Search

High blood pressure (BP) contributes to 12.8% (or 7.5 million) of deaths worldwide.1 Although BP traits have a substantial genetic component (heritability estimates ranging 31%–68%),2 only a small fraction of the BP variation has been explained by significant single nucleotide polymorphisms identified through genome-wide association studies.3–11 The high prevalence of obesity (44.1% of black, 32.8% of White, and 37.9% of Hispanic American adults are obese (body mass index (BMI) ≥ 30kg/m2)),12 coupled with reports of significant interactions between genes and BMI from candidate gene and twin studies of BP,13–20 has inspired large-scale systematic investigations of gene–obesity interactions. However, meta-analyses of genome-wide association study results using massive sample sizes have yet to identify any genome-wide significant (P ≤ 5×10−8) single nucleotide polymorphism–BMI interactions. We investigated whether large and racially diverse family studies provided any evidence for gene–BMI interactions in hypertension pathophysiology and whether the shape (unimodal, linear increasing, linear decreasing) of this interaction was race dependent. Specifically, we investigated the BP heritability dependence on BMI using 4,153 black, 1,538 Asian, 4,013 White, and 2,199 Hispanic American participants from the Family Blood Pressure Program (FBPP). Within each of 10 race and network subgroups, we employed the Shi and Rao21 generalized variance components model to allow the polygenic component, and hence BP heritability, to vary by BMI level. We modeled 2 polygenic–BMI interaction functions (linear and Gaussian) to permit a variety of heritability curve shapes (increasing, decreasing, unimodal) for each of 4 BP traits (systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP)). The resulting heritability curves may provide insight into the genetic and environmental architecture of BP and is an important first step in exploring the existence and shape of gene–BMI interactions.

Recent studies suggest that oxidative stress and vascular dysfunction contribute to heart failure with preserved ejection fraction (HFPEF). In salt-sensitive HFPEF animal models, diets low in sodium and high in potassium, calcium, magnesium, and antioxidants attenuate oxidative stress and cardiovascular damage. We hypothesized that the sodium-restricted Dietary Approaches to Stop Hypertension diet (DASH/SRD) would have similar effects in human hypertensive HFPEF. Thirteen patients with treated hypertension and compensated HFPEF consumed the DASH/SRD for 21 days (all food/most beverages provided). The DASH/SRD reduced clinic systolic (155–138 mm Hg; P =0.02) and diastolic blood pressure (79–72 mm Hg; P =0.04), 24-hour ambulatory systolic (130–123 mm Hg; P =0.02) and diastolic blood pressure (67–62 mm Hg; P =0.02), and carotid-femoral pulse wave velocity (12.4–11.0 m/s; P =0.03). Urinary F2-isoprostanes decreased by 31% (209–144 pmol/mmol Cr; P =0.02) despite increased urinary aldosterone excretion. The reduction in urinary F2-isoprostanes closely correlated with the reduction in urinary sodium excretion on the DASH/SRD. In this cohort of HFPEF patients with treated hypertension, the DASH/SRD reduced systemic blood pressure, arterial stiffness, and oxidative stress. These findings are characteristic of salt-sensitive hypertension, a phenotype present in many HFPEF animal models and suggest shared pathophysiological mechanisms linking these 2 conditions. Further dietary modification studies could provide insights into the development and progression of hypertensive HFPEF.

Orthostatic hypotension (OH) is strongly age-dependent, with a prevalence ranging from 5% to 11% in middle age to 30% or higher in the elderly. It is also closely associated with other common chronic diseases, including hypertension, congestive heart failure, diabetes mellitus, and Parkinson's disease. Most studies of OH have been performed in population cohorts or elderly residents of extended care facilities, but in this review, we draw attention to a problem little studied to date: OH in hospitalized patients. The prevalence of OH in all hospitalized patients is not known because most studies have included only older individuals with multiple comorbid diseases, but in some settings as many as 60% of hospitalized adults have postural hypotension. Hospitalized patients are particularly vulnerable to the consequences of OH, particularly falls, because postural blood pressure (BP) regulation may be disturbed by many common acute illnesses as well as by bed rest and drug treatment. The temporal course of OH in hospitalized patients is uncertain, both because the reproducibility of OH is poor and because conditions affecting postural BP regulation may vary during hospitalization. Finally, OH during hospitalization often persists after discharge, where, in addition to creating an ongoing risk of falls and syncope, it is strongly associated with risk of incident cardiovascular complications, including myocardial infarction, heart failure, stroke, and all-cause mortality. Because OH is a common, easily diagnosable, remediable condition with important clinical implications, we encourage caregivers to monitor postural BP change in patients throughout hospitalization.

Blood pressure (BP) is affected by many environmental factors including ambient temperature, altitude, latitude, noise, and air pollutants. Given their pervasiveness, it is plausible that such factors may also have an impact on hypertension prevalence and control rates. Health care providers should be aware that the environment can play a significant role in altering BP. Although not among the established modifiable risk factors (eg, obesity) for hypertension, reducing exposures when pertinent should be considered to prevent or control hypertension. The authors provide a concise review of the evidence linking diverse environmental factors with BP and suggest an approach for incorporating this knowledge into clinical practice. The authors propose using the term environmental hypertensionology to refer to the study of the effects of environmental factors on BP in clinical and research settings.

The association between hypertension in pregnancy and future cardiovascular disease (CVD) increasingly is recognized. We aimed to assess the role of hypertension in pregnancy as an independent risk factor for hypertension, coronary heart disease (CHD), and stroke later in life.Women who participated in the Phase 2 (2000-2004) Family Blood Pressure Program study (n = 4782) were categorized into women with no history of pregnancy lasting more than 6 months (n = 718), women with no history of hypertension in pregnancy (n = 3421), and women with a history of hypertension in at least one pregnancy (n = 643). We used Kaplan-Meier and Cox proportional hazard models to estimate and contrast the risks of subsequent diagnoses of hypertension, CHD, and stroke among the groups.Women with a history of hypertension in pregnancy, compared with those without such a history, were at increased risks for the subsequent diagnoses of hypertension (50% hypertensive at the age 53 vs. 60, P0.001), CHD (14% estimated event rate vs. 11%, P = 0.009), and stroke (12% estimated event rate vs. 5%, P0.001). The increased risk for subsequent hypertension remained significant after controlling for race, family history of CVD, smoking, dyslipidemia, and diabetes mellitus, with an adjusted hazard ratio of 1.88 [95% confidence interval (CI) 1.49-2.39, P0.001]. After controlling for traditional risk factors, including subsequent hypertension, the increased risk for stroke remained statistically significant (hazard ratio 2.10, 95% CI 1.19-3.71, P = 0.01), but not for CHD.Hypertension in pregnancy may be an independent risk factor for subsequent diagnoses of hypertension and stroke.

J Clin Hypertens (Greenwich). 2010;12:82–88. ©2009 Wiley Periodicals, Inc. Arm size can affect the accuracy of blood pressure (BP) measurement, and “undercuffing” of large upper arms is likely to be a growing problem. Therefore, the authors investigated the relationship between upper arm and wrist readings. Upper arm and wrist circumferences and BP were measured in 261 consecutive patients. Upper arm auscultation and wrist BP was measured in triplicate, rotating measurements every 30 seconds between sites. Upper arm BP was 131.9±20.6/71.6±12.6 mm Hg in an obese population (body mass index, 30.6±6.6 kg/m2) with mean upper arm size of 30.7±5.1 cm. Wrist BP was higher (2.6±9.2 mm Hg and 4.9±6.6 mm Hg, respectively, P

Dopamine is an endogenous natriuretic amine that contributes to the maintenance of sodium homeostasis. Deficiencies in the renal production of dopamine and the action of dopamine on renal tubular receptors have been observed in human hypertension and may contribute to salt sensitivity of blood pressure. Ethnic differences in the sodium-to-dopamine relationship may contribute to the higher prevalence of salt sensitivity in blacks. The authors assessed dopaminergic activity in two studies. In the first, daytime and nighttime excretion of sodium and dopamine were compared in 11 black and 17 white normotensive patients. No racial difference in the rate of sodium or dopamine excretion during either period was observed. In the second study, a graded infusion of the dopamine-1 receptor agonist, fenoldopam, was performed in 14 black and 17 white normotensive patients. There was no racial difference in the natriuretic responses. Previously described lower rates of renal free water clearance and potassium excretion in blacks compared with whites were maintained during fenoldopam infusion, suggesting that dopamine is not a mediator of those differences. The authors conclude that there are no race-related differences in dopamine excretion or activity in normotensive patients.

Hypertension places a major burden on individual and public health, but the genetic basis of this complex disorder is poorly understood. We conducted a genome-wide association study of systolic and diastolic blood pressure (SBP and DBP) in Amish subjects and found strong association signals with common variants in a serine/threonine kinase gene, STK39 . We confirmed this association in an independent Amish and 4 non-Amish Caucasian samples including the Diabetes Genetics Initiative, Framingham Heart Study, GenNet, and Hutterites (meta-analysis combining all studies: n = 7,125, P < 10 −6 ). The higher BP-associated alleles have frequencies > 0.09 and were associated with increases of 3.3/1.3 mm Hg in SBP/DBP, respectively, in the Amish subjects and with smaller but consistent effects across the non-Amish studies. Cell-based functional studies showed that STK39 interacts with WNK kinases and cation-chloride cotransporters, mutations in which cause monogenic forms of BP dysregulation. We demonstrate that in vivo, STK39 is expressed in the distal nephron, where it may interact with these proteins. Although none of the associated SNPs alter protein structure, we identified and experimentally confirmed a highly conserved intronic element with allele-specific in vitro transcription activity as a functional candidate for this association. Thus, variants in STK39 may influence BP by increasing STK39 expression and consequently altering renal Na + excretion, thus unifying rare and common BP-regulating alleles in the same physiological pathway.

To determine the independent and combined effects of three quantitative trait loci (QTL) for blood pressure in the Genetically Hypertensive (GH/Omr) rat by generating and characterizing single and combined congenic strains that have QTL on rat chromosomes (RNO) 2, 6, and 18 from the GH rat introduced into a hypertension resistant Brown Norway (BN) background.Linkage analysis and QTL identification (genome wide QTL scan) were performed with MapMaker/EXP to build the genetic maps and MapMaker/QTL for linking the phenotypes to the genetic map. The congenic strains were derived using marker-assisted selection strategy from a single male F1 offspring of an intercross between the male GH/Omr and female BN/Elh, followed by 10 generations of selective backcrossing to the female BN progenitor strain. Single congenic strains generated were BN.GH-(D2Rat22-D2Mgh11)/Mcwi (BN.GH2); BN.GH-(D6Mit12-D6Rat15)/Mcwi (BN.GH6); and BN.GH-(D18Rat41-D18Mgh4)/Mcwi (BN.GH18). Blood pressure measurements were obtained either via a catheter placed in the femoral artery or by radiotelemetry. Responses to angiotensin II (ANGII), norepinephrine (NE), and baroreceptor sensitivity were measured in the single congenics.Transferring one or more QTL from the hypertensive GH into normotensive BN strain was not sufficient to cause hypertension in any of the developed congenic strains. There were no differences between the parental and congenic strains in their response to NE. However, BN.GH18 rats revealed significantly lower baroreceptor sensitivity (beta=-1.25-/+0.17), whereas BN.GH2 (beta=0.66-/+0.09) and BN.GH18 (beta=0.71-/+0.07) had significantly decreased responses to ANGII from those observed in the BN (beta=0.88-/+0.08).The failure to alter blood pressure levels by introducing the hypertensive QTL from the GH into the hypertension resistant BN background suggests that the QTL effects are genome background-dependent in the GH rat. BN.GH2 and BN.GH18 rats reveal significant differences in response to ANGII and impaired baroreflex sensitivity, suggesting that we may have captured a locus responsible for the genetic control of baroreceptor sensitivity, which would be considered an intermediate phenotype of blood pressure.

Essential hypertension is a principal cardiovascular risk factor whose origin remains unknown. Classical genetic studies have shown that blood pressure is at least partially heritable, opening a window to understanding the pathophysiology of essential hypertension in the human using modern genetic tools. The Wellcome Trust Case Control Consortium has recently published the results of screening the genomes of 2000 essential hypertension cases and 3000 controls using 500 000 genome-wide single nucleotide polymorphisms (SNPs). None of the variants proved to be genome-wide significant after correction for multiple tests but the most significantly associated SNPs (P

Background and Purpose— Atherothrombotic diseases, including stroke and myocardial infarction, share a common pathogenesis. Chromosomal regions have been linked to atherothrombotic diseases in family studies, and association studies have identified candidate gene polymorphisms that affect the risk of stroke and/or myocardial infarction. Using data from the Family Blood Pressure Program, we tested for chromosomal regions linked to the composite phenotype of stroke or myocardial infarction in a large set of hypertensive families. Methods— Nonparametric linkage analysis was implemented in MERLIN, which tests for excess allele-sharing among affected siblings. Empirical distributions based on gene dropping simulations were constructed for each test statistic, and the −log 10 of the associated probability values were compared. Results— Analyses were based on 9607 individuals in 226 black, 395 Hispanic, and 207 white families; 106 families had multiple affected individuals. Several regions showed linkage to stroke or myocardial infarction, most significantly in Hispanics on chromosomes 2p21 (−log 10 P =3.0) and 7q21.1 (−log 10 P =2.8), 9q32 in blacks and Hispanics (−log 10 P =3.0), 11p13 in blacks (−log 10 P =2.1), and 12q24.33 in whites (−log 10 P =3.0). Conclusions— There is statistically significant evidence for loci affecting stroke or myocardial infarction on chromosomes 2, 9, and 12.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. J.T. and P.H. are consultants for Servier. J.C. received research grants and honoraria from Servier. K.S. obtained research support from Boehringer Ingelheim. The remaining authors declared no competing financial interests.

To dissect the genetic architecture of blood pressure (BP) and assess how its elevation promotes downstream cardiovascular diseases, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry. Genotypes from an additional 140,886 individuals of European ancestry were used as validation for loci reaching genome-wide significance but without prior support in the literature. We identified 66 BP loci, of which 17 were novel and 15 harbored multiple distinct association signals, and which together explain up to 3.5% of BP variation. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in BP control through modulating blood vessel tone and fluid filtration across multiple tissues, not solely the kidney. Importantly, the 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent (South-Asian, East-Asian and African), confirming that these are ancestral physiological effects that arose prior to human migration out of Africa. The 66-SNP BP risk score was significantly associated with target-organ damage in multiple tissues, with minor effects in the kidney. Our data expand current knowledge of BP pathways, and also, highlight that BP regulation and its effects may occur in multiple organs and tissues beyond the classic renal system.

Evolution by natural selection is the supreme organizing principle of biology, but it has not been widely applied in medicine.1 Medicine has historically been concerned with mechanistic, or “proximate,” answers to questions of how diseases develop and cause pathology. In contrast, evolutionary, or “ultimate,” questions, frequently ask “why” structures or functions are as they are.2 A full explanation of a disease should ideally address both, and what follows is a review of aspects of proximate and evolutionary thinking in hypertension. As animals evolved, body size increased, and delivery of nutrients to cells came to exceed the range of diffusion. Simple systems capable of supporting cellular metabolism arose, and natural selection went on to shape our staggeringly complex, highly integrated cardiovascular system. Contemporary cardiovascular research is almost exclusively concerned with detailed descriptions of the proximate features of cardiovascular function and structure, and we now understand many aspects in exquisite detail. Blood pressure, however, cannot be reduced to the individual elements of the circulation. It is a function of all of them acting in concert; it is an emergent property of the entire system. All hierarchically organized biological systems have higher-order emergent functions that depend on, but are not predictable from, the structures and functions of lower levels,3 and because emergent properties are lost when a system is disaggregated, integrative physiology is critical to understanding blood pressure regulation. The most comprehensive description of cardiovascular system physiology and blood pressure control is the systems analysis mathematical model developed by Guyton et al,4 which proposes renal pressure-natriuresis as the dominant regulator of blood pressure. The relationship of chronic pressure-natriuresis to the regulation of blood pressure level has been the focus of a great deal of research, and we now understand some of the regulatory mechanisms (reviewed in Reference 5). Pressure-natriuresis …

Essential hypertension, defined as elevated levels of blood pressure (BP) without any obvious cause, is a major risk factor for coronary heart disease, stroke, and renal disease. BP levels and susceptibility to development of essential hypertension are partially determined by genetic factors that are poorly understood. Similar to other efforts to understand complex, non-Mendelian phenotypes, genetic dissection of hypertension-related traits employs genomewide linkage analyses of families and association studies of patient cohorts, to uncover rare and common disease alleles, respectively. Family-based mapping studies of elevated BP cover the large intermediate ground for identification of genes with common variants of significant effect. Our genomewide linkage and candidate-gene-based association studies demonstrate that a replicated linkage peak for BP regulation on human chromosome 1q, homologous to mouse and rat quantitative trait loci for BP, contains at least three genes associated with BP levels in multiple samples: ATP1B1, RGS5, and SELE. Individual variants in these three genes account for 2-5-mm Hg differences in mean systolic BP levels, and the cumulative effect reaches 8-10 mm Hg. Because the associated alleles in these genes are relatively common (frequency >5%), these three genes are important contributors to elevated BP in the population at large.

Objective Cardiac changes of hypertensive pregnancy include left ventricular hypertrophy (LVH) and diastolic dysfunction. These are thought to regress postpartum. We hypothesised that women with a history of hypertensive pregnancy would have altered LV geometry and function when compared with women with only normotensive pregnancies. Methods In this cohort study, we analysed echocardiograms of 2637 women who participated in the Family Blood Pressure Program. We compared LV mass and function in women with hypertensive pregnancies with those with normotensive pregnancies. Results Women were evaluated at a mean age of 56 years: 427 (16%) had at least one hypertensive pregnancy; 2210 (84%) had normotensive pregnancies. Compared with women with normotensive pregnancies, women with hypertensive pregnancy had a greater risk of LVH (OR: 1.42; 95% CI 1.01 to 1.99, p=0.05), after adjusting for age, race, research network of the Family Blood Pressure Program, education, parity, BMI, hypertension and diabetes. When duration of hypertension was taken into account, this relationship was no longer significant (OR: 1.19; CI 0.08 to 1.78, p=0.38). Women with hypertensive pregnancies also had greater left atrial size and lower mitral E/A ratio after adjusting for demographic variables. The prevalence of systolic dysfunction was similar between the groups. Conclusions A history of hypertensive pregnancy is associated with LVH after adjusting for risk factors; this might be explained by longer duration of hypertension. This finding supports current guidelines recommending surveillance of women following a hypertensive pregnancy, and sets the stage for longitudinal echocardiographic studies to further elucidate progression of LV geometry and function after pregnancy. Clinical trial registrations GENOA- NCT00005269; HyperGEN- NCT00005267; Sapphire- NCT00005270; GenNet- NCT00005268.

Atherosclerosis accounts for 75% of all deaths from cardiovascular disease and includes coronary heart disease (CHD), stroke, and other diseases of the arteries. More than half of all CHD is attributable to abnormalities in levels and metabolism of lipids. To locate genes that affect total cholesterol, high density lipoprotein cholesterol (HDL-C), and triglycerides, genome-wide linkage scans for quantitative trait loci were performed using variance components methods as implemented in SOLAR on a large diverse sample recruited as part of the Family Blood Pressure Program. Phenotype and genetic marker data were available for 9,299 subjects in 2,953 families for total cholesterol, 8,668 subjects in 2,736 families for HDL, and 7,760 subjects in 2,499 families for triglycerides. Mean lipid levels were adjusted for the effects of sex, age, age2, age-by-sex interaction, body mass index, smoking status, and field center. HDL-C and triglycerides were further adjusted for average total alcoholic drinks per week and estrogen use. Significant linkage was found for total cholesterol on chromosome 2 (LOD = 3.1 at 43 cM) in Hispanics and for HDL-C on chromosome 3 (LOD = 3.0 at 182 cM) and 12 (LOD = 3.5 at 124 cM) in Asians. In addition, there were 13 regions that showed suggestive linkage (LOD ≥ 2.0); 7 for total cholesterol, 4 for HDL, and 2 for triglycerides. The identification of these loci affecting lipid phenotypes and the apparent congruence with previous linkage results provides increased support that these regions contain genes influencing lipid levels.

Background Dopamine receptor genes are candidates for hypertension susceptibility. Locally released dopamine increases renal sodium excretion, and defective renal dopamine receptor signaling has been shown to play a role in hypertension. Dopamine-4 receptors are expressed in juxtaglomerular and cortical collecting cells, where dopamine activation could alter sodium and water metabolism and affect blood pressure (BP). The dopamine-4 receptor (DRD4) gene has a 16 amino acid (48 base pairs [bp]) repeat polymorphism located in exon 3 where a G-protein binding area is encoded. The long allele (defined as at least one 7 to 10 repeat) has been associated with the personality trait Novelty Seeking and with substance abuse, but associations between dopamine-4 receptor polymorphisms and BP have not been reported. Methods We genotyped 479 female and 385 male subjects of white ethnicity at the DRD4 repeat polymorphism site and classified each subject as having either the long or short genotype. Results We found associations between the DRD4 long allele and increased systolic BP (P = .031), diastolic BP (P = .034), and a history of regular alcohol use (P = .008). Furthermore, for systolic BP (P = .009) and pulse pressure (P = .002), we found evidence for an interaction between dopamine-4 receptor alleles and age, indicating that the effects of dopamine-4 receptor variants on BP increase with age. Conclusion In this white population, the long variant of the DRD4 gene is associated with a 3–mm Hg higher systolic and 2–mm Hg higher diastolic BP.

Genome-wide linkage analyses were performed using a multipoint variance components method in eight study groups from four multicenter networks (whites and blacks in GenNet; whites, blacks, and Mexican Americans in GENOA; whites and blacks in HyperGEN; and Asians in SAPPHIRe) that comprise the National Heart, Lung, and Blood Institute Family Blood Pressure Program (FBPP), in order to identify quantitative trait loci (QTLs) influencing fasting glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR). These study populations were enriched with subjects who had elevated blood pressure. Participants fasting

Chromosome 2 has been consistently identified as a genomic region with genetic linkage evidence suggesting that one or more loci contributes to blood pressure and hypertension status. As with all complex disease traits, following-up linkage evidence to identify the underlying susceptibility gene(s) is an arduous yet biologically and clinically important task. Using combined positional candidate gene methods, the Family Blood Pressure Program (FBPP) has concentrated efforts in narrowing a large region of chromosome 2, demonstrating evidence for linkage in several populations, and identifying underlying candidate hypertension susceptibility gene(s). Initial informatics efforts identified the boundaries of the region and the known genes within it. A total of 82 polymorphic sites in 8 genes were genotyped in a large hypothesis-generating sample consisting of 1640 African Americans, 1339 whites, and 1616 Mexican Americans. After resampling-based false discovery adjustment, SLC4A5 , a sodium bicarbonate transporter, was identified as a primary candidate gene for hypertension. Polymorphisms in SLC4A5 were subsequently genotyped and analyzed for validation in two other subcomponents of the FBPP, each contributing African Americans (N=461; N=778) and whites (N=550; N=967). Again, single nucleotide polymorphisms within this gene were significantly associated with blood pressure levels and hypertension status. Although not identifying a single causal gene variant that is significantly associated with blood pressure levels and hypertension status across all samples, the results further implicate SLC4A5 as a candidate hypertension susceptibility gene. Moreover, the present study validates previous evidence for one or more genes on chromosome 2 that influence hypertension-related phenotypes in the population-at-large.

Background A tendency to experience negative affect, as measured by the neuroticism component of the Neuroticism, Extraversion, and Openness Personality Inventory (NEO-PI), is a trait marker for major depression. Epidemiologic studies indicate a strong genetic component, but to date few specific genetic variants have been definitively implicated. A serotonin transporter promoter polymorphism (5-HTTLPR) has been extensively studied in neuroticism and several psychiatric disorders, with inconclusive results. A GABA(A) receptor α6 subunit variant (Pro385Ser) has been associated with alcohol-related traits but has not been studied in neuroticism or depression. Methods A total of 384 subjects who completed the NEO-PI were genotyped at 5-HTTLPR and Pro385Ser. Associations between polymorphisms and both alcohol use and personality domains were tested. Results The 5-HTTLPR short allele (p = .008) and Pro385Ser Pro allele (p = .003) are associated with higher neuroticism scores. The 5-HTTLPR long allele (p = .006), but not Pro385Ser, is also associated with an increased presence of alcohol use. In addition, there is a nonsignificant suggestion of an interaction: the effect of 5-HTTLPR on neuroticism might be dependent on the Pro385Ser genotype. Conclusions These findings support a role for the serotonin transporter and GABA(A) α6 subunit in depression-related traits.

Sodium glomerulopathy: Tubuloglomerular feedback and renal injury in African Americans. African Americans are prone to develop not only essential hypertension but also progressive renal injury. We present a simple model to explain salt-induced renal injury (sodium glomerulopathy) in African Americans, the central features of which are the tubuloglomerular feedback and the balance/imbalance between the vascular tones of the afferent and efferent glomerular arterioles. We propose that in African Americans, habitual consumption of high salt causes chronic intermittent tubular hyperperfusion of the macula densa, resulting in a rightward and upward resetting of the operating point for the tubuloglomerular feedback. The resetting of the operating point causes an imbalance between the vascular tones of the afferent/efferent arterioles, a rise in the glomerular capillary hydraulic pressure, and consequent hyperfiltration. Increased susceptibility to glomerular hyperfiltration of African Americans on a high salt intake may explain their proclivity to progressive renal injury associated with essential hypertension.

Purpose:To determine the incremental cost-effectiveness of prophylactic percutaneous transluminal angioplasty with stent placement (PTA-S) in patients with incidentally discovered, asymptomatic renal artery stenosis (RAS) compared to delaying PTA-S until patients develop refractory hypertension or renal insufficiency (therapeutic PTA-S).Methods:The Markov decision analysis model was used to determine the incremental cost per quality adjusted life year (QALY) saved for prophylactic PTA-S as compared to therapeutic PTA-S in a hypothetical cohort of patients with 50% unilateral atherosclerotic RAS followed from age 61 to death.Results:Prophylactic PTA-S compared to therapeutic PTA-S results in more QALYs/patient (10.9 versus 10.3) at higher lifetime costs ($23,664 versus $16,558). The incremental cost effectiveness of prophylactic PTA-S was estimated to be $12,466/QALY. Prophylactic stenting was not cost effective (>$50,000/QALY) if the modeled incidence of stent restenosis exceeded 15%/year and the incidence of progression in the contralateral renal artery was Conclusions:PTA-S of incidental, asymptomatic unilateral RAS may improve patients' quality of life at an acceptable incremental cost. However, this technology should be used hesitantly until a randomized comparison confirms its effectiveness.

PURPOSE To determine the incremental cost-effectiveness of prophylactic percutaneous transluminal angioplasty with stent placement (PTA-S) in patients with incidentally discovered, asymptomatic renal artery stenosis (RAS) compared to delaying PTA-S until patients develop refractory hypertension or renal insufficiency (therapeutic PTA-S). METHODS The Markov decision analysis model was used to determine the incremental cost per quality adjusted life year (QALY) saved for prophylactic PTA-S as compared to therapeutic PTA-S in a hypothetical cohort of patients with 50% unilateral atherosclerotic RAS followed from age 61 to death. RESULTS Prophylactic PTA-S compared to therapeutic PTA-S results in more QALYs/patient (10.9 versus 10.3) at higher lifetime costs ($23,664 versus $16,558). The incremental cost effectiveness of prophylactic PTA-S was estimated to be $12,466/QALY. Prophylactic stenting was not cost effective (>$50,000/QALY) if the modeled incidence of stent restenosis exceeded 15%/year and the incidence of progression in the contralateral renal artery was

Background Four multicenter Networks (GenNet, GENOA, HyperGEN, SAPPHIRe) form the National Heart, Lung and Blood Institute Family Blood Pressure Program (FBPP), to search for hypertension/blood pressure (BP) genes. The networks used different family designs and targeted multiple ethnic groups, using standardized protocols and definitions. Linkage genome scans were done on samples within each network (N = 6245 relatives). Methods The evidence was synthesized using meta-analysis. Results Combining ethnic groups, no region reached LOD >2, but several small peaks were identified, including chromosome 2p where two other recent reports find hypertension linkage. Conclusions No regions show uniformly large effects on BP/hypertension in all populations.

Association studies of candidate genes with complex traits have generally used one or a few single nucleotide polymorphisms (SNPs), although variation in the extent of linkage disequilibrium (LD) within genes markedly influences the sensitivity and precision of association studies. The extent of LD and the underlying haplotype structure for most candidate genes are still unavailable. We sampled 193 blacks (African-Americans) and 160 whites (European-Americans) and estimated the intragenic LD and the haplotype structure in four genes of the renin–angiotensin system. We genotyped 25 SNPs, with all but one of the pairs spaced between 1 and 20 kb, thus providing resolution at small scale. The pattern of LD within a gene was very heterogeneous. Using a robust method to define haplotype blocks, blocks of limited haplotype diversity were identified at each locus; between these blocks, LD was lost owing to the history of recombination events. As anticipated, there was less LD among blacks, the number of haplotypes was substantially larger, and shorter haplotype segments were found, compared with whites. These findings have implications for candidate-gene association studies and indicate that variation between populations of European and African origin in haplotype diversity is characteristic of most genes.[The sequence data described in this paper are available in GenBank under the following accession nos: AGT, MIM 106150; Renin, MIM 179820;ACE, MIM 106180; Angiotensin receptor I, MIM 106165. Supplementary material is available online athttp://www.genome.org.]

The organization of the normal perceptual processing subserving tactile object recognition is poorly understood. While perceptual deficits associated with cases of tactile agnosia may pinpoint sites of critical interference with normal tactile information processing, the precise character of such deficits remains unclear. The aim of the present study was to explore the behavioural and neuroanatomical correlates of perceptual disturbances in two cases of unilateral aperceptive tactile agnosia. Perception of microgeometrical and macrogeometrical features was tested using an alternative forced choice paradigm. While both patients were impaired in the assessment of microgeometrical properties of objects (i.e. detecting subtle differences in grating profiles), one patient showed an additional deficit in the perception of macrogeometrical properties of objects (i.e. detecting differences in length of cuboids). The pattern of perceptual deficits for both patients suggested a severely compromised (if not totally lost) ability to recognize everyday objects. Perceptual performance improved when the patients had complementary tactile information (i.e. for intramodal comparison), despite a persistent inability to explicitly name the objects. That is, the patients were able to recognize objects, but only implicitly. Improved perceptual performance was also observed when complementary visual information was available (i.e. transmodal information transfer). In this case, the perceptual improvement was accompanied by a corresponding improvement in explicit object recognition. High resolution MRIs identified lesions in the postcentral gyrus in both patients, and additionally in the secondary somatosensory area (SII) and the posterior parietal cortex in the more severely affected patient. The results demonstrate that the underlying failure in tactile agnosia is mainly impaired perception of microgeometrical properties of objects due to a lesion of primary sensory cortex. The related neuroanatomical findings suggest a degradation of serial information processing within postcentral gyrus. In one case tactile agnosia was almost complete due to additionally impaired perception of macrogeometrical properties of objects, which correlated with the extension of lesion to the posterior parietal cortex. Importantly, the findings indicate traces of two distributed networks for tactile information processing and the associated parallel processing of complementary micro- and macrogeometrical information within postcentral gyrus and posterior parietal lobe.

but with traits, such as personality factors, that are themselves associated with risk for the disorder (Lander and Schork, 1994; Stolten-berg and Burmeister, 2000). Often such traits have a higher heritability than the disease status (Almasy and Blangero, 2001). Neuroticism, as measured by the NEO personality inventory (NEO-PI) (Costa and McCrae, 1997), a psycho-metrically sound and widely used instrument, is one such trait. High scorers on the Neuroticism domain are char-acterized by frequent experience of “negative emotional-ity” such as anxiety, low mood, and hostility. Converging lines of evidence point to brain-derived neurotrophic fac-tor (BDNF) as a factor in the pathophysiology of depres-sion. To explore the possibility that variation in the BDNF gene is, in part, responsible for the population variation in Neuroticism, we studied a community sample of 441 sub-jects, genotyping a G→A single-nucleotide polymorphism (SNP) responsible for a valine→methionine substitution in the prodomain of BDNF. The less common, nonconserved Met allele was associated with significantly lower mean Neuroticism scores (

The Family Blood Pressure Program (FBPP) consists of 4 independently established multicenter networks of investigators who have complementary approaches to the genetics of blood pressure levels and hypertension. The program has recruited participants from the African American, Mexican American, Asian, and non-Hispanic white populations. Each network utilized study designs, laboratory measurements, and analytic methods that made efficient use of the unique characteristics of their populations and the investigators’ expertise. The individual networks subsequently unified core study components into a single cohesive program. The unified FBPP includes (1) standardized clinic and laboratory protocols for core variables to facilitate direct comparison of results among networks, (2) coordination among laboratories to avoid unnecessary duplication of effort, (3) utilization of a single laboratory for genome-wide marker typing, and (4) a pooled data set containing phenotype and genotype information from >11 000 individuals.

3 Abstract To assess evidence for a gene with large effect on systolic blood pressure (SBP), diastolic blood pressure (DBP), and body mass index (BMI), we conducted segregation analyses on 261 nuclear families collected from a rural Caucasian community in Michigan. The families were ascertained through a hypertensive proband. Each phenotype was adjusted for significant covariate effects (e.g., gender and age). We used class D regressive models to conduct the segregation analyses. Our analysis results support the segrega- tion of a major gene for BMI, but not for SBP or DBP. A recessive locus ef- fect provided the best explanation for BMI where ∼43% of the variance of BMI was due to this gene. Elevated or high blood pressure (HBP) and obesity (OB) are significant risk fac- tors for cardiovascular disease, diabetes, and essential hypertension. They are also the leading causes of morbidity and mortality in Western societies (McGill 1996). An estimated 55% of adults are classified as overweight, and obesity is as- sociated with increased morbidity and mortality from several chronic diseases (Dorn et al. 1997; Taubes 1998). Blood pressure and obesity level are complex quantitative traits, thought to be influenced by a variety of physiological, behav- ioral, and sociocultural factors (Ward 1983; Ward 1990). As a result, the identifi- cation of susceptibility genes that contribute to HBP and OB will be difficult. We have undertaken segregation analyses to determine the likelihood that a gene with large effect influences blood pressure and obesity level. The analyses can be seen as a precursor to the actual identification of genes by means of linkage and/or as- sociation analyses. It is also important to assess the degree to which any single

Physicians treat chronic hypertension almost exclusively in ambulatory care settings according to evidence-based guidelines1 based on blood pressure (BP) measurements obtained under prescribed conditions.2 Other recommendations cover how to deal with hypertension in dialysis units2 and emergency departments,3 but none address a very commonly encountered problem: what to do about acutely elevated BP (which I refer to below in the common parlance of “acute hypertension”) in patients hospitalized for reasons other than hypertension. Indeed, excluding articles on patients with hypertensive emergencies and urgencies, there is little published about treatment of acutely elevated BP in hospitalized patients, although the practice seems to be common and based on firmly held, but poorly justified, beliefs.4 In this commentary, I argue for developing a rational approach to treating acute hypertension that de-emphasizes “treating the numbers” and focuses on patient safety. ### How Common Is Acute Hypertension in Hospitalized Patients? Most patients hospitalized for reasons other than hypertensive emergency or urgency who subsequently sporadically manifest acute hypertension deemed worthy of clinical concern probably also have chronic hypertension. In recent national data of hospitalizations, hypertension was listed as a primary diagnosis (International Classification of Diseases [ICD]–9 CM code 401) for 301 000 admissions but as a secondary diagnosis for 9 003 000 hospitalizations.5 These figures are probably an underestimate of the actual prevalence of hypertension in inpatients because 29% of the US adult population is now affected.6 One estimate of the rate of hypertension in patients in our center (the University of Michigan Health System[UMHS]) can be derived from patients attending our anesthesiology preoperative evaluation clinic, who have an incidence of 26.7% of stage 1 and 10.9% of stage 2 hypertension (unpublished data, 2010). Using these prevalence figures, during a 1-year period (October 1, 2007, to September 30, 2008) in which there were 29 545 adult admissions to …

Hypertension guidelines recommend following published standardized protocols to obtain accurate blood pressure (BP) readings in clinical practice. However, the various measurement techniques among clinical trials that provide the basis for evidence-based management have not been evaluated or compared with guideline recommendations. We reviewed published information regarding BP measurement in clinical trials (n = 64) from 1990-2014 by searching PubMed and Google Scholar databases. Every trial failed to provide published information regarding at least one of the 10 methodological aspects we evaluated. Details regarding the health-care provider(s) performing measurement(s), temporal-relation to last medication dosage, number of readings, resting time before (and between recordings), and the device(s) used varied among the trials and often differed from clinical recommendations. Most studies did evaluate ≥2 BP readings in a seated position, presumably from the upper arm (although explicit acknowledgment of this latter detail was rare). When indicated, "trough" BP levels were most commonly obtained (15 of 16 trials), whereas the usage of automated devices increased over time. Numerous aspects of BP measurement varied considerably across trials and often from most recent guideline recommendations. The lack of uniform methodologies in outcome studies that form the foundation of evidence-based guidelines may have significant clinical implications.

This large multicenter study, tested the antihypertensive effects of isradipine, a dihydropyridine calcium channel blocker and enalapril, an angiotensin-converting enzyme inhibitor, in salt-sensitive hypertensive patients under low and high salt intake diets. After a 3-week (weeks − 9 to − 6) of ad lib salt diet, those patients who had a sitting diastolic blood pressure (SDBP) of ≥ 95 but ≤ 115 mm Hg qualified to enter a 3-week (weeks − 6 to − 3) placebo run-in low salt diet (50 to 80 mmol Na + /day). Then high salt (200 to 250 mmol Na + /day) was added to the placebo treatment for 3 weeks (weeks − 3 to 0). Those patients who demonstrated an increase in SDBP ≥ 5 mm Hg from the low to high salt diet were considered salt sensitive and were randomized into a 4-week (weeks 0 to 4) double-blind treatment period of either isradipine 2.5 to 10 mg twice a day, enalapril 2.5 to 20 mg twice a day, or placebo. Then they entered a 3-week (weeks 4 to 7) placebo washout phase of low salt diet (50 to 80 mmol Na + /day). After week 7 and while the low salt diet was continued the patients were restarted on their double-blind treatment for 4 more weeks (weeks 7 to 11) and the study was completed. Of 1916 patients screened, 464 were randomized into the double-blind treatment phase and 397 completed the study. Both isradipine and enalapril decreased the sitting systolic blood pressure (SSBP) and SDBP during the high salt diet, to a similar degree, whereas enalapril caused a greater reduction in SSBP and SDBP than isradipine during the low salt diet (11.3 ± 1.2/7.7 ± 0.7 mm Hg v 7.7 ± 0.9/4.8 ± 0.6 mm Hg, mean ± SEM, respectively, P .02). Within drugs, the effect of isradipine on blood pressure (BP) was higher during the high than the low salt diet (14.9 ± 1.5 v 7.6 ± 1.3 mm Hg for SSBP and 10.1 ± 0.6 v 4.8 ± 0.9 mm Hg for SDBP, P .001), but enalapril exerted a similar effect during both diets. Because salt restriction lowered both SSBP and SDBP, the lowest BP achieved with both drugs were during the salt restriction phase.

Practice PearlThis study demonstrates a clinically important difference between 2 combination-therapy antihypertensive regimens.

Sequence variation in human genes is largely confined to single-nucleotide polymorphisms (SNPs) and is valuable in tests of association with common diseases and pharmacogenetic traits. We performed a systematic and comprehensive survey of molecular variation to assess the nature, pattern and frequency of SNPs in 75 candidate human genes for blood-pressure homeostasis and hypertension. We assayed 28 Mb (190 kb in 148 alleles) of genomic sequence, comprising the 5' and 3' untranslated regions (UTRs), introns and coding sequence of these genes, for sequence differences in individuals of African and Northern European descent using high-density variant detection arrays (VDAs). We identified 874 candidate human SNPs, of which 22% were confirmed by DNA sequencing to reveal a discordancy rate of 21% for VDA detection. The SNPs detected have an average minor allele frequency of 11%, and 387 are within the coding sequence (cSNPs). Of all cSNPs, 54% lead to a predicted change in the protein sequence, implying a high level of human protein diversity. These protein-altering SNPs are 38% of the total number of such SNPs expected, are more likely to be population-specific and are rarer in the human population, directly demonstrating the effects of natural selection on human genes. Overall, the degree of nucleotide polymorphism across these human genes, and orthologous great ape sequences, is highly variable and is correlated with the effects of functional conservation on gene sequences.

A rare case of Wernicke-Korsakoff syndrome due to malnutrition (in a 35-year-old woman) is reported. It was probably the result of a psychiatric condition progressing to severe inanition. In the course of the malnutrition typical Wernicke-Korsakoff syndrome developed. Vitamin B1 deficiency was confirmed by determining erythrocyte transketolase. At the same time there was hypomagnesiaemia; substitution treatment led to complete recovery.

Abstract —Dietary salt restriction is a recommended adjunct with antihypertensive therapy. There may be racial differences in blood pressure response to salt restriction while on antihypertensive therapy. We performed a multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial (black, n=96; Hispanic, n=63; white, n=232). Participants were initially preselected for stage I to III hypertension and then further selected for salt sensitivity (≥5 mm Hg increase in diastolic blood pressure after 3 weeks of low salt [≤88 mmol/d Na + ] and high salt [>190 mmol/d Na + ] diet). We compared the antihypertensive effect of an angiotensin-converting enzyme inhibitor (enalapril 5 or 20 mg BID) or a calcium channel antagonist (isradipine 5 or 10 mg BID) during alternating periods of high and low salt intake. The main outcome measure was blood pressure change and absolute blood pressure level achieved with therapy. During the high salt diet (314.7±107.5 mmol/d urinary Na + ) there was greater downward change in blood pressure with both enalapril and isradipine compared with the low salt diet (90.1±50.8 mmol/d Na + ); however, the absolute blood pressure achieved in all races was consistently lower on a low salt diet for both agents. Black, white, and Hispanic isradipine-treated salt-sensitive hypertensives demonstrated a smaller difference between high and low salt diets (black, −3.6/−1.6 mm Hg; white, −6.2/−3.9 mm Hg; Hispanic, −8.1/−5.3 mm Hg) than did enalapril-treated patients (black, −9.0/−5.3 mm Hg; white, −11.8/−7.0 mm Hg; Hispanic, −11.1/−5.6 mm Hg). On the low salt diet, blacks, whites, and Hispanics had similar blood pressure control with enalapril and isradipine. On the high salt diet, blacks had better blood pressure control with isradipine than with enalapril, whereas there was no difference in the blood pressure control in whites and Hispanics treated with either drug. Dietary salt reduction helps reduce blood pressure in salt-sensitive hypertensive blacks, whites, and Hispanics treated with enalapril or isradipine. These data demonstrate that controlling for salt sensitivity diminishes race-related differences in antihypertensive activity.

The term syndrome X has been applied to the association of hypertension, non-insulin-dependent diabetes mellitus (NIDDM), android obesity, insulin resistance, and dyslipidemia. In this paper, based on population samples from Tecumseh, Michigan, and Hiroshima, Japan, characterized by persons > or = 40 years of age, we examine the validity of regarding this constellation of traits as a true syndrome, i.e., an array of traits with a single, unifying pathophysiology underlying its components. Data were not available on insulin resistance and dyslipidemia, and obesity was expressed as body mass index (BMI) without the division into android and non-android types. The four ethnic-gender data sets were analyzed on the basis of two age classes, age > or = 40 years and age > or = 50 years, and two obesity classes, BMI > or = 27 and > or = 30. A simple chi 2 test of goodness-of-fit under a model of independence revealed non-random associations between hypertension, NIDDM, and BMI which were in part attributable to an excess of persons with all three traits. However, when the four data sets were subjected to separate log-linear analyses of the three-way association tables, none of the three-factor interaction terms (i.e., syndrome X) was significant. High significance was, however, observed in the two-factor interaction term for BMI*hypertension. It is concluded that the significant association between these three traits is driven by the BMI*hypertension interaction, and there is no evidence in these data sets of a significant role for a syndrome X. Genet.

We evaluated time-related blood pressure trends in the Tecumseh study participants, none of whom received antihypertensive treatment. At baseline the blood pressures were measured in the field clinic and by self measurement at home (twice daily for 7 days). After a mean of 3.2 +/- 0.42 years, the clinic and home pressure readings were repeated. Nine hundred forty-six subjects had clinic and home blood pressure readings at baseline. Of these 735 (380 men, 355 women; average age, 32 years) also completed the second examination. Blood pressure, morphometric data, and biochemical measures at the first examination were used as predictors of future clinic blood pressures. Five hundred ninety-six subjects were normotensive on both examinations (81%). Of 79 subjects (10.7%) with clinic hypertension (> 140 mg Hg systolic or 90 mm Hg diastolic) at baseline, 38 remained hypertensive ("sustained hypertension") and 41 became normotensive ("transient hypertension") after 3 years. Another 60 normotensives at baseline (10.4%) became hypertensive on second examination ("de novo hypertensives"; incidence; 8.1%). The home blood pressure readings on both examinations were reproducible. The three hypertensive groups had elevated home blood pressure, were overweight, had dyslipidemia, and higher insulin values. Only the home blood pressure proved predictive of subsequent blood pressure trends. A home blood pressure of 128 and 83 mm Hg or higher detected "sustained" hypertension with a 48% sensitivity and 93% specificity. Readings of 120 and 80 mm Hg or lower predicted future normotension with a 45% sensitivity and a 91% specificity. We conclude that self determination of the blood pressure at home is useful in the management of borderline hypertension. An algorithm for the management of these patients is proposed.

Abstract Non-modulators are a subset of essential hypertensive individuals in whom renal hemodynamic and adrenal aldosterone responses to angiotensin II fail to modulate appropriately during high dietary salt intake. The main aim of this study was to investigate the familial aggregation of non-modulation and several erythrocyte Na + transport systems in normotensive and hypertensive individuals as well as offspring of hypertensive parents. An additional aim was to evaluate the effect of treatment with enalapril on erythrocyte Na + transport. We studied 15 normotensive subjects (6 males, 27±6 years), 14 untreated modulating essential hypertensive subjects (7 males, 38±7 years), 12 untreated non-modulating essential hypertensive subjects (7 males, 38±6 years), 14 modulating offspring of hypertensive parents (8 males, 25±6 years), and 14 non-modulating offspring of hypertensive parents (8 males, 26±4 years). Blood pressure was recorded with an oscillometric device and renal plasma flow and glomerular filtration rate by clearances of para-aminohippurate and inulin, respectively. Non-modulating subjects were identified as individuals who failed to increase effective renal plasma flow by 30% and decrease filtration fraction by at least 30% 10 days after changing from a low (20 mmol/d) to a high (250 mmol/d) sodium intake. Erythrocyte Na + transport was characterized by measurements of the Na + -K + pump, Na + -Li + countertransport, Na + -K + -Cl − cotransport, passive Na + permeability, and Na + content. After the initial studies, hypertensive individuals were treated with enalapril (20 mg/d PO) for 6 months, after which erythrocyte Na + transport measurements were again made. The main findings were that Na + -Li + countertransport is increased in non-modulating hypertensive subjects and non-modulating offspring of hypertensive parents, that the increase in blood pressure in response to high salt intake is greater in non-modulating than modulating hypertensive subjects, and that enalapril decreases Na + -Li + countertransport activity to normal in non-modulating hypertensive subjects. These findings provide support for a possible genetic role in the development of salt sensitivity and suggest that Na + -Li + countertransport and non-modulation are related phenotypes.

The aim of the study was to assess the clinical significance of the blood pressure (BP) reaction to standing in 1029 stage I hypertensives. Office BP was measured six times in the supine position and six times after 2 min of standing. All subjects underwent 24-h ambulatory BP monitoring, and measurements of 24-h urinary epinephrine and norepinephrine excretion. Echocardiography was performed in 636 patients. With use of mixture analysis we could single out a population with abnormal diastolic BP response to standing (hyperreactors, n = 95). These subjects had a diastolic BP increase from lying to standing of >11 mm Hg. The other subjects were defined as normoreactors (n = 934). Office systolic BP was similar in the two groups. Diastolic BP was lower (91 +/- 6 mm Hg v 95 +/- 5 mm Hg, P < .0001) and heart rate was higher in the hyperreactors (77 +/- 10 beats/min v 75 +/- 9 beats/min, P = .004). After adjusting for age, gender, and smoking habits the statistical significance did not change. Adjusted 24-h systolic BP (P = .02) and diastolic BP (P = .02) were higher in the hyperreactors than in the normoreactors. Hyperreactors were characterized by higher cardiac index (3.2 +/- 0.8 L/min/m2 v 3.0 +/- 0.7 L/min/m2, P = .008 for adjusted values), lower total peripheral resistance (1420 +/- 330 dyne/sec/cm(-5) v 1600 +/- 380 dyne/sec/cm(-5), P = .003), and higher urinary norepinephrine output (114.9 +/- 80.3 microg/24 h v 90.6 +/- 78.5 microg/24 h, P = .03). Dimensional echocardiographic data and albumin excretion rate did not differ between the two groups. In conclusion, mixture analysis allowed us to identify a population of young mild hypertensives with exaggerated BP response to standing. Hyperreactors were characterized by higher whole-day BP and by a hyperkinetic hemodynamic pattern as a result of increased sympathetic tone.

This multicenter, randomized, controlled clinical trial assessed the influence of sodium chloride intake on the antihypertensive effect of the calcium channel blocker isradipine. Participants with uncomplicated hypertension controlled by isradipine entered a 4-week sodium-restricted (60 to 80 mmol/24 h) period. Participants with urinary sodium levels120 mmol/24 h (n = 99) were randomized to placebo or sodium chloride (100 mmol/24 h) for 4 weeks, and then crossed over to the alternative treatment for an additional 4 weeks. Mean baseline systolic blood pressure was 151.9 +/- 16.7 mm Hg (mean +/- SD). During open-label isradipine treatment, systolic blood pressures for ad libitum sodium chloride and restriction were 134.1 +/- 11.1 and 132.1 +/- 12.2 mm Hg respectively; for double-blind sodium chloride restriction and supplementation: 133.6 +/- 12.6 and 138.5 +/- 12.8 mm Hg (P.01). Urinary sodium excretion values for open-label isradipine ad libitum versus restricted were 140.6 +/- 61.9 versus 76.9 +/- 32.4 mmol/24 h; for double-blind restricted versus supplemented, sodium excretion was 120.5 +/- 68.9 v 175.9 +/- 68.7 mmol/24 h (Por = .0001). Changes in urinary sodium excretion were not predictive of variations in blood pressure. Urinary sodium excretion during sodium restriction correlated directly with HDL-cholesterol (P.02) and inversely with total cholesterol:HDL-cholesterol (P = .02), despite decreased total and saturated fat intake (P.01). Sodium restriction was associated with significant reductions (P.01) in virtually all macronutrients and electrolytes, and thus had an adverse impact on overall nutrition. The antihypertensive action of isradipine was not enhanced by dietary sodium chloride restriction, and the lipoprotein profile was least favorable with sodium chloride restriction.