Quantitative founder-effect analysis of French Canadian families identifies specific loci contributing to metabolic phenotypes of hypertension.

The Saguenay-Lac St-Jean population of Quebec is relatively isolated and has genealogical records dating to the 17th-century French founders. In 120 extended families with at least one sib pair affected with early-onset hypertension and/or dyslipidemia, we analyzed the genetic determinants of hypertension and related cardiovascular and metabolic conditions. Variance-components linkage analysis revealed 46 loci after 100,000 permutations. The most prominent clusters of overlapping quantitative-trait loci were on chromosomes 1 and 3, a finding supported by principal-components and bivariate analyses. These genetic determinants were further tested by classifying families by use of LOD score density analysis for each measured phenotype at every 5 cM. Our study showed the founder effect over several generations and classes of living individuals. This quantitative genealogical approach supports the notion of the ancestral causality of traits uniquely present and inherited in distinct family classes. With the founder effect, traits determined within population subsets are measurably and quantitatively transmitted through generational lineage, with a precise component contributing to phenotypic variance. These methods should accelerate the uncovering of causal haplotypes in complex diseases such as hypertension and metabolic syndrome.

Predictors of target organ damage in hypertensive blacks and whites.

The purpose of this study was to evaluate the association of the insulin resistance syndrome with both blood pressure and target organ damage in blacks and whites with essential hypertension. Eighty-two black and 63 white French Canadian patients were studied. None had diabetes, and antihypertensive medications had been discontinued for >/=1 week. Measurements included 24-hour blood pressure monitoring, fasting plasma lipids, insulin sensitivity determined with the Bergman minimal model, echocardiogram, microalbumin excretion, and inulin and lithium clearances. Compared with the white French Canadians, black patients had an attenuated nighttime reduction in blood pressure (P<0.02), increased cardiac dimensions (P<0.001), greater microalbumin excretion (P<0.05), increased inulin clearance (indicative of glomerular hyperfiltration; P<0.001), and decreased lithium clearance (indicative of increased sodium reabsorption in the proximal tubule; P<0.001). Blood pressure levels were not related to insulin resistance; although in blacks, the nighttime reduction in systolic blood pressure was inversely related to fasting plasma insulin (r=-0.18, P<0.04). In a stepwise multivariate analysis (including blood pressure levels and components of the insulin resistance syndrome as independent variables), race was the strongest predictor of left ventricular mass (r=0.53, P<0.000), relative wall thickness (r=0.49, P<0.000), and both inulin (r=0.53, P<0.000) and lithium (r=0.41, P<0.000) clearances. Nighttime systolic blood pressure was also a significant determinant of concentric left ventricular hypertrophy (r=0.37, P<0.000). In blacks, microalbumin excretion was related to insulin resistance. These observations are consistent with the hypothesis that there is a genetic contribution to cardiac hypertrophy, glomerular hyperfiltration, and sodium retention in blacks with essential hypertension.

Heritability estimates of obesity measures in siblings with and without hypertension.

The goal of the present study was to evaluate mean values and heritability estimates of 3 global and 11 regional obesity measures in siblings with (HPT, n=209) or without (non-HPT, n=91) early-onset (age

Arterial pressure, left ventricular mass, and aldosterone in essential hypertension.

The purpose of the present study was to evaluate the relationship of aldosterone to blood pressure and left ventricular size in black American (n=109) and white French Canadian (n=73) patients with essential hypertension. Measurements were obtained with patients off antihypertensive medications and included 24-hour blood pressure monitoring, plasma renin activity and aldosterone, and an echocardiogram. Compared with the French Canadians, the black Americans had higher body mass indexes, higher systolic blood pressures, attenuated nighttime reduction of blood pressure, and lower serum potassium concentrations (P:<0.01 for each). Left ventricular mass index, posterior wall thickness, interventricular septal thickness, and relative wall thickness were also greater (P:<0.01 for each) in the black American patients. Supine and standing plasma renin activity was lower (P:<0.01 and P:<0.05, respectively) in the black Americans, whereas supine plasma aldosterone concentrations did not differ, and standing plasma aldosterone was greater (P:<0.05) in the black Americans (9.2+/-0.7 ng/dL) than in the French Canadians (7.3+/-0.6 ng/dL). In the black Americans, supine plasma aldosterone was positively correlated with nighttime systolic (r=0.30; P:<0.01) and diastolic (r=0.39; P:<0.001) blood pressures and inversely correlated with the nocturnal decline of systolic (r=-0.29; P:<0.01) and diastolic (r=-0.37; P:<0.001) blood pressures. In the black Americans, standing plasma aldosterone was positively correlated with left ventricular mass index (r=0.36; P:<0.001), posterior wall thickness (r=0.33; P:<0.01), and interventricular septal thickness (r=0.26; P:<0.05). When the black American patients were divided into obese and nonobese groups, significant correlations between plasma aldosterone and both blood pressure and cardiac mass were observed only in the obese. In the French Canadians, overall, plasma aldosterone did not correlate with either blood pressure or any measures of heart size. However, among obese French Canadians, supine plasma aldosterone correlated with nighttime diastolic (r=0.53, P:<0.02) and systolic (r=0.44, P:<0.01) blood pressures but not with cardiac mass. These results are consistent with the hypothesis that aldosterone contributes to elevated arterial pressure in obese black American and obese white French Canadian patients with essential hypertension and to the attenuated nocturnal decline of blood pressure and left ventricular hypertrophy in obese, hypertensive black Americans.

Impact of diet on blood pressure and age-related changes in blood pressure in the US population: analysis of NHANES III.

BACKGROUND: The impact of diet on blood pressure and the age-related changes in blood pressure have been difficult to detect within one population. We designed this analysis to study the association of major dietary factors with blood pressure and with age-related changes in blood pressure in a representative sample of the US population. METHODS: Data were obtained on all individuals 20 years or older (n = 17 030) surveyed in the Third National Health and Nutrition Examination Survey (NHANES III), including demographic data, anthropometric data, dietary intake (sodium, potassium, calcium, magnesium, protein, alcohol, and total energy) based on 24-hour recall, and blood pressure. Multivariate models relating diet to blood pressure were constructed using stepwise regression, best subset regression, and multiple regression. RESULTS: Systolic blood pressure was positively associated with higher sodium, alcohol, and protein intakes (P<.05) and negatively associated with potassium intake (P =.003). Diastolic blood pressure was negatively associated with potassium and alcohol intakes (P<.001). Pulse pressure was positively associated with sodium, protein, and alcohol intakes (P<.001). A higher intake of calcium (P =.01) was associated with a lower rate of rise in systolic blood pressure with age. CONCLUSION: A diet low in sodium, alcohol, and protein is associated with lower systolic blood and pulse pressure. Potassium intake was associated with lower systolic and diastolic blood pressure, whereas alcohol intake was associated with lower diastolic blood pressure. In addition, the age-related changes in systolic blood pressure were attenuated by higher calcium and protein intakes. Magnesium was not associated with any changes in blood pressure.

Role of tumor necrosis factor-alpha gene locus in obesity and obesity-associated hypertension in French Canadians.

Obesity represents a serious risk factor for the development of cardiovascular diseases, including hypertension. Segregation studies suggest that obesity and obesity-associated hypertension may share some genetic determinants. The results of the present candidate gene investigation suggest that in hypertensive pedigrees of French-Canadian origin, one such determinant is the tumor necrosis factor (TNF)-alpha gene locus. Gender-pooled quantitative sib-pair analysis demonstrated a significant effect of the gene locus on 3 global and 7 regional measures of obesity (P=0.05 to 0.0004). Gender-separate quantitative sib-pair analyses showed that the impact of the locus on obesity is most significant in the abdominal region in men and in the thigh region in women. Furthermore, the haplotype relative-risk test demonstrated a significant association between the TNF-alpha gene locus and both obesity (P=0.006) and obesity-associated hypertension (P=0.02). These effects were most significant in individuals with nonmorbid obesity. In conclusion, the results of linkage and association analyses suggest that in hypertensive pedigrees of French-Canadian origin, the TNF-alpha gene locus contributes to the determination of obesity and obesity-associated hypertension. In addition, the data indicate that gender modifies the effect of the locus on the regional distribution of body fat.

Genetic determinants of hypertension: identification of candidate phenotypes.

Our long-term objective is to identify genes whose expression results in hypertension and in phenotypic changes that may contribute to hypertension. The purpose of the present study was to describe evidence for the heritability of hypertension-related phenotypes in hypertensive, hyperlipidemic black sib pairs. Outpatient anthropomorphic measurements were obtained in >200 affected sib pairs. In addition, 68 of these sib pairs were studied under controlled, standardized conditions at an inpatient clinical research center while off both antihypertensive and lipid-lowering medications. Heritability was estimated on the basis of sib-sib correlations and with an association model. Higher heritability estimates for blood pressure were observed with multiple measurements averaged over 24 hours than with measurements at a single time point, and heritability estimates for nighttime blood pressures were higher than those for daytime blood pressures. Heritability estimates for several of the phenotypes were augmented by obtaining measurements in response to a standardized stimulus, including (1) blood pressure responses to the assumption of upright posture, standardized psychological stress, and norepinephrine infusion; (2) plasma renin, aldosterone, epinephrine, and cAMP and cGMP responses to the assumption of upright posture; (3) para-aminohippurate and inulin clearances in response to norepinephrine infusion; and (4) plasma arginine vasopressin in response to NaCl infusion. High heritability estimates were also observed for various measures of body size and body fat, left ventricular size, cardiac index, stroke volume, total peripheral resistance, and serum concentrations of LDL and HDL cholesterol and leptin. These heritability estimates identify the hypertension-related phenotypes that may facilitate the identification of specific genetic determinants of hypertension in blacks with hyperlipidemia.

Glomerular hyperfiltration in hypertensive African Americans.

The incidence of end-stage renal disease attributable to hypertension is 5-fold greater in African Americans than in whites. To determine whether glomerular hyperfiltration is an antecedent to renal failure, we compared responses of renal blood flow and glomerular filtration rate to graded infusions of norepinephrine (0. 01, 0.025, and 0.05 microg. kg(-1). min(-1) for 30 minutes each) in 29 African Americans and 33 age-matched French Canadian whites with essential hypertension. Renal blood flow and glomerular filtration rate were measured by using a constant-infusion technique of PAH and inulin, respectively. Studies were conducted on an inpatient clinical research center, and antihypertensive medications had been discontinued for at least 1 week. Based on 24-hour blood pressure monitoring, nighttime blood pressures decreased (P<0.01) in the French Canadians but not in the African Americans. Baseline renal blood flow was higher (P<0.05) in the African Americans (1310+/-127 mL. min(-1) per 1.73 m(2)) than in the French Canadians (1024+/-42 mL. min(-1) per 1.73 m(2)); baseline glomerular filtration rate was also higher (P<0.01) in the African Americans (140+/-4 versus 121+/-4 mL. min(-1) per 1.73 m(2)). In response to norepinephrine-induced blood pressure increases, renal blood flow was autoregulated and did not change in either patient group. In the African Americans, glomerular filtration rate increased (P<0.01) to 167 mL. min(-1) per 1.73 m(2) during the first norepinephrine infusion, without subsequent change. In contrast, glomerular filtration rate did not change with norepinephrine-induced increases of blood pressure in the French Canadians. In the African Americans, the elevation of baseline glomerular filtration rate, with a further increase in response to norepinephrine, may be indicative of glomerular hyperfiltration. Glomerular hyperfiltration and lack of nocturnal blood pressure decline may contribute to the higher incidence of end-stage renal disease in hypertensive African Americans.

A high sucrose, high linoleic acid diet potentiates hypertension in the Dahl salt sensitive rat.

Insulin resistance can be induced by diets high in simple carbohydrates or fatty acids. To determine whether these nutrients also affect arterial pressure in genetic models of salt sensitive and salt resistant hypertension, Dahl salt sensitive (S) and salt resistant (R) rats were each fed the following isocaloric diets containing 3% NaCl for 4 weeks (10 rats/group): 1) control; 2) high sucrose (60%); 3) high linoleic acid (LA, provided as 10% safflower oil); and 4) high sucrose plus high LA. Tail systolic blood pressures (SBP) were measured weekly, and at 4 weeks, direct mean arterial pressures (MBP) were measured in conscious animals. Insulin sensitivity was assessed by in vitro uptake of tritiated glucose by adipocytes in response to graded doses of insulin. Weight gain did not differ among groups. High sucrose alone and high LA alone did not affect blood pressure in either strain. However, SBP and MBP were increased (P < .05) by the high sucrose plus high LA diet in Dahl-S but not in Dahl-R rats. Sucrose alone and LA alone decreased (P < .05) insulin sensitivity in Dahl-S and Dahl-R rats. In both strains, sucrose plus LA decreased insulin sensitivity to a greater extent (P < .05) than sucrose alone or LA alone. Thus, the sucrose plus LA diet decreased insulin sensitivity in both Dahl-S and Dahl-R rats, whereas blood pressure was increased only in Dahl-S rats. The phenotype of elevated arterial pressure is influenced both by a genetic-nutrient interaction and by an interaction among specific nutrients resulting in insulin resistance.

New therapeutic approaches to reversing insulin resistance.

Insulin resistance may be associated with hypertension and additional cardiovascular disease risk factors. Troglitazone, a thiazolidinedione, is an insulin sensitizing agent that has recently been approved by the USA Food and Drug Administration for the treatment of type II diabetes. Thiazolidinediones and other agents that increase insulin sensitivity, and lipid lowering drugs attenuate the development of hypertension in animal models and in limited clinical studies.

Hypertension control and access to medical care in the inner city.

OBJECTIVES: This study assessed hypertension control among high-risk African Americans. METHODS: We interviewed 583 African Americans aged 18 years and older residing in 438 randomly selected inner-city households. RESULTS: Forty-two percent of the respondents were hypertensive. Blood pressure was uncontrolled in 74% of hypertensive persons, although 64% of hypertensive persons reported having seen a physician within the previous 3 months. Hypertension control was associated with female gender and higher socioeconomic strata but not with public versus private sources of medical care. CONCLUSIONS: Hypertension control is inadequate in this population, although health care services are used frequently. Hypertension control efforts should focus on the effectiveness of health care delivery.

Increasing insulin sensitivity lowers blood pressure in the fructose-fed rat.

In the rat, simple carbohydrate feeding induces insulin resistance, and insulin resistance is associated with impaired endothelium dependent vasodilation. To determine if increasing insulin sensitivity corrects this defect of endothelial function, we evaluated the effects of an insulin-sensitizing agent, pioglitazone, on arterial pressure and in vitro vascular reactivity in three groups of Sprague Dawley rats: 1) control; 2) 60% fructose diet for 4 weeks; 3) 60% fructose diet plus pioglitazone (20 mg/kg daily, by oral gavage). Direct mean arterial pressure did not differ in Groups 1 (120 mm Hg +/- 2) and 2 (121 +/- 2) and was lower (P < .05) in Group 3 (112 +/- 2). In vitro uptake of tritiated glucose by adipocytes in response to insulin was reduced (P < .05) by fructose and increased (P < .01) by pioglitazone. In strips of thoracic aorta, norepinephrine-induced vasoconstriction and nitroprusside induced vasodilation did not differ among groups. However, in response to graded dose of acetylcholine, vasodilation was reduced (P < .05) by fructose; this was normalized by pioglitazone. In all groups, N(G)-nitro-L-arginine methyl ester (L-NAME) completely blocked acetylcholine-induced vasodilation. Thus, pioglitazone increased insulin sensitivity, lowered blood pressure, and normalized acetylcholine-induced vasodilation in insulin resistant, fructose-fed rats. Increasing insulin sensitivity may lower arterial pressure by augmenting endothelium dependent vasodilation.

Dietary sodium and blood pressure: interactions with other nutrients.

This paper reviews the evidence that salt sensitivity of blood pressure is related both to the anion ingested with sodium as well as to other components of the diet. In several experimental models of salt-sensitive hypertension and in humans, blood pressure is not increased by a high sodium intake provided with anions other than chloride. Salt-induced increase of blood pressure depends on the concomitant ingestion of both sodium and chloride. Both epidemiologic and clinical evidence suggest that sodium chloride-induced increases of blood pressure are augmented by diets deficient in potassium or calcium. In experimental animals, a high intake of simple carbohydrates also augments sodium chloride sensitivity of blood pressure. These observations indicate that the effect of dietary sodium on blood pressure is modulated by other components of the diet.