Schwartz, Gary L.

Background —Atherosclerosis 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 Results —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. 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. Conclusions —High blood pressure is independently associated with aortic atherosclerosis. Among subjects with atherosclerosis, high blood pressure is associated with complex atherosclerosis.

To identify genes influencing blood pressure response to an angiotensin II receptor blocker, single nucleotide polymorphisms identified by genome-wide association analysis of the response to candesartan were validated by opposite direction associations with the response to a thiazide diuretic, hydrochlorothiazide. We sampled 198 white and 193 blacks with primary hypertension from opposite tertiles of the race-sex–specific distributions of age-adjusted diastolic blood pressure response to candesartan. There were 285 polymorphisms associated with the response to candesartan at P <10 −4 in whites. A total of 273 of the 285 polymorphisms, which were available for analysis in a separate sample of 196 whites, validated for opposite direction associations with the response to hydrochlorothiazide (Fisher χ 2 1-sided P =0.02). Among the 273 polymorphisms, those in the chromosome 11q21 region were the most significantly associated with response to candesartan in whites (eg, rs11020821 near FUT4 , P =8.98×10 −7 ), had the strongest opposite direction associations with response to hydrochlorothiazide (eg, rs3758785 in GPR83 , P =7.10×10 −3 ), and had the same direction associations with response to candesartan in the 193 blacks (eg, rs16924603 near FUT4 , P =1.52×10 −2 ). Also notable among the 273 polymorphisms was rs11649420 on chromosome 16 in the amiloride-sensitive sodium channel subunit SCNN1G involved in mediating renal sodium reabsorption and maintaining blood pressure when the renin-angiotensin system is inhibited by candesartan. These results support the use of genomewide association analyses to identify novel genes predictive of opposite direction associations with blood pressure responses to inhibitors of the renin-angiotensin and renal sodium transport systems.

Recent experimental and clinical studies suggested that apart from playing an essential role in blood pressure homeostasis, aldosterone is involved in the pathophysiology of cardiovascular and renal diseases by inducing structural changes in the heart, kidney, and vessel wall. The interindividual variation of aldosterone response to antihypertensive treatment is considerable, and is at least partially explained by genetic variation. In this study, we investigated aldosterone response to two antihypertensive drugs—a thiazide diuretic and an angiotensin receptor blocker (ARB). Genetic variations in 50 candidate genes were tested for association with aldosterone response in four independent samples: African American (AA) responders to a diuretic ( n = 289), AA responders to an ARB ( n = 252), European American (EA) responders to a diuretic ( n = 295) and EA responders to an ARB ( n = 300). Linear regression was used to test the association with inclusion of age, sex, and body mass index as covariates. The results indicated the existence of one or more variants in the kininogen gene (KNG) that influence interindividual variation in aldosterone response. The significant association was replicated in three of four studied groups. The single nucleotide polymorphism rs4686799 was associated in AA and EA responders to the diuretic ( P = 0.04 and P = 0.07, respectively), and rs5030062 and rs698078 were significantly associated in EA responders to the diuretic ( P = 0.05 and P = 0.01) and EA responders to the ARB ( P = 0.04 and P = 0.02). Although the clinical implication of KNG gene variation to antihypertensive drug response is yet to be determined, this novel candidate locus provides important new insights into drug response physiology.

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.

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.

OBJECTIVE—The aim of the present study was to assess the diagnostic accuracy of the Adult Treatment Panel III (ATP-III) definition of the metabolic syndrome in identifying insulin-resistant individuals and to explore alternative approaches to improve identification of insulin-resistant individuals among asymptomatic adults from the general population. RESEARCH DESIGN AND METHODS—The sample consisted of 256 non-Hispanic white subjects without treated hypertension or diabetes, from the Rochester (Minnesota) Heart Family Study (123 men and 133 women; aged 20–60 years). Frequently sampled intravenous glucose tolerance tests were performed in all subjects. The reference standard for insulin resistance was determined by Bergman’s minimal model; insulin resistance was defined as an insulin sensitivity index &lt;2 × 10 min−1 · μU−1 · ml−1. Component metabolic syndrome measures included blood pressure determined by sphygmomanometer; fasting serum triglycerides, HDL cholesterol, and glucose concentrations determined enzymatically; and waist circumference determined by tape measure. RESULTS—By ATP-III criteria, the prevalence of metabolic syndrome was 15.6% (16.3% in men and 15.1% in women; P = 0.465). The presence of metabolic syndrome had low sensitivity to identify insulin resistance (45% in men and 39% in women; sex difference, P = 0.137) but high specificity (93% in men and 95% in women; sex difference, P = 0.345). Based on the area under the receiver operating characteristic curve (AUC) constructed by counting metabolic syndrome components as recommended by ATP-III, diagnostic accuracy was fair (AUC = 0.797 in men and 0.747 in women). When component metabolic syndrome measures were considered as quantitative traits rather than dichotomized, use of waist circumference alone, rather than counting metabolic syndrome components, improved diagnostic accuracy for insulin resistance (in men, AUC = 0.906, P = 0.001; in women, AUC = 0.822, P = 0.10). CONCLUSIONS—Application of the ATP-III metabolic syndrome criteria provides good specificity but low sensitivity to screen asymptomatic white adults for insulin resistance. Measuring just waist circumference is simpler and may provide greater accuracy for identifying insulin resistance.

Single nucleotide polymorphisms (SNPs) in genes encoding or influencing renal sodium transport systems were investigated as potential predictors of blood pressure (BP) response to a thiazide diuretic. A sample of 585 adults with essential hypertension (30 to 59.9 years of age; 50% blacks; 47% women) were treated with hydrochlorothiazide for 4 weeks (25 mg daily, orally) to determine office BP responses. Ambulatory BP responses were measured in a subset of 228 subjects. After adjustment for ethnicity, sex, age, and waist-to-hip ratio, 3 SNPs in WNK1 (rs2107614, rs2277869, and rs1159744), encoding a lysine-deficient protein kinase that regulates thiazide-sensitive sodium-potassium cotransport, made statistically significant contributions to predicting ambulatory BP responses, accounting for 2% to 4% of variation in systolic and diastolic responses ( P <0.05). SNPs in the β 2 -adrenoceptor (rs2400707) and the epithelial sodium channel γ-subunit (rs5723 and rs5729) were associated with similar magnitude of variation in ambulatory systolic BP response ( P =0.028) or office diastolic BP response ( P <0.05), respectively. However, SNPs evaluated in the furosemide-sensitive sodium-potassium chloride cotransporter, potassium inwardly rectifying channel, chloride channel, thiazide-sensitive sodium chloride cotransporter, epithelial sodium channel β-subunit, and the mineralocorticoid receptor were not associated with significant variation in ambulatory or office BP responses. Polymorphisms in genes regulating renal sodium transport, in particular WNK1 , predict interindividual differences in antihypertensive responses to hydrochlorothiazide.

Abstract Background: The ratio of plasma aldosterone concentration to plasma renin activity (PRA) is considered the screening test of choice for primary aldosteronism. Uncertainty exists, however, regarding its diagnostic accuracy and the effects of antihypertensive drugs and dietary sodium balance on test characteristics. Methods: We measured PRA and aldosterone in 118 white adults [71 men and 47 women; mean (SD) age, 51 (7) years] with previously diagnosed essential hypertension. Measurements were made while individuals were on antihypertensive drug therapy, after a 2-week drug-free period, after 4 days of dietary sodium loading, and after acute furosemide diuresis. We measured 24-h urine aldosterone excretion and PRA on the 4th day of dietary sodium loading to establish the diagnosis of primary aldosteronism. ROC curves were constructed for ratios measured under each clinical condition, and likelihood ratios were determined for individuals on or off antihypertensive drug therapy. Results: Fifteen patients [13%; 95% confidence interval (CI), 7–20%] met the reference standard for primary aldosteronism. The mean (SD) areas under the ROC curves did not differ significantly across conditions of measurement [range, 0.80 (0.10) to 0.85 (0.04); P = 0.72]. When measured on and off antihypertensive drug therapy, the 95% CIs for the optimum cutpoint for the ratio overlapped. Point estimates of sensitivity on and off therapy were 73% (95% CI, 50–96%) and 87% (70–100%), respectively, and specificities were 74% (65–83%) and 75% (66–84%). Under either condition, increased ratios were associated with 2.4- to 13-fold increases of posttest odds above pretest odds. Conclusions: The aldosterone:PRA ratio provides only fair diagnostic accuracy in screening for primary aldosteronism, but concomitant antihypertensive drug therapy or acute variation in dietary sodium balance does not adversely affect test accuracy. Reporting of likelihood ratios associated with ranges of values of the aldosterone:PRA ratio, rather than use of a single “optimum” cutpoint, may enhance the usefulness of the test.