Palliative cancer care in Middle Eastern countries: accomplishments and challenges.

BACKGROUND: In larger parts of the Middle East palliative care is still misunderstood among health professionals, cancer patients and the public at large. One reason to that is because the term does not obviously communicate the intent of this clinical discipline, which is lending better quality of life while combating cancer. Further, culture, tradition and religion have contributed to this misgiving and confusion especially at the terminal stage of the disease. METHODS: The Middle East Cancer Consortium jointly with the American Society of Clinical Oncology, the American Oncology Nursing Society, the San Diego Hospice Center for Palliative Medicine and the Children's Hospital & Clinics of Minnesota initiated a series of training courses and workshops in the Middle East to provide updated training to physicians, nurses, social workers and psychologists from throughout the region with basic concepts of palliative care and pain managements in adults and children cancers. RESULTS: During the past 6 years hundreds of professionals took part in these educational and training activities, thereby creating the core of trained caregivers who start to make the change in their individual countries. CONCLUSIONS: The outcome of consecutive training activities can overcome geopolitical instabilities, and yield a genuine change in approach of both regulators, medical administrators, medical staff and the public; as to the important contribution of palliative care services to the welfare of the patient and his/her family.

Comparison of Postprandial Responses to a High-Fat Meal in Hypertriglyceridemic Men and Women before and after Treatment with Fenofibrate in the Genetics and Lipid Lowering Drugs and Diet Network (GOLDN) Study.

CONTEXT: The fenofibrate effect on the subclass size distribution of lipoproteins before and after a high-fat challenge is not well studied. OBJECTIVE: To characterize the baseline and post-prandial response (PPL) to a high-fat challenge following fenofibrate therapy, on changes in LDL, HDL, and VLDL particle subclasses, number, and size in 271 hypertriglyceridemic participants. METHODS: Participants from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study who conducted PPL studies both before and after three weeks of fenofibrate (160 mg/d) treatment were analyzed. Particle size distributions were determined using nuclear magnetic resonance imaging, and lipid determinations were measured at fasting (0 hr), 3.5 hours, and 6 hours after ingestion of a standardized high-fat meal. Analyses were stratified by gender. Changes in particle subclass distributions were assessed using repeated measures analysis of variance adjusted for pedigree. RESULTS: Before PPL, fenofibrate in men (adjusted for age, field center, smoking status, diabetes, and weight circumference) lowered fasting and postprandial VLDL primarily due to reductions in postprandial levels of large and medium VLDL particles (9 SE +/-0.7 to 4 +/-0.4 and 78 / -4 to 36 / -3 nmol/L both P < .0001, resp.). Fenofibrate also reduced fasting and postprandial total LDL particles, primarily a result of reduced small LDL particles (1497 = / - 37 to 1088 = / - 36 nmol/L, P < .0001). Directional changes were similar in men and women but the magnitude of change was different for some parameters. CONCLUSION: Fenofibrate treatment resulted in a lower triglyceride excursion following a high-fat meal. This investigation provides new knowledge of the magnitude and time course of fenofibrate induced attenuation of Lipoprotein subclass size distribution following a postprandial lipid challenge.

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.

Sex-specific findings from a genome-wide linkage analysis of human fatness in non-Hispanic whites and African Americans: the HyperGEN study.

OBJECTIVE: To conduct a full genome search for genes potentially influencing two related phenotypes: body mass index (BMI, kg/m2) and percent body fat (PBF) from bioelectric impedance in men and women. DESIGN: A total of 3383 participants, 1348 men and 2035 women; recruitment was initiated with hypertensive sibpairs and expanded to first-degree relatives in a multicenter study of hypertension genetics. MEASUREMENTS: Genotypes for 387 highly polymorphic markers spaced to provide a 10 cM map (CHLC-8) were generated by the NHLBI Mammalian Genotyping Service (Marshfield, WI, USA). Quantitative trait loci for obesity phenotypes, BMI and PBF, were examined with a variance components method using SOLAR, adjusting for hypertensive status, ethnicity, center, age, age2, sex, and age2 x sex. As we detected a significant genotype-by-sex interaction in initial models and because of the importance of sex effects in the expression of these phenotypes, models thereafter were stratified by sex. No genotype-by-ethnicity interactions were found. RESULTS: A QTL influencing PBF in women was detected on chromosome12q (12q24.3-12q24.32, maximum empirical LOD score=3.8); a QTL influencing this phenotype in men was found on chromosome 15q (15q25.3, maximum empirical LOD score=3.0). These QTLs were detected in African-American and white women (12q) and men (15q). QTLs influencing both BMI and PBF were found over a broad region on chromosome 3 in men. QTLs on chromosomes 3 and 12 were found in the combined sample of men and women, but with weaker significance. CONCLUSION: The locations with highest LOD scores have been previously reported for obesity phenotypes, indicating that at least two genomic regions influence obesity-related traits. Furthermore, our results indicate the importance of considering context-dependent effects in the search for obesity QTLs.

A genome-wide affected sibpair linkage analysis of hypertension: the HyperGEN network.

Results are reported here from a genome-wide linkage analysis of hypertension in a large sample of hypertensive (affected) sibpairs (650 African American and 915 white sibpairs) recruited by the HyperGEN Network of the National Heart, Lung and Blood Institute (NHLBI) Family Blood Pressure Program (FBPP). Analysis using MAPMAKER/SIBS suggests one interesting region with a LOD score of 2.08 at 63 cM from the p telomere on chromosome 2 in the African American sibpairs, which may harbor hypertension susceptibility genes.

Genome-wide linkage analysis of lipids in the Hypertension Genetic Epidemiology Network (HyperGEN) Blood Pressure Study.

Full genome scans were performed for quantitative lipid measurements in 622 African American and 649 white sibling pairs not taking lipid-lowering medications who were ascertained through the Hypertension Genetic Epidemiology Network (HyperGEN) of the National Heart, Lung, and Blood Institute (NHLBI) Family Blood Pressure Program. Genotypes for 391 markers spaced roughly equally throughout the genome were typed by the NHLBI Mammalian Genotyping Service. Each of the phenotypes was adjusted for covariates within sex and race and then subjected to variance components linkage analysis, which was performed separately within race by using race-specific marker allele frequencies from additional random samples. The highest lod score detected was 2.77 for logarithmically transformed triglyceride (TG) on chromosome 20 (at 28.6 cM) in the African American sibling pairs. The highest score detected in the white sibling pairs was 2.74 for high density lipoprotein cholesterol on chromosome 5 (at 48.2 cM). Although no scores >3.0 were obtained, positive scores were found in several regions that have been reported in other genome scans in the literature. For example, a score of 1.91 for TG was found on chromosome 15 (at 28.8 cM) in white sibling pairs. This score overlaps the positive findings for TG in 2 other genome scans.

Relation of various degrees of body mass index in patients with systemic hypertension to left ventricular mass, cardiac output, and peripheral resistance (The Hypertension Genetic Epidemiology Network Study).

The impact of different methods of indexation of left ventricular (LV) mass and systemic hemodynamic variables on prevalences and correlates of cardiovascular abnormalities in relation to level of obesity in populations remains unclear. We evaluated 1,672 participants in the Hypertension Genetic Epidemiology Network Study to investigate the relations of overweight and level of obesity to LV mass and prevalences of LV hypertrophy, abnormal cardiac output, and peripheral resistance detected using different indexations for body size. In our study population, 1,577 subjects were clinically healthy nondiabetic hypertensive and 95 were normotensive normal-weight nondiabetic reference subjects. Fat-free mass (FFM) did not differ between the reference group and the normal-weight hypertensive subjects, and increased with overweight. In hypertensive subjects, LV mass and cardiac output increased and total peripheral resistance decreased with overweight. Indexation of LV mass for FFM or body surface area (BSA) resulted in no difference or even lower prevalence of LV hypertrophy in severely obese compared with normal-weight hypertensive subjects. In contrast, indexation of LV mass for height(2.7) identified an increased prevalence of LV hypertrophy with overweight and obesity. Absolute cardiac output increased and total peripheral resistance decreased with overweight. Prevalence of elevated cardiac output indexed for height(1.83) increased and for elevated total peripheral resistance-height(1.83) index decreased with greater overweight, whereas opposite trends were seen when cardiac output and total peripheral resistance were indexed for BSA or FFM. Thus, in hypertensive subjects, FFM increases with overweight and is directly related to LV mass, stroke volume, and cardiac output, and inversely related to total peripheral resistance. Indexations of LV mass and systemic hemodynamics for FFM or BSA obscured associations of LV hypertrophy and abnormal cardiac and total peripheral resistance indexes with overweight, whereas LV mass/height(2,7), cardiac output/height(1.83), and total peripheral resistance-height(1.83) detected significant preclinical cardiovascular abnormalities with obesity.

Linkage of left ventricular contractility to chromosome 11 in humans: The HyperGEN Study.

Impaired left ventricular (LV) contractility is a major cause of cardiovascular death, especially congestive heart failure. The identification of susceptibility genes that contribute to impaired LV contractility may uncover mechanisms underlying LV contractile impairment and the development of congestive heart failure. The Hypertension Genetic Epidemiology Network (HyperGEN) collected echocardiographic measurements of myocardial contractility in a large biethnic sample of hypertensive siblings (390 blacks and 398 whites in 179 and 165 sibships, respectively). All participants expressed hypertension before age 60 years, and the mean age of siblings was 52 years in blacks and 61 years in whites. We adjusted myocardial contractility for gender, age, and age(2), and we calculated standardized residuals separately for men and women in both ethnic groups. We conducted multipoint variance components linkage analysis using GENEHUNTER2 and 387 anonymous markers (CHCL8 marker set). We found evidence for significant linkage to a microsatellite marker, D11S1993 (lod, 3.93 in blacks), approximately 54 cM from the tip of the short arm of chromosome 11, that accounted for 72% of the phenotypic variation in LV contractility. A chromosome 22 locus showed suggestive evidence for linkage (lod, 2.83 in whites and 1.15 in blacks). The chromosome 11 peak coincides with the region containing myosin-binding protein C. Mutations in this gene are linked to familial hypertrophic cardiomyopathy. Our results show strong evidence for linkage of a region of chromosome 11 with LV contractility in blacks and suggest that an important gene for impaired LV contractility is harbored in this region.

Left ventricular systolic dysfunction in a biracial sample of hypertensive adults: The Hypertension Genetic Epidemiology Network (HyperGEN) Study.

To determine the prevalence and correlates of left ventricular systolic dysfunction in hypertensive patients in a biracial population-based sample, clinical evaluation and echocardiography were performed in 2086 participants in the Hypertension Genetic Epidemiology Network (HyperGEN) examination; 86% had normal ejection fraction (>54%), 10% had mild ventricular dysfunction (ejection fraction 41% to 54%), and 4% had severe ventricular dysfunction (ejection fraction

Relationship between left ventricular diastolic relaxation and systolic function in hypertension: The Hypertension Genetic Epidemiology Network (HyperGEN) Study.

The relation of impaired left ventricular relaxation, as measured by prolonged isovolumic relaxation time, to ventricular systolic function in hypertension remains uncertain in population-based samples. In the Hypertension Genetic Epidemiology Network (HyperGEN) Study, echocardiograms were analyzed in 1457 hypertensive participants without diabetes, >/=2+ valvular regurgitation, or coronary disease. Impaired relaxation (isovolumic relaxation time >100 ms) was present in 219 (15%) of the participants; they were older and had higher arterial pressure than did those with normal relaxation. Ventricular chamber size, wall thicknesses, mass, and relative wall thickness were greater, and stress-corrected midwall shortening and end-systolic stress/end-systolic volume index were lower with impaired relaxation than with normal relaxation time. Fractional shortening and ejection fraction did not differ between the groups. In logistic regression, the likelihood of prolonged isovolumic relaxation time decreased with higher stress-corrected midwall shortening (odds ratio, 0.97%; 95% confidence interval, 0.96 to 0.99), independently of age, heart rate, and ventricular mass. Neither ejection fraction nor the end-systolic stress/end-systolic volume index was independently related to isovolumic relaxation time. In hypertension, impaired left ventricular relaxation parallels ventricular midwall dysfunction but not systolic chamber function. Whether combined diastolic and systolic dysfunction identifies hypertensive patients at especially high risk of cardiovascular events requires further study.

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.

Aortic root dilatation at sinuses of valsalva and aortic regurgitation in hypertensive and normotensive subjects: The Hypertension Genetic Epidemiology Network Study .

The association of sinuses of Valsalva dilatation and aortic regurgitation with hypertension is disputed, and few data are available in population-based samples. We explored the relations of sinuses of Valsalva dilatation and aortic regurgitation to hypertension and additional clinical and echocardiographic data in 2096 hypertensive and 361 normotensive participants in the Hypertension Genetic Epidemiology Network study. Age and body surface area were used to predict aortic root diameter using published equations developed from a separated reference population. Aortic dilatation was defined as measured sinuses of Valsalva diameter exceeding the 97.5th percentile of the confidence interval of predicted diameter for age and body size. Aortic dilatation was present in 4.6% of the population. After adjustment for age and body surface area, mean aortic root diameter was larger in hypertensives with suboptimal blood pressure control than normotensives or hypertensives with optimal blood pressure control. In multivariate models, sinuses of Valsalva diameter was weakly positively related to diastolic blood pressure and to left ventricular mass independent of aortic regurgitation. Subjects with aortic dilatation were slightly older, were more frequently men, had higher left ventricular mass, and had lower left ventricular systolic chamber function independent of covariates. Sinuses of Valsalva dilatation was independently related to male gender, aortic valve fibrocalcification, and echocardiographic wall motion abnormalities but not to diastolic blood pressure (or history of hypertension in a separate model). The likelihood of aortic regurgitation increased with larger aortic root diameter, older age, female gender, presence of aortic valve fibrocalcification, and lower body mass index but not hypertension or diabetes. In a subsequent model, diastolic blood pressure was negatively related to aortic regurgitation independent of covariates. In a large population-based sample, sinuses of Valsalva diameter was only mildly larger in subjects with suboptimally controlled hypertension than in normotensives or well-controlled hypertensives, which did not result in differences in prevalence of aortic regurgitation among groups. Sinuses of Valsalva dilatation was associated with higher left ventricular mass and lower systolic function, which may contribute to higher cardiovascular risk in subjects with aortic root dilatation.

Effect of exercise intensity and frequency on lipid levels in men with coronary heart disease: Training Level Comparison Trial.

The objective of the Training Level Comparison Trial was to determine whether a more intense exercise program versus a less intensive program has additional favorable effects on blood lipids in men with coronary heart disease (CHD) over a 12-month period. The study-a randomized, controlled trial conducted at 2 clinical centers-enrolled 185 patients with documented CHD. A simple randomization procedure led to unequal numbers of patients in the 2 interventions: 82 in the low-intensity and 103 in the high-intensity group. Target heart rate during exercise corresponded to 50% of maximum oxygen uptake (VO(2 max)) +/- 5 beats/min in the low-intensity group and 85% +/- 5 beats/min in the high-intensity group. The intensity of exercise made little difference on lipid improvements. However, the attendance rates for the 6- and 12-month periods (percentage of total exercise sessions attended) were significantly related to increased high-density lipoprotein (HDL) cholesterol (r(s) [Spearman rank correlation coefficient 0.20 to 0.26, p <0.05]), and decreases in the ratios of low-density lipoprotein (LDL)-to-HDL cholesterol (LDL:HDL, r(s) = -0.24 to -0.28, p < 0.01) and total-to-HDL cholesterol (total:HDL, r(s) = -0.25 to -0.29, p < 0.01) at 6 and 12 months. The relation of the attendance rate to LDL:HDL and total:HDL ratios remained significant in repeated-measures regression analysis. Exercise frequency may be more important than intensity in improving HDL cholesterol and LDL:HDL and total:HDL ratios in men with CHD.

Effect of type 2 diabetes mellitus on left ventricular geometry and systolic function in hypertensive subjects: Hypertension Genetic Epidemiology Network (HyperGEN) study.

BACKGROUND: Type 2 diabetes is a cardiovascular risk factor. It remains to be elucidated in a large, population-based sample whether diabetes is associated with changes in left ventricular (LV) structure and systolic function independent of obesity and systolic blood pressure (BP). METHODS AND RESULTS: Among 1950 hypertensive participants in the HyperGEN Study without overt coronary heart disease or significant valve disease, 20% (n=386) had diabetes. Diabetics were more likely to be women, black, older, and have higher BMI and waist/hip ratio than were nondiabetics. After adjustment for age and sex, diabetics had higher systolic BP, pulse pressure, and heart rate; lower diastolic BP; and longer duration of hypertension than nondiabetics. LV mass and relative wall thickness were higher in diabetic than nondiabetic subjects independent of covariates. Compared with nondiabetic hypertensives, diabetics had lower stress-corrected midwall shortening, independent of covariates, without difference in LV EF. Insulin levels and insulin resistance were higher in non-insulin-treated diabetics (n=195) than nondiabetic (n=1439) subjects (both P:<0.01). Insulin resistance positively but weakly related to LV mass and relative wall thickness. CONCLUSIONS: In a relatively healthy, population-based sample of hypertensive adults, type 2 diabetes was associated with higher LV mass, more concentric LV geometry, and lower myocardial function, independent of age, sex, body size, and arterial BP. structural and functional abnormalities in addition to, and independent of, atherosclerosis.(13) (14) In the Framingham cohort, diabetes was associated with higher LV mass in women but not men.(15) High blood pressure (BP), obesity, and abnormal lipid profile, which often coexist with diabetes, tend to be associated with preclinical cardiovascular abnormalities(16) and may contribute to the association of diabetes with cardiovascular events. Cardiac features of diabetic and nondiabetic hypertensive subjects remain incompletely described in population-based samples. Therefore, we compared clinical and metabolic characteristics, LV geometry, and systolic function between diabetic and nondiabetic hypertensive participants in the Hypertension Genetic Epidemiology Network (HyperGEN) Study.

Sibling correlation of left ventricular mass and geometry in hypertensive African Americans and whites: the HyperGEN study. Hypertension Genetic Epidemiology Network.

BACKGROUND: Evidence suggests that left ventricular (LV) mass is under genetic control, independently of risk factors known to influence LV size and geometry. METHODS: As part of the HyperGEN study, four field centers recruited African American and white hypertensive siblings (n = 1,664), aged 23 to 87 years. Two-dimensionally guided M-mode echocardiography was performed, and LV mass and relative wall thickness (RWT) were measured at a central reading center. Familial correlations were calculated separately for each ethnic group using maximum likelihood methods, adjusted for the potential confounding influences of age, gender, systolic blood pressure, and obesity. RESULTS: In African Americans, brother-sister, brother-brother, and sister-sister correlation coefficients and standard errors for LV mass were 0.29 (0.08), 0.44 (0.10), and 0.33 (0.05). In whites, the corresponding correlations were lower than in African Americans at 0.05 (0.08), 0.12 (0.11), and 0.22 (0.09), respectively. Sibling correlation of LV geometry, assessed by RWT, was less in African Americans than in whites: brother-sister, 0.04 (0.10) v 0.21 (0.10), brother-brother, 0.12 (0.22) v 0.28 (0.09), and sister-sister, 0.11 (0.07) v 0.19 (0.11). CONCLUSIONS: LV mass is strongly correlated in hypertensive African American siblings, and modestly correlated in their white counterparts, whereas RWT has stronger sibling correlation in whites. The patterns of familial correlation of echocardiographic LV mass and RWT suggest that the genetic underpinnings of LV hypertrophy and geometric remodeling may differ among ethnic groups.

Possible locus on chromosome 18q influencing postural systolic blood pressure changes.

We conducted a genome-wide scan for quantitative trait loci influencing the systolic blood pressure, diastolic blood pressure, and pulse responses to a postural challenge in 498 white sibling-pairs from the Hypertension Genetic Epidemiology Network, a multicenter study of the genetic susceptibility to hypertension. All participants were hypertensive (systolic blood pressure >/=140 mm Hg, diastolic blood pressure >/=90 mm Hg, or on antihypertensive medications) with diagnosis before age 60. Blood pressure and pulse were measured by an oscillometric method after a 5-minute rest in a supine position and again immediately on standing. The genome scan included a total of 387 autosomal short-tandem-repeat polymorphisms typed by the National Heart, Lung, and Blood Institute Mammalian Genotyping Service at Marshfield. We used multipoint variance-components linkage analysis to identify possible quantitative trait loci influencing postural change phenotypes after adjusting for sex, age, and use of antihypertensive medications. There was suggestive evidence for linkage on chromosome 18q for the postural systolic blood pressure response (maximum logarithm of the odds score=2.6 at 80 centiMorgans). We also observed a maximum logarithm of the odds score of 1.9 for the systolic blood pressure response and 1.7 for the diastolic blood pressure response on chromosome 6p. The marker that demonstrated the strongest evidence for linkage for the systolic blood pressure response (D18S858) lies within 20 centiMorgans of a marker previously linked to rare familial orthostatic hypotensive syndrome. Our findings indicate that there may be 1 or more genes on chromosome 18q that regulate systolic blood pressure during the physiological recovery period after a postural stressor.

NHLBI family blood pressure program: methodology and recruitment in the HyperGEN network. Hypertension genetic epidemiology network.

PURPOSE: Hypertension is a common precursor of serious disorders including stroke, myocardial infarction, congestive heart failure, and renal failure in whites and to a greater extent in African Americans. Large genetic-epidemiological studies of hypertension are needed to gain information that will improve future methods for diagnosis, treatment, and prevention of hypertension, a major contributor to cardiovascular morbidity and mortality. METHODS: We report successful implementation of a new structure of research collaboration involving four NHLBI "Networks," coordinated under the Family Blood Pressure Program. The Hypertension Genetic Epidemiology Network (HyperGEN) involves scientists from six universities and the NHLBI who seek to identify and characterize genes promoting hypertension. Blood samples and clinical data were projected to be collected from a sample of 2244 hypertensive siblings diagnosed before age 60 from 960 sibships (half African-American) with two or more affected persons. Nonparametric sibship linkage analysis of over one million genotype determinations (20 candidate loci and 387 anonymous marker loci) was projected to have sufficient power for detecting genetic loci promoting hypertension. For loci showing evidence for linkage in this study and for loci reported linked or associated with hypertension by other groups, genotypes are compared in hypertensive cases versus population-based controls to identify or confirm genetic variants associated with hypertension. For some of these genetic variants associated with hypertension, detailed physiological and biochemical characterization of untreated adult offspring carriers versus non-carriers may help elucidate the pathophysiological mechanisms that promote hypertension. RESULTS: The projected sample size of 2244 hypertensive participants was surpassed, as 2407 hypertensive individuals (1262 African-Americans and 1145 whites) from 917 sibships were examined. Detailed consent forms were designed to offer participants several options for DNA testing; 94% of participants gave permission for DNA testing now or in the future for any confidential medical research, with only 6% requesting restrictions for tests performed on their DNA. Since this is a family study, participants also are asked to list all first degree relatives (along with names, addresses, and phone numbers) and to indicate for each relative whether they were willing to allow study staff to make a contact. Seventy percent gave permission to contact some relatives; about 30% gave permission to contact all first degree relatives; and less than 1% asked that no relatives be contacted. Successes after the first four years of this study include: 1) productive collaboration of eight centers from six different locations; 2) early achievement of recruitment goals for study participants including African-Americans; 3) an encouraging rate of consent for DNA testing (including future testing) and relative contacting; 4) completed analyses of genetic linkage and association for several candidate gene markers and polymorphisms; 5) completed genotyping of random markers for over half of the full sample; and 6) early sharing of results among the four Family Blood Pressure Program networks for candidate and genome search analyses. CONCLUSIONS: Experience after four years of this five-year program (1995-2000) suggests that the newly initiated NHLBI Network Program mechanism is fulfilling many of the expectations for which it was designed. It may serve as a paradigm for future genetic research that can benefit from large sample sizes, frequent sharing of ideas among laboratories, and prompt independent confirmation of early findings, which are required in the search for common genes with relatively small effects such as those that predispose to human hypertension.

Autonomic and neurohumoral control of postprandial blood pressure in healthy aging.

BACKGROUND: Postprandial hypotension (PPH) is a common and morbid problem in elderly people that is associated with an impaired vascular response to meal digestion. Healthy aging in the absence of blood pressure elevation is associated with autonomic and neurohumoral changes that may influence the vascular response to meal ingestion. However, it is not known whether these age-related changes are associated with the development of PPH. METHODS: We measured hemodynamic (blood pressure, heart rate, and forearm vascular resistance), autonomic (power spectral analysis of heart rate and blood pressure variability), and neurohumoral (plasma norepinephrine, renin, aldosterone, and endothelin) responses to a mixed 425 kilocalorie (kcal) meal in 89 rigorously screened healthy subjects aged 20-39, 40-59, and 60-83 years. RESULTS: After the meal, supine mean arterial blood pressure fell significantly only in the middle-aged group by 5.4 +/- 7.9 mm Hg at 30 minutes (p = .02). Forearm vascular resistance fell after the meal in all age groups ( p = .0001). Older groups had higher plasma norepinephrine (p = .02), lower heart rate (p = .03), lower cardiovagal activity (p = .0001), and lower sympathetic vasomotor (p = .000) activity, but there was no difference in the response of these variables to a meal. CONCLUSION: Healthy aging, in the absence of blood pressure elevation, alters the level of autonomic activity without further impairing the ability to maintain blood pressure during meal digestion. Hemodynamic, autonomic, and neurohumoral responses to meal ingestion remain unchanged in very healthy, normotensive elderly adults.

Association between the alpha-adducin gene and hypertension in the HyperGEN Study.

This report from the HyperGEN Study, one of four networks participating in the NHLBI-sponsored Family Blood Pressure Program, presents the results of an association study based on 822 white and 572 black subjects (cases and controls) participating in the HyperGEN Network from five geographically diverse field centers. All cases met the Joint National Committee on Detection and Treatment of High Blood Pressure (JNC VI) criteria for hypertension (Stage I or higher). Each subject was clinically examined for risk factors for hypertension as well as genotyped for the point mutation Gly460Trp at the alpha-adducin locus on chromosome 4p. In the white group, the prevalence of genotypes with one or more Trp alleles was 26% in normotensives, versus 33% in hypertensives randomly selected from the population, and 39% among the multiply affected hypertensive sibships. Overall, in whites, the Trp allele significantly increased the odds of hypertension (P = .0056), with an odds ratio (OR) of 1.73 (95% confidence interval [CI] = 1.17, 2.54). The alpha-adducin gene remained a significant independent predictor of hypertension in a multivariate logistic model even after correcting for other risk factors for hypertension, including gender, age, body mass index (BMI), smoking, LDL cholesterol, triglycerides, urine sodium (Na), and urine potassium (K), (OR = 1.55, 95% CI = 1.03, 2.34). Through the use of regression trees, several gene-by-environment interactions were implicated, suggesting that alpha-adducin appears to be a particularly important risk factor (OR = 4.2) for older (age > 60.5 years), less lean (BMI < 25.8 kg/m2) subjects with moderately high triglycerides (between 145.5 and 218.5 mg/dL). In the black group, the relationship was less clear. Overall, it was protective against hypertension. The prevalence of genotypes with one or more Trp alleles was 24% among normotensive versus 11% in hypertensive black subjects randomly selected from the population, and 13% among multiply affected hypertensive sibships, resulting in an OR of 0.48 (P = .0231; 95% CI = 0.25, 0.90). However, the Trp genotype was no longer a significant independent predictor of hypertension risk in the multivariate logistic model (OR = 0.79; 95% CI = 0.37, 1.67), suggesting that it may be operating through one or more of these other factors. Thus, we conclude that the alpha-adducin gene is a significant, independent risk factor for hypertension in whites, but not in blacks, and may play a particularly important role for subjects with certain constellations of other risk factors.