 92%, p < 0.01) and with their level of financial compensation. Compared with men, women expressed less overall satisfaction (69% vs. 84%) and more dissatisfaction with their ability to achieve professional goals (21% vs. 9%). These differences were most pronounced for women in academic practice. Women reported greater family responsibilities, which may limit their opportunities for career advancement. Women were more likely to alter training or practice focus to avoid radiation. A majority of women (71%) reported gender discrimination, whereas only 21% of men reported any discrimination, largely due to race, religion or foreign origin. CONCLUSIONS: Women cardiologists report overall lower satisfaction with work and advancement, particularly within academic practice. They report more discrimination, more concerns about radiation and more limitations due to family responsibilities, which may ultimately explain the low percentage of women in cardiology. Attention to these issues may result in programs to improve professional satisfaction and attract the best candidates into cardiology in the future.

The role of hormone replacement therapy in preventing coronary artery disease in women.

Many reports show a reduction in cardiovascular disease events in cohorts of women taking postmenopausal hormone replacement. Newer reports detail the possible mechanisms for reduction in cardiac events, including beneficial changes in arterial function and lipid metabolism. Clinical studies now show that combination estrogen and progestin therapy appears to also result in a reduction in cardiovascular risk, but women are receiving mixed messages about why they should or should not take hormones and many discontinue or never start therapy. Several organizations have provided guidelines for evaluating the individual risk-benefit ratio for hormone replacement therapy for a given woman. Until randomized clinical trials are reported, adherence to established guidelines for treatment is the recommended course of action.

Exercise and rehabilitation in women. Indications and outcomes.

Women have been shown to improve their cardiovascular risk profiles with increasing levels of physical activity and physical fitness. All-cause mortality is lower among more fit women, but reductions in cardiovascular death rates have not been established, owing to the limited number and size of existing studies. Because older women are at greater risk for cardiac events and are the least likely to engage in regular physical activity, concerted effort should be made to increase the proportion of older women who participate in regular physical activity. Attention to concerns raised by older, sedentary women and development of personalized programs that proceed gradually in intensity and duration and avoid high-impact activities should improve the likelihood of initiation and continuation of greater activity levels. Cardiac rehabilitation programs are under-used by women. Personal and social barriers have been identified as well as the potential for referral bias. Reduction in cardiovascular risk levels and improvements in exercise capacity have been demonstrated for women who do participate. Approaches that meet the needs of older women may require considerable alteration from the standard program established for middle-aged men. Yet women may have the most to gain from participation in multidisciplinary, personalized rehabilitation programs.

Effects of age, physical training, and physical fitness on coronary heart disease risk factors in older track athletes at twenty-year follow-up.

OBJECTIVE: To compare current coronary heart disease (CHD) risk factor values in older athletes with mid-life measures and to examine the associations between changes in CHD risk factors with aging, physical training, and physical fitness. DESIGN: Prospective study with three longitudinal evaluation points: initial (T1), 10-year (T2), and 20-year (T3). Subjects were selected because of their elite status in Masters track competition. SETTING: University and medical center laboratories. PARTICIPANTS: Participants were 60 to 92 years of age and included 21 of the initial 27 subjects. At T3, subjects were divided into three groups, based on physical activity levels: high intensity (H), remained elite in national and international competition (n = 9); moderate intensity (M) continued frequent rigorous endurance training but rarely competed (n = 10); and low intensity (L) greatly reduced their training volume and intensity (n = 2). MEASUREMENTS: Smoking history; family history of coronary or cerebrovascular disease; resting blood pressure; resting electrocardiogram (ECG); serum total cholesterol, plasma glucose; body weight, % body fat, body mass index, waist:hip ratio; training pace and mileage; maximal oxygen consumption VO2 max). MAIN RESULTS: Several risk factors (smoking, diabetes, obesity) were never present, and the prevalence of other risk factors (family history of cardiovascular disease, abnormal resting ECG) remained low through T3 (< or = 14% of subjects). Mean systolic and diastolic blood pressure remained low without medication, but diastolic blood pressure measurements had the greatest redistribution between evaluation periods of any risk factor (r = .16, P = .479, T1 to T2). Mean total cholesterol was lower at T2 (-13%, P = .005) and T3 (-14%, P = .019) compared with T1. Change in VO2 max was correlated with changes in body weight (r = -.44, P = .048) and % fat (r = -.52, P = .015) from T1 to T2, whereas age was correlated to changes in systolic blood pressure (r = -.61, P = .003) and total cholesterol (r = -.49, P = .023) from T2 to T3. CONCLUSIONS: The prevalence of CHD risk factors remained low, and mean risk factor values remained low and generally stable in older athletes who had maintained habitual exercise training.

Twenty-year follow-up of aerobic power and body composition of older track athletes.

The purpose was to determine the aerobic power (maximal oxygen uptake) and body composition of older track athletes after a 20-yr follow-up (T3). At 20 yr, 21 subjects [mean ages: 50.5 +/- 8.5 yr at initial evaluation (T1), 60.2 +/- 8.8 yr at 10-yr follow-up (T2), and 70.4 +/- 8.8 yr at 20-yr follow-up (T3)] were divided into three intensity groups: high (H; remained elite; n = 9); moderate (M; continued frequent moderate-to-rigorous endurance training; n = 10); and low (L; greatly reduced training; n = 2). All groups decreased in maximal oxygen uptake at each testing point (H, 8 and 15%; M, 13 and 14%; and L, 18 and 34% from T1 to T2 and T2 to T3, respectively). Maximal heart rate showed a linear decrease of approximately 5-7 beats.min-1.decade-1 and was independent of training status. Body weight remained stable for the H and M groups and percent fat increased approximately 2-2.5%/decade. Although fat-free weight decreased at each testing point, there was a trend for those who began weight-training exercise to better maintain it. Cross-sectional analysis at T3 showed that leg strength and bone mineral density were generally maintained from age 60 to 89 yr. Those who performed weight training had a greater arm region bone mineral density than those who did not. These longitudinal data show that the physiological capacities of older athletes are reduced despite continued vigorous endurance exercise over a 20-yr period (approximately 8-15%/decade). Changes in body composition appeared to be less than those shown for the healthy sedentary population and were related to changes in training habits.

Fluid homeostasis after heart transplantation: the role of cardiac denervation.

BACKGROUND: Orthotopic heart transplantation may interrupt key neural and humoral homeostatic mechanisms that normally adjust Na+ and fluid excretion to changes in intake. Such an interruption could lead to plasma volume expansion. METHODS: We measured plasma volume and fluid regulatory hormones under standardized conditions in 11 heart transplant recipients (58 +/- 7 years old; mean +/- standard deviation) 21 +/- 4 months after transplantation, in 6 liver transplant recipients (51 +/- 6 years old) 13 +/- 8 months after transplantation (cyclosporine control group), and in 7 normal healthy control subjects (61 +/- 9 years old). Administration of all diuretics and antihypertensive drugs was discontinued before the study. After 3 days during which subjects ate a constant diet containing 87 mEq of Na+ per 24 hours, plasma volume was measured by a modified Evans blue dye (T-1824) dilution technique. Renal creatinine clearance was measured and blood samples were drawn for determination of plasma levels of vasopressin, angiotensin II, aldosterone, atrial natriuretic peptide, and plasma renin activity. RESULTS: Supine resting plasma renin activity, angiotensin II, and aldosterone (renin-angiotensin-aldosterone axis) and vasopressin levels were not different among the control, heart transplant, and liver transplant groups. However, there was a trend toward elevated angiotensin II (p < or = 0.08) and aldosterone (p < or = 0.08) levels in the heart transplant recipients. Atrial natriuretic peptide levels were significantly elevated two to threefold in the heart transplant recipients when compared with those in the two control groups. Blood volume, normalized for body weight (milliliters per kilogram), was significantly greater (14%) in the heart transplant recipients when compared with that in liver transplant recipients and normal healthy control subjects. Blood volume values did not differ (p > or = 0.05) between the two control groups. CONCLUSIONS: Extracellular fluid volume expansion (+14%) occurs in clinically stable heart transplant recipients who become hypertensive. Although hyperactivity of the renin-angiotensin-aldosterone axis is not apparent during supine resting conditions, our data suggest that the renin-angiotensin-aldosterone system is not responsive to a hypervolemic stimulus and this is likely a consequence of chronic cardiac deafferentation. Thus, poor adaptation of the renin-angiotensin-aldosterone system to fluid retention may be partly responsible for the incidence and severity of posttransplantation hypertension in some heart transplant recipients.

Coronary heart disease in women. Past gaps, present state and future promises.

Women in the United States are more likely to die of coronary heart disease than any other cause. Determining risk for future disease events can be aided by a full assessment of risk factors and behaviors, but it should be noted that some factors, for example, diabetes and HDL cholesterol, impact a woman's risk differently than for a man. Studies evaluating women have shown a lower referral rate for catheterization and higher mortality rates following myocardial infarction and bypass surgery. Differentiating practitioner and patient biases from biological explanations is a challenge of future research. The possibility of hormone replacement therapy preventing coronary heart disease has given rise to the landmark NIH sponsored "Women's Health Initiative" which will provide definitive answers about the risks and benefits of long-term hormone treatment and dietary modification on coronary heart disease and cancer.

Relation of ventricular size and function to heart failure status and ventricular dysrhythmia in patients with severe left ventricular dysfunction.

Patients with severe left ventricular (LV) dysfunction may or may not have overt heart failure and ventricular dysrhythmia. To study factors behind this variability, we examined a subset of 311 patients from the Studies of Left Ventricular Dysfunction-95 with a history of moderate heart failure (treatment trial) and 216 with no failure (prevention trial), all with ejection fractions <0.35. Echocardiographic variables were compared between trials and also correlated with dysrhythmia in 258 patients, and with neurohormones in 199 patients. Compared with prevention patients, treatment patients had larger LV end-diastolic diameter, end-systolic volume, sphericity index, and ratio of early to late diastolic filling velocity by Doppler (E/A ratio), lower LV ejection fraction and atrial contribution to ventricular filling, and similar LV mass, end-diastolic volume, and estimates of systolic wall stress. With prevention and treatment patients combined, the prevalence of abnormally elevated atrial natriuretic peptide was 92% in the highest tertile of E/A ratio compared with 55% in the lower tertiles (p=0.006). Across tertiles of LV end-diastolic volume, there was an increase in the prevalence of nonsustained ventricular tachycardia (24%, 45%, and 45%; p=0.007) and premature ventricular complexes >10/hour (48%, 62%, and 80%; p<0.001). Thus, in severe LV dysfunction, ventricular filling indexes suggestive of high filling pressures, along with larger and more spherical ventricles, are particularly common in patients with overt heart failure, thus suggesting that diastolic properties and the degree of ventricular remodeling affect clinical status. Once ejection fraction is significantly reduced, the prevalence of ventricular dysrhythmia correlates with LV size rather than systolic function. This observation lends support to previous experimental findings on the role of myocardial stretch and scar in the genesis of dysrhythmia.

Extreme blood pressure fluctuations in a patient with intact autonomic reflexes and intact sodium conservation.

A patient who had episodes of profound hypotension alternating with severe hypertension without an obvious precipitating cause is reported. The hypotensive episodes were accompanied by tiredness, syncope, bradycardia, and a low norepinephrine concentration while supine or standing. In contrast, the hypertensive episodes were associated with marked tachycardia, sweating, anxiety, abdominal pain, and very high levels of plasma norepinephrine concentration. Extensive investigations failed to support a diagnosis of pheochromocytoma. The testing of baroreceptor function and autonomic reflexes was normal. Blood pressure was not salt sensitive. It was concluded that this patient has a unique clinical syndrome of extreme fluctuation of blood pressure and sympathetic nervous activity yet intact cardiovascular reflexes and normal sodium conservation. The abnormal blood pressure regulation most likely has a central origin.