Gary L. Schwartz

C825T Polymorphism of the G Protein β3-Subunit and Antihypertensive Response to a Thiazide Diuretic

The T allele of the C825T polymorphism of the gene encoding the &bgr;3-subunit of G proteins has been associated with increased sodium-hydrogen exchange and low renin in patients with essential hypertension. To assess its association with blood pressure response to diuretic therapy, we measured the C825T polymorphism in 197 blacks (134 men, 63 women) and 190 non-Hispanic whites (76 men, 114 women) with essential hypertension (mean±SD age 48±7 years), who underwent monotherapy with hydrochlorothiazide for 4 weeks. Mean declines in systolic and diastolic blood pressures were 6±2 (P <0.001) and 5±1 (P <0.001) mm Hg greater, respectively, in TT than in CC homozygotes. Responses in heterozygotes were intermediate between the homozygous groups. Other univariate predictors of greater blood pressure responses included black race, female gender, higher pretreatment blood pressure, older age, lower waist-to-hip ratio, and measures of lower renin-angiotensin-aldosterone system activity. After the effects of the other predictors were considered, the TT genotype remained a significant predictor of greater declines in systolic and diastolic blood pressures. Thus, the C825T polymorphism of the G protein &bgr;3-subunit may help identify patients with essential hypertension who are more responsive to diuretic therapy.

Detection and Control of High Blood Pressure in the Community Do We Need a Wake-Up Call?

At the community level, the effect of national programs in increasing hypertension awareness, prevention, treatment, and control is unclear. This study evaluated the degree of detection and control of high blood pressure in a random population-based sample of Olmsted County, Minnesota, residents >/=45 years old, of whom 636 subjects among 1245 eligible residents agreed to participate. Home interview and home and office measurements of blood pressure were used to estimate awareness, treatment, and control rates for hypertension in the community. Mean blood pressures (+/-SD) were 138/80+/-20/12 mm Hg for men and 137/76+/-23/11 mm Hg for women. The overall prevalence of hypertension was 53%. The percentage of subjects with treated and controlled hypertension was 16.6%. Thirty-nine percent of subjects were unaware of their hypertension. Despite clinical trial evidence of reduced morbidity and mortality with antihypertensive therapy, recently reported national data suggest a leveling-off trend for treatment and control of hypertension. This population-based study supports these observations and suggests that at a community level, hypertension awareness and blood pressure control rates are suboptimal, presumably because of decreased attention to the detection and control of hypertension.

Pharmacogenomics of antihypertensive drugs : Rationale and design of the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study

BACKGROUND Selection of antihypertensive therapy is often empiric, and use of genetic information to guide drug therapy selection holds future promise. TRIAL DESIGN The objective of this trial is to identify the genetic determinants of the antihypertensive and adverse metabolic responses to a thiazide diuretic (hydrochlorothiazide), a beta-blocker (atenolol), and their combination. This will be accomplished through candidate gene and genome-wide association approaches. Individuals with uncomplicated hypertension (N = 800), with ages 17 and 65 years, are being enrolled. Current antihypertensive therapy is discontinued, and hypertension is confirmed, along with collection of other baseline data. Subjects are then randomized to either hydrochlorothiazide or atenolol, with 1 dose titration step, followed by assessment of response to therapy after at least 6 weeks on the target dose. Those with blood pressure >120/70 mm Hg have the second drug added, with similar dose titration and response assessment procedures. Data collected include home, office, and 24-hour ambulatory blood pressure. Biological samples collected in the fasting state include plasma, serum, DNA (buffy coat), and urine. Epstein-Barr virus transformed lymphocyte cell lines are also being created. CONCLUSIONS Pharmacogenetic-guided therapy holds clinical potential for hypertension, but the literature in the field is limited. This trial will add substantially to our understanding of the genetic determinants of antihypertensive and adverse metabolic responses to 2 commonly used antihypertensive drug classes.

Effects of endothelial nitric oxide synthase, α-adducin, and other candidate gene polymorphisms on blood pressure response to hydrochlorothiazide

BACKGROUND Pharmacogenetic discoveries may enable greater individualization of antihypertensive drug therapy. We investigated polymorphisms in the genes encoding endothelial nitric oxide synthase (Glu298-->Asp), alpha-adducin (Gly460-->Trp), the beta(1)-adrenoceptor (Arg389-->Gly), beta2-adrenoceptor (Arg16-->Gly), and lipoprotein lipase (Ser447-->Stop) for their potential influences on blood pressure (BP) response to a thiazide diuretic. METHODS The sample consisted of 291 unrelated non-Hispanic African American adults (150 women and 141 men) and 294 unrelated non-Hispanic white adults (126 women and 168 men) who were between 30 and 59.9 years of age and who had essential hypertension. Previous antihypertensive drug therapy was withdrawn for at least 4 weeks, and subjects were then treated with hydrochlorothiazide (25 mg daily) for 4 weeks to determine BP response. RESULTS The covariates of ethnicity, gender, age, and waist-to-hip ratio accounted for 26% of interindividual variation in systolic BP response and 11% of interindividual variation in diastolic BP response. After adjustment for covariates, the endothelial nitric oxide synthase Glu298-->Asp polymorphism made an additional statistically significant contribution to predicting diastolic BP response to hydrochlorothiazide, accounting for another 1% of interindividual variation in response (P =.034). In contrast, the other polymorphisms, including the alpha-adducin Gly460-->Trp polymorphism, made no statistically significant contributions to prediction of BP response. CONCLUSIONS Although we reject the null hypothesis of no genetic effects on BP response to hydrochlorothiazide, the influence of variation at single sites is likely to be small. More extensive characterization of genetic variation is required for pharmacogenetic approaches to become clinically useful in tailoring antihypertensive drug therapy for individual patients.

Independent Association of High Blood Pressure and Aortic Atherosclerosis A Population-Based Study

BackgroundAtherosclerosis of the thoracic aorta is associated with stroke. The association between hypertension, a major risk factor for stroke, and aortic atherosclerosis has not been determined in the general population. Methods and ResultsTransesophageal echocardiography was performed in 581 subjects, a random sample of the Olmsted County (Minnesota) population aged ≥45 years participating in the Stroke Prevention: Assessment of Risk in a Community (SPARC) study. Blood pressure was assessed by multiple office measurements and 24-hour ambulatory blood pressure monitoring. The association between blood pressure variables and aortic atherosclerosis was evaluated by multiple logistic regression, adjusting for other associated variables. Among subjects with atherosclerosis, blood pressure variables associated with complex aortic atherosclerosis (protruding plaques ≥4 mm thick, mobile debris, or ulceration) were determined. Age and smoking history were independently associated with aortic atherosclerosis of any degree (P ≤0.001) and with complex atherosclerosis (P =0.002), whereas sex, diabetes mellitus, and body mass index were not. Multiple systolic and pulse pressure variables (office and ambulatory), but none of the diastolic blood pressure variables, were associated with atherosclerosis and complex atherosclerosis, adjusting for age and smoking. Among subjects with atherosclerosis, the odds of complex atherosclerosis increased as ambulatory out-of-bed systolic blood pressure increased (odds ratio 1.43 per 10 mm Hg increase, 95% CI 1.10 to 1.87) and with hypertension treatment, adjusting for age and smoking history. ConclusionsHigh blood pressure is independently associated with aortic atherosclerosis. Among subjects with atherosclerosis, high blood pressure is associated with complex atherosclerosis.

Relation of coronary artery disease and cerebrovascular disease with atherosclerosis of the thoracic aorta in the general population

The association between clinical coronary artery disease, cerebrovascular disease, and aortic atherosclerosis has not been examined in the general population. Transesophageal echocardiography was performed in 581 subjects, a random sample of the Olmsted County (Minnesota) population aged >/=45 years, participating in the Stroke Prevention: Assessment of Risk in a Community (SPARC) study. The frequency and severity of atherosclerosis of the thoracic aorta were determined in the population and the association between clinical coronary artery disease, cerebrovascular disease, and aortic atherosclerosis was examined. Previous myocardial infarction, angina pectoris, and coronary artery bypass surgery were significantly associated with aortic atherosclerosis, adjusting for age and gender (p </=0.01). Among subjects with atherosclerosis, these manifestations were associated with complex atherosclerosis (plaques >4-mm thick, ulcerated plaques, or mobile debris), adjusting for age and gender (p <0.05). Age, smoking, pulse pressure, previous myocardial infarction (odds ratio [OR] 4.67; 95% confidence interval [CI] 1.42 to 15.40), and coronary artery bypass surgery (OR 5.12; 95% CI 1.01 to 26.01) were independently associated with aortic atherosclerosis. Among subjects with atherosclerosis, age, smoking, pulse pressure, hypertension treatment, and coronary artery disease (OR 2.50; 95% CI 1.18 to 5.30) were independently associated with complex atherosclerosis. Weak associations were observed between previous ischemic stroke, transient ischemic attack, and aortic atherosclerosis, associations that were not significant after age- and gender-adjustment (p >0.2). Thus, coronary artery disease is strongly associated with aortic atherosclerosis and complex atherosclerosis in the general population. Cerebrovascular disease is weakly associated with aortic atherosclerosis, thereby questioning the overall importance of aortic atherosclerosis in the pathogenesis of cerebrovascular events in the general population.

Genomic Association Analysis Suggests Chromosome 12 Locus Influencing Antihypertensive Response to Thiazide Diuretic

We conducted a genome-wide association study to identify novel genes influencing diastolic blood pressure (BP) response to hydrochlorothiazide, a commonly prescribed thiazide diuretic preferred for the treatment of high BP. Affymetrix GeneChip Human Mapping 100K Arrays were used to measure single nucleotide polymorphisms across the 22 autosomes in 194 non-Hispanic black subjects and 195 non-Hispanic white subjects with essential hypertension selected from opposite tertiles of the race- and sex-specific distributions of age-adjusted diastolic BP response to hydrochlorothiazide (25 mg daily, PO, for 4 weeks). The black sample consisted of 97 “good” responders (diastolic BP response [mean±SD]=−18.3±4.2 mm Hg; age=47.1±6.1 years; 51.5% women) and 97 “poor” responders (diastolic BP response=−0.18±4.3; age=47.4±6.5 years; 51.5% women). Haplotype trend regression identified a region of chromosome 12q15 in which haplotypes constructed from 3 successive single nucleotide polymorphisms (rs317689, rs315135, and rs7297610) in proximity to lysozyme (LYZ), YEATS domain containing 4 (YEATS4), and fibroblast growth receptor substrate 2 (FRS2) were significantly associated with diastolic BP response (nominal P=2.39×10−7; Bonferroni corrected P=0.024; simulated experiment-wise P=0.040). Genotyping of 35 additional single nucleotide polymorphisms selected to “tag” linkage disequilibrium blocks in these genes provided corroboration that variation in LYZ and YEATS4 was associated with diastolic BP response in a statistically independent data set of 291 black subjects and in the sample of 294 white subjects. These results support the use of genome-wide association analyses to identify novel genes influencing antihypertensive drug responses.

Validity of the aldosterone-renin ratio used to screen for primary aldosteronism

OBJECTIVE To determine whether the calculated ratio of plasma aldosterone concentration (PAC) to plasma renin activity (PRA), a proposed screening test for primary aldosteronism, provides a renin-independent measure of circulating aldosterone that is suitable to judge whether PAC is inappropriately elevated relative to PRA. SUBJECTS AND METHODS This study consisting of 221 black and 276 white subjects with previously diagnosed essential hypertension was conducted between 1996 and 2000. Antihypertensive drugs were withdrawn for at least 4 weeks; PAC and PRA were measured while subjects were supine and then seated after 30 minutes of ambulation. The seated measurements were repeated after 4 weeks of oral diuretic therapy with hydrochlorothiazide (25 mg/d). RESULTS The variation in the aldosterone-renin ratio was strongly and inversely dependent on PRA (R2=0.71; P<.001). When subjects changed position from supine to seated, the increase in mean +/- SD PRA (from 1.18 +/- 1.06 to 1.31 +/- 1.19 ng x mL(-1) x h(-1); P<.001) was associated with an increase in the mean ratio (from 18.6 +/- 52.8 to 25.8 +/- 38.1 h x 10(2); P<.001), whereas the increase in mean +/- SD PRA in response to diuretic therapy (from 1.31 +/- 1.19 to 2.72 +/- 2.67 ng x mL(-1) x h(-1); P=.007) was associated with a decrease in the mean ratio (from 25.8 +/- 38.1 to 16.4 +/- 31.6 h 10(2); P<.001). CONCLUSION In patients with previously diagnosed essential hypertension, calculation of the aldosterone-renin ratio does not provide a renin-independent measure of circulating aldosterone that is suitable for determining whether PAC is elevated relative to PRA. Because elevation of the aldosterone-renin ratio is predominantly an indicator of low PRA, its perceived value in screening for primary aldosteronism most likely derives from additional diagnostic tests being done in patients with low-renin hypertension.

Association of Ambulatory Blood Pressure With Ischemic Brain Injury

Cerebral white matter hyperintensities on brain MRI (leukoaraiosis) are associated with increased risk of stroke and dementia. To assess the relationships of blood pressure level and circadian pattern with leukoaraiosis, we obtained 24-hour ambulatory blood pressure recordings and brain magnetic resonance images in 343 white and 267 black adults who were members of sibships that had ≥2 siblings with essential hypertension. In multiple linear regression models, factors associated with greater leukoaraiosis in both racial groups included age (P≤0.002), homocysteine levels (P≤0.006), and brain volume (P≤0.008). In blacks, ambulatory blood pressure measures associated with greater leukoaraiosis were higher awake, asleep, and 24-hour systolic and diastolic levels (P≤0.009 for each). In addition, there was a trend for smaller nocturnal declines in systolic and diastolic levels (ie, nondipping patterns) to be associated with greater leukoaraiosis, and all of these associations, except nondipping of diastolic level, remained or became significant after controlling for office blood pressure (P<0.05 for each). In whites, among ambulatory blood pressure measures, only higher asleep diastolic levels trended toward association with greater leukoaraiosis. However, similar to findings in blacks, nondipping of systolic and diastolic ambulatory blood pressure levels were each associated with greater leukoaraiosis (P≤0.008), and all of these associations remained or became significant after controlling for office blood pressure (P≤0.009 for each). Higher ambulatory blood pressure levels and a nondipping circadian pattern contribute to greater leukoaraiosis volume after controlling for office blood pressure.

For estimating creatinine clearance measuring muscle mass gives better results than those based on demographics

Estimation of creatinine clearance requires knowledge of creatinine generation which can vary in different groups of patients. Since the main source of creatinine is muscle we used dual-energy X-ray absorptiometry to measure the mass of muscle in a cohort of adult men and women in Rochester, Minnesota. Serum and 24 h urinary creatinines were measured directly. The urinary creatinine was estimated using equations based on age and gender and muscle mass in order to calculate creatinine clearance. Among 664 subjects with a mean age of 55+/-20 years, 51% of whom were women, the model fit for urinary creatinine estimated with age and gender (R2=0.359) was similar to that estimated with measured muscle mass (R2=0.359). The likelihood of chronic kidney disease (creatinine clearance of less than 60 ml/min per 1.73 m2) in older subjects was highest with equations that used age, and likelihood of CKD in women was highest with equations that used gender. The outcomes of mortality and cardiovascular disease had stronger associations with decreased creatinine clearance calculated with age and gender than by the clearance calculated with muscle mass. This could be explained by age being a potent predictor of mortality and cardiovascular disease independent of urinary creatinine, muscle mass, and gender. Our study shows that the likelihood of chronic kidney disease in the elderly and in women and the risk of adverse outcomes may be inflated by equations that use patient demographics to estimate creatinine generation.