Calcium Antagonism Abolishes the Antipressor Action of Vasopressin (V1) Receptor Antagonism

Previous studies demonstrate that vasopressin (V₁) receptor antagonism lowers arterial pressure in blacks. This action of V₁ receptor blockade may be mediated through various mechanisms including changes in intracellular calcium fluxes. This study was undertaken to test the hypothesis that inhibition of calcium entry may attenuate the reduction in arterial pressure observed with V₁ receptor blockade. Sixteen hypertensive patients, 8 whites and 8 blacks, were examined. Each had their antihypertensive therapy stopped for 1 week. Following three baseline blood pressure measurements, all patients were given an intravenous bolus injection of a V₁ receptor antagonist. Blood pressure was monitored every 10 min for a period of 3 h. Subjects were then randomized to either 0.2 mg clonidine twice daily or 300 mg diltiazem CD daily for a period of 3 days and the previous experiments repeated. Patients were then crossed over to the other drug for an additional 3 days and the experiments repeated. There was a significant reduction from baseline in the mean arterial pressure among blacks but not whites (−11 ± 3 Δmm Hg blacks versus −1 ± 2 Δmm Hg whites, P < .01). In the presence of clonidine, there were similar reductions in arterial pressure in both groups (P = .026) with a further reduction following V₁ receptor blockade only in the blacks (−7 ± 3 Δmm Hg blacks versus 6 ± 2 Δmm Hg whites; P < .001). Conversely, in the presence of diltiazem CD, there were no further reductions in arterial pressure in either group following the V₁ receptor antagonist. We conclude that calcium channel blockade abolishes the blood pressure lowering response of V₁ receptor blockade in blacks.     

Continuous and intermittent walking alters HDL(2)-C and LCATa

Purpose

The purpose of this study was to determine if exercise, whether continuous (CE: completed all in one session) or intermittent (completed in either two (IE 2) or three (IE 3) exercise sessions) expending the same number of calories alters reverse cholesterol transport or low density lipoprotein (LDL) particle size.

Methods

Sixteen healthy (22 ± 2.1 year old) men (VO₂ max = 37.0 ± 3.3 mL/kg/min) randomly completed three exercise trials, CE, IE 2 and IE 3, expending 450 calories. Blood samples were drawn immediately post-exercise (IPE) and 24 and 48 h following exercise and analyzed for total cholesterol (TC), triglycerides (TG), low density lipoprotein (LDL-C), high density lipoprotein (HDL-C) and subfractions (HDL₂-C, HDL₃-C). Samples were also analyzed to determine LDL-C particle size, lecithin cholesterol acyl transferase activity (LCATa) and cholesterol ester transfer protein activity (CETPa).

Results

HDL₂-C increased significantly 48 h post-exercise in the CE and IE 2 groups. Additionally, the IE 3 group had significant increases in HDL₂-C at 24 (39%) and 48 h post-exercise by 66%. This change in HDL₂-C was significantly and positively correlated (r = 0.62; p < 0.05) to the changes in LCATa which increased compared to baseline at 48 h post-exercise in the CE and IE 3 groups. No significant changes in LDL particle size or alterations in CETPa were seen.

Conclusions

The results of this study indicate that whether the exercise is continuous or intermittent, keeping calorie expenditure the same, causes significant changes in the HDL₂-C subfraction, which was augmented by an increase in LCATa.     

ω-3 Fatty acids selectively raise high-density lipoprotein 2 levels in healthy volunteers

The effects of ω-3 fatty acid supplementation on high-density lipoprotein (HDL) subfraction distribution and composition were evaluated in five healthy volunteers taking 2.8g/d of eicosapentaenoic acid (EPA) and 1.7g/d of docosahexaenoic acid (DHA) for 6 weeks. This supplementation resulted in marked changes of the plasma fatty acid composition. Plasma total cholesterol (TC), HDL-cholesterol (HDL-C), and triglyceride (TG) levels did not change. HDL₂-C increased by 74%, with a concomitant 19% decrease of HDL₃-C; the HDL₂ to HDL₃ mass ratio increased from 0.30 ± 0.19 to 0.47 ± 0.28. The increase of HDL₂ was confirmed by nondenaturing polyacrylamide gradient gel electrophoretic separation of HDL subclasses, otherwise showing no change in HDL particle size. After ω-3 supplementation, both HDL₂ and HDL₃ became cholestryl ester (CE)- and TG-enriched and free cholesterol (FC)- and phospholipid (PL)-depleted. The reported findings provide a useful adjunct to the antithrombotic potential of ω-3 fatty acids.     

HDL2-cholesterol/HDL3-cholesterol ratio was associated with insulin resistance,high-molecular-weight adiponectin,and components for metabolic syndrome in Japanese

AimsRecent data have suggested a relationship between the high-density lipoprotein (HDL) subclass ratio and metabolic syndrome (MetS). However, limited information is available regarding the relationships between the HDL subclass ratio and insulin resistance, associated adipocytokine levels, and MetS components. The associations of the high-density lipoprotein 2 cholesterol (HDL₂-C) to high-density lipoprotein 3 cholesterol (HDL₃-C) ratio with the homeostasis model assessment of insulin resistance (HOMA-IR) index, high-molecular-weight adiponectin (HMW-Ad) levels, and MetS components were examined.MethodsThe study included 1155 Japanese subjects who met our inclusion criteria and underwent an annual health examination that included an HDL subclass analysis.ResultsThe HDL₂-C/HDL₃-C ratio and the HMW-Ad level gradually decreased as the number of MetS components increased. In contrast, HOMA-IR gradually increased as the number of MetS components increased. The HDL₂-C/HDL₃-C ratio correlated inversely with HOMA-IR and positively with the HMW-Ad level. A strong positive correlation was observed between the HDL₂-C/HDL₃-C ratio and the HDL-C level. The HDL₂-C/HDL₃-C ratio exhibited moderate negative correlations with the body mass index, waist circumference, and triglyceride level. Weak negative correlations were observed for the HDL₂-C/HDL₃-C ratio with the systolic and diastolic blood pressure and fasting plasma glucose levels.ConclusionsOur data indicated that the HDL₂-C/HDL₃-C ratio was associated with insulin resistance, the HMW-Ad level, and MetS components, and it was useful for evaluating MetS in Japanese individuals.     

HDL associates with insulin resistance and beta-cell dysfunction in South Asian families at risk of type 2 diabetes

ObjectiveDyslipidemia precedes type 2 diabetes (T2D) and worsens with increasing glucose intolerance. First degree relatives of T2D patients have an increased risk to develop dyslipidemia and glucose intolerance. The aim of the present study was to assess the relation between the development of dyslipidemia and glucose intolerance in first-degree relatives of T2D patients.Research design and methodsFasting lipoprotein profiles were determined by density gradient ultracentrifugation in T2D patients and their first-degree relatives (42 Caucasians and 33 South Asians), and in 29 normoglycemic controls from non-T2D families. Glucose tolerance, insulin sensitivity index (ISI) and insulin disposition index (DI) were assessed by an extended, frequently sampled oral glucose tolerance test (OGTT), and fractional insulin synthesis rate (FSR) was measured by ¹³C-leucine enrichment in urinary C-peptide during the OGTT.ResultsOf the first-degree relatives, 40, 16 and 19 had NGT, prediabetes and T2D, respectively. NGT family members had lower plasma HDL-cholesterol (HDLC) (1.34 ± 0.07 vs 1.58 ± 0.06 mmol/L; p = 0.015), HDL₂-C (0.41 ± 0.05 vs 0.57 ± 0.05 mmol/L; p = 0.021) and HDL₃-C (0.62 ± 0.03 vs 0.72 ± 0.02 mmol/L; p = 0.043) than controls. HDL₂-C levels tended to decrease with increasing glucose intolerance state. In South Asians, buoyant LDL-C levels decreased with increasing glucose intolerance state (p = 0.006). In South Asian families, HDL-C correlated with both ISI and DI (β 0.42; p = 0.04 and β 0.53; p = 0.01, respectively), whereas HDL₂-C and HDL₃-C levels correlated with DI (β 0.64; p = 0.002 and β 0.57; p = 0.005, respectively). HDL₂-C and plasma triglyceride correlated with FSR (β 0.48; p = 0.033 and β −0.50; p = 0.029, respectively).ConclusionsLow HDL₂-C and HDL₃-C levels are present in NGT first-degree relatives of T2D patients, and HDL₂-C tend to decrease further with increasing glucose intolerance. In South Asian families HDL₂-C and HDL₃-C levels linked predominantly to deteriorating beta cell function.     

HDL3-C is a Marker of Coronary Artery Disease Severity and Inflammation in Patients on Statin Therapy

IntroductionLow high-density lipoprotein (HDL-C) and inflammation are risk factors for coronary artery disease (CAD). However, limited data are available determining the role of HDL-C sub-particles HDL₂-C and HDL₃-C for assessing CAD severity in patients on statin therapy.MethodsBlood samples were obtained prior to cardiac catheterization in 304 consecutive patients with suspected CAD on statin therapy in this sub-analysis of Multi-Analyte, thrombogenic, and Genetic Markers of Atherosclerosis (MAGMA, NCT01276678) study. Detailed lipid profiling and oxidized LDL (ox-LDL) were analyzed. CAD severity was angiographically defined as severe CAD (>75% luminal diameter stenosis [LDS]) and non-severe CAD (≤75% LDS). Multi-regression analysis was performed to test for statistical significance. Receiver operator curve (ROC) analysis was performed to determine cut-point for predicting severe CAD.ResultsPatients with severe CAD had a significantly lower total-HDL-C, lower HDL₃-C and higher lipoprotein(a) levels. HDL₃-C and lipoprotein(a) cholesterol [Lp(a)-C] retained statistical significance on multiple regression analysis. ROC analysis showed HDL₃-C to have a C-statistic of 0.60 (p = 0.003) and Lp(a)-C to have a C-statistic of 0.61 (p = 0.0007). Patients with HDL₃-C ≤ 33 mg/dL and Lp(a)-C > 7 mg/dL were found to have significantly elevated ox-LDL levels.ConclusionIn patients on statin therapy, HDL₃-C and Lp(a)-C improve prediction of severe CAD compared to a traditional lipid panel. In addition, patients with HDL₃-C ≤ 33 mg/dL and Lp(a)-C > 7 mg/dL have greater inflammation marked by ox-LDL. Further studies are needed to evaluate the utility of these novel biomarkers in predicting CAD severity.     

Urinary sodium and potassium profile of blacks and whites in relation to education in two different geographic urban areas

The high Na/low K environment of modern society is related to the genesis of hypertension and stroke. There is prior evidence of racial, geographical, and social class differences in Na and K intake and blood pressure. Baseline data from the Treatment of Mild Hypertension Study (TOMHS) was used to assess urinary Na and K excretion profiles by race, clinic geographic area, and education. Participants were adult black and white hypertensive patients from the Birmingham, Alabama, and Chicago, Illinois, area. Level of education was categorized as: less than college graduate and college graduate or more. Two overnight urine samples were collected and analyzed for Na and K at entry from 154 blacks and 281 whites. The urinary Na:K ratio was significantly higher in both blacks (5.1 v 3.8, P < .001) and whites (4.1 v 3.4, P < .005) in Birmingham compared with Chicago. This was primarily due to the lower excretion of urinary K in blacks (12.8 v 16.9 mmol/8 h, P < .01) and whites (14.0 v 16.5 mmol/8 h, P < .01). The highest urinary Na:K ratio was observed in blacks in Birmingham with lower education level; urinary Na excretion was high in blacks with a lower education level in both cities. No such differences were seen in whites. Although TOMHS was not population-based, these findings suggest the possibility that potassium intake among persons with stage 1 hypertension is related to geographic area in both blacks and whites, and sodium intake is inversely related to education level in blacks.     

Whites and Blacks Have Similar Risk of Metachronous Advanced Colorectal Neoplasia

Background

Current guidelines for surveillance of colonic neoplasia are based on data from predominantly white populations, yet whether these recommendations are applicable to blacks is unknown.

Aim

To define the prevalence of advanced colorectal neoplasia (ACN) among whites and blacks undergoing surveillance colonoscopy.

Methods

This was a retrospective, cross-sectional analysis of asymptomatic, average-risk non-Hispanic white (N = 246) and non-Hispanic black (N = 203) patients with colorectal neoplasia who underwent baseline screening colonoscopy between January 1, 2000, and December 31, 2007, and a surveillance colonoscopy before December 31, 2010, at an academic safety-net hospital. The main outcome measure was the prevalence of ACN, defined as a tubular adenoma or sessile serrated adenoma (SSA) ≥10 mm, any adenoma with villous histology or high-grade dysplasia, any serrated lesion with dysplasia, or invasive cancer at surveillance.

Results

During a median follow-up of 4.3 years, the overall prevalence of ACN at surveillance was similar among blacks and whites (11.3 vs. 9.8 %; P = 0.59) with an odds ratio of 1.18 (95 % CI 0.65–2.26). Blacks and whites with non-advanced neoplasia had similar rates of ACN at the 1–3, 4–5, and >5 year follow-up intervals. Blacks with ACN or multiplicity at baseline had higher rates of ACN at the 1- to 3-year interval compared with whites, but the difference was non-significant (26.7 vs. 12.5 %; P = 0.32). No interval cancers were observed for either group.

Conclusions

The overall prevalence of ACN was similar between non-Hispanic blacks and non-Hispanic whites undergoing surveillance in a safety-net healthcare setting suggesting that current surveillance guidelines are appropriate for both blacks and whites.     

Effects of transdermal 17β-oestradiol combined with oral progestogen on lipids and lipoproteins in hypercholesterolaemic postmenopausal women

Abstract. Objectives. The purpose of the study was to evaluate the effect of transdermal 17β-oestradiol with oral progestogen on the plasma levels of lipids, lipoproteins and apolipoproteins in hypercholesterolaemic postmenopausal women. Design. During 6 months of replacement therapy with transdermal 17β-oestradiol combined with oral progestogen, plasma lipids, lipoproteins and apolipoproteins after 3 and 6 months were measured and compared with pretreatment values by Student's t-test. Setting. From January 1992 until September 1992 patients were diagnosed and treated in an outpatient clinic of the Department of Endocrinology Medical Centre for Postgraduate Education, Warsaw. Subjects. The patients studied were 11 non-obese postmenopausal women with hypercholesterolaemia based on the World Health Organization criteria. Interventions. Venous blood samples were obtained before and 3 and 6 months after the beginning of cyclic replacement therapy with transdermal 17β-oestradiol (E2 100 μg day^?1 combined with oral chlormadinone acetate (2 mg day^?1 for 7 days in each cycle). Main outcome measures. The antiatherogenic effect of transdermal oestrogen replacement therapy exerted by increased levels of high-density lipoprotein sub-fraction 2 cholesterol (HDL₂-C) leading to the decrease of the total cholesterol level was anticipated. Results. After 6 months of the treatment the concentrations of HDL₂ cholesterol (HDL₂-C) increased from 0.45 ± 0.07 mmol l^?1 to 0.73 ± 0.03 mol l^?1 (P < 0.05) but the levels of HDL₃ cholesterol (HDL₃-C) decreased from 1.15 ± 0.06 mmol l^?1 to 0.89 ± 0.07 mmol l^?1 (P < 0.05). The concentrations of total cholesterol decreased from 6.9 ± 0.13 mmol l^?1 to 6.2 ± 0.2 mmol l^?1 (P < 0.05). No changes were observed in the plasma levels of total triglycerides, HDL cholesterol, low-density lipoprotein (LDL) cholesterol, very-low-density lipoprotein (VLDL) cholesterol, VLDL triglycerides, apolipoproteins A-I and B. Conclusions. In hypercholesterolaemic postmenopausal women, transdermally administered 17β-oestradiol 100 μg daily in combination with oral chlormadinone acetate has a beneficial effect through raising the level of the antiatherogenic HDL₂-C subfraction and decreasing the level of total cholesterol.     

Relation of age and race with hospital death after acute myocardial infarction

Background

Prior studies have suggested that young blacks with acute myocardial infarction (AMI) may have higher hospital mortality rates than whites of similar age. However, the influence of age and race on short-term death has not been explored in detail. We examined the relation of age and race on short-term death in a large AMI population and ascertained the factors that may have contributed to differences in mortality rates.

Methods

We compared the crude and adjusted hospital mortality rates stratified by age among 40,903 blacks and 501,995 whites with AMI enrolled in the National Registry of Myocardial Infarction-2 in 1482 participating US hospitals from June 1994 through March 1998.

Results

Overall crude mortality was lower among blacks compared with whites (10.9% vs 12.0%, P < .0001). However, blacks had a significantly higher crude mortality rate compared with the whites in the age groups <65 years (<45 years, and 5-year age groups between 45 and 64 years). There was a statistically significant interaction between age and black race on hospital death (P value for interaction <.001). Each 5-year decrement in age from 85 years was associated with 7.2% higher odds of death in blacks compared with whites (95% CI, 5.7% to 7.6%). After adjusting for differences in the baseline, clinical presentation, early treatment, and hospital characteristics, 5-year decrements in age was still associated with increases in the odds for death in blacks compared with whites (5.4%; 95% CI, 3.6% to 7.2%). This interaction between age and black race was present in both sexes but was stronger among men.

Conclusions

Blacks younger than 65 years had higher hospital mortality rates compared with whites hospitalized for AMI, and decreasing age was associated with progressively higher risk of hospital death for blacks. Differences in the clinical presentation, early treatment, and hospital characteristics could only partly explain this age-race interaction.     

Relationship between apolipoprotein C-III concentrations and high-density lipoprotein subclass distribution

High-density lipoprotein (HDL) subclasses have different antiatherogenic potentials and functional properties. This work presents our findings and discussions on their metabolic implications on apolipoprotein (apo) C-III together with other apolipoprotein levels and HDL subclass distribution profile. Apolipoprotein A-I contents of plasma HDL subclasses were quantitated by 2-dimensional gel electrophoresis coupled with immunodetection in 511 subjects. Concentrations of triglycerides and of apo B-100, C-II, and C-III were higher, whereas those of HDL cholesterol were lower, for subjects in the highest tertile of apo C-III levels group, which presented a typical hypertriglyceridemic lipid profile. Subjects in the middle and highest tertile of apo C-III levels groups had increased preβ₁-HDL, HDL_3c, HDL_3b (only in the highest tertile of apo C-III group), and HDL_3a, but decreased HDL_2a and HDL_2b contents compared with subjects in the lowest tertile of apo C-III levels group. With the elevation of apo C-III together with apo C-II levels, contents of small-sized preβ₁-HDL increased successively and significantly; but those of large-sized HDL_2b reduced successively and significantly. With a rise in apo C-III and apo A-I levels, those of preβ₁-HDL increased significantly. Moreover, subjects with high apo A-I levels showed a substantial increase in HDL_2b; on the contrary, HDL_2b declined progressively and obviously for subjects in the low apo A-I levels with the elevation of apo C-III levels. Correlation analysis illustrated that apo C-III levels were positively associated with preβ₁-HDL, preβ₂-HDL, and HDL_3a. The particle size of HDL shifted toward smaller sizes with the increase of plasma apo C-III levels, and the shift was more remarkable when the elevation of apo C-III and apo C-II was simultaneous; and besides, higher apo A-I concentrations could modify the effect of apo C-III on HDL subclass distribution profile. Large-sized HDL_2b particles decreased greatly for hypertriglyceridemic subjects who were characterized by elevated apo C-III and C-II accompanied with significantly lower apo A-I, which, in turn, blocked the maturation of HDL.     

Growth of uterine leiomyomata among premenopausal black and white women

Uterine leiomyomata (fibroids) are the leading cause of hysterectomy in the United States. Black women have a greater fibroid burden than whites, yet no study has systematically evaluated the growth of fibroids in blacks and whites. We prospectively tracked growth for 262 fibroids (size range: 1–13 cm in diameter) from 72 premenopausal participants (38 blacks and 34 whites). Fibroid volume was measured by computerized analysis of up to four MRI scans over 12 months. We used mixed effects models to identify factors that are associated with growth, and results were converted to percent change per 6 months for clinical relevance. The median growth rate was 9% (range: −89% to +138%). Seven percent of fibroids regressed (>20% shrinkage). Tumors from the same woman grew at different rates (within-woman component of variation was twice the component among women; both were significant, P < 0.001). Black and white women less than 35 years of age had similar fibroid growth rates. However, growth rates declined with age for whites but not for blacks (P = 0.05). The odds of a tumor growing more than 20% in 6 months also decreased with age for whites but not for blacks (P < 0.01). Growth rates were not influenced by tumor size, location, body mass index, or parity. We conclude that (i) spontaneous regression of fibroids occurs; (ii) fibroids from the same woman grow at different rates, despite a uniform hormonal milieu; (iii) fibroid size does not predict growth rate; and (iv) age-related differences in fibroid growth between blacks and whites may contribute to the higher symptom burden for black women.     

Diabetes and age-related demographic differences in risk factor control

Disparate vascular outcomes in diabetes by race and/or ethnicity may reflect differential risk factor control, especially pre-Medicare. Assess concurrent target attainment for glycohemoglobin <7%, non–high density lipoprotein-cholesterol <130 mg/dL, and blood pressure <140/<90 mm Hg in white, black, and Hispanic diabetics <65 years and ≥65 years of age. The National Health and Nutrition Examination Surveys 1999–2010 data were analyzed on diagnosed and undiagnosed diabetics ≥18 years old. Concurrent target attainment was higher in whites (18.7%) than blacks (13.4% [P = .02] and Hispanics [10.3%, P < .001] <65 years but not ≥65 years of age; 20.0% vs. 15.9% [P = .13], 19.5% [P = .88]). Disparities in health care insurance among younger whites, blacks, and Hispanics, respectively, (87.4% vs. 81.1%, P < .01; 68.0%, P < .001) and infrequent health care (0–1 visits/y; 14.3% vs. 15.0%, P = not significant; 32.0%, P < .001) declined with age. Cholesterol treatment predicted concurrent control in both age groups (multivariable odds ratio >2, P < .001). Risk factor awareness and treatment were lower in Hispanics than whites. When treated, diabetes and hypertension control were greater in whites than blacks or Hispanics. Concurrent risk factor control is low in all diabetics and could improve with greater statin use. Insuring younger adults, especially Hispanic, could raise risk factor awareness and treatment. Improving treatment effectiveness in younger black and Hispanic diabetics could promote equitable risk factor control.     

Reasons for Differences in the Incidence of Venous Thromboembolism in Black Versus White Americans

IntroductionVenous thromboembolism incidence rates are 30%-100% higher in US blacks than whites. We examined the degree to which differences in the frequencies of socioeconomic, lifestyle, medical risk factors, and genetic variants explain the excess venous thromboembolism risk in blacks and whether some risk factors are more strongly associated with venous thromboembolism in blacks compared with whites.MethodsWe measured venous thromboembolism risk factors in black and white participants of the Atherosclerosis Risk in Communities study in 1987-1989 and followed them prospectively through 2015 for venous thromboembolism incidence.ResultsOver a mean of 22 years, we identified 332 venous thromboembolisms in blacks and 578 in whites, yielding 65% higher crude incidence rates per 1000 person-years in blacks. The age and sex-adjusted hazard ratio (95% confidence interval) of venous thromboembolism for blacks compared with whites was 2.04 (1.76, 2.37) for follow-up > 10 years and was attenuated to 1.14 (0.89, 1.46) when adjusted for baseline confounders or mediators of the race association, which tended to be more common in blacks. For example, adjustment for just baseline weight, family income, and concentration of plasma factor VIII reduced the regression coefficient for race by 75%. There were no significant (P < 0.05) 2-way multiplicative interactions of race with any risk factor, except with a 5-single nucleotide polymorphism (5-SNP) genetic risk score (a weaker venous thromboembolism risk factor in blacks) and with hospitalization for heart failure (a stronger venous thromboembolism risk factor in blacks).ConclusionThe higher incidence rate of venous thromboembolism in blacks than whites was mostly explained by blacks having higher frequencies of venous thromboembolism risk factors.     

Relationship between metabolic control and HDL2-cholesterol in type I diabetic patients

Summary The relationship of the degree of metabolic control to the serum lipoprotein pattern has been studied in 62 young insulin treated diabetic patients. Stable HbA₁ and 24-h mean blood glucose, but not daily insulin dosage, were positively correlated to VLDL-TG (p<0.001) and negatively correlated to HDL₂-C (p<0.05). HDL₂-C was higher in patients with HbA₁<10% than in patients with HbA₁>10%. In 13 patients, in whom an improvement of metabolic control was achieved, a significant increase of HDL₂-C was recorded after three months. Our data are consistent with the view that in insulin-treated patients, good metabolic control is associated with low VLDL-TG and high HDL₂-C levels.     

Race-Specific Comparisons of Antihypertensive and Metabolic Effects of Hydrochlorothiazide and Chlorthalidone

BackgroundChlorthalidone is recommended over hydrochlorothiazide (HCTZ) as the preferred thiazide, but the supporting evidence is not robust at routinely used doses, or in whites vs blacks, in whom differences in response to thiazides are well known. We compare the efficacy and safety of HCTZ and chlorthalidone as first-line therapies for white and black hypertensive patients.MethodsWe compared treatment-related outcomes between the HCTZ arm (12.5 mg for 2-3 weeks; 25 mg for additional 6 weeks) of the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR, n = 376) and chlorthalidone arm (15 mg for 2 weeks; 25 mg for additional 6 weeks) of PEAR-2 (n = 326) clinical trials, in 17–65-year-old mild-moderate uncomplicated hypertensive whites and blacks.ResultsMean systolic/diastolic blood pressure (SBP/DBP) reduction with HCTZ vs chlorthalidone: 8 ± 8/4 ± 5 vs 12 ± 9/7 ± 5 mm Hg in whites (P < 10^?6 SBP and DBP); 12 ± 10/7 ± 6 vs 15 ± 10/9 ± 6 in blacks (P = .008 SBP, P = .054 DBP). Treatment with HCTZ vs chlorthalidone in whites resulted in significantly fewer patients achieving target BP (<140/90 mm Hg) (44% vs 57%, P = .018) and clinical response rate (≥10 mm Hg DBP reduction); and significantly higher nonresponse rate (<6 mm Hg DBP reduction); but no significant differences in rates among blacks (eg, target-BP rate: 56% vs 63%, P = .31). HCTZ treatment led to significantly lower rates of hypokalemia and hyperuricemia in whites and blacks, vs chlorthalidone, and significantly lower odds of requiring potassium supplementation among blacks (odds ratio 0.16; 95% confidence interval, 0.07-0.37; P = 3.4e^?7).ConclusionCompared with HCTZ, chlorthalidone showed greater blood pressure lowering and adverse metabolic effects in whites, but similar blood pressure lowering and greater adverse effects in blacks; suggesting that the recent guideline recommendations to choose chlorthalidone over HCTZ may not be warranted in blacks.     

Apolipoprotein E polymorphism influences orthotopic liver transplantation outcomes in patients with hepatitis C virus-induced liver cirrhosis

BACKGROUNDHepatitis C virus (HCV) infection is responsible for a chronic liver inflammation, which may cause end-stage liver disease and hepatocellular carcinoma. Apolipoprotein E (protein: ApoE, gene: APOE), a key player in cholesterol metabolism, is mainly synthesized in the liver and APOE polymorphisms may influence HCV-induced liver damage. AIMTo determine whether APOE alleles affect outcomes in HCV-infected patients with liver cirrhosis following orthotopic liver transplantation (OLT). METHODSThis was a cohort study in which 179 patients, both genders and aged 34-70 years, were included before or after (up to 10 years follow-up) OLT. Liver injury severity was assessed using different criteria, including METAVIR and models for end-stage liver disease. APOE polymorphisms were analyzed by quantitative real-time polymerase chain reaction. RESULTSThe APOE3 allele was the most common (67.3%). In inflammation severity of biopsies from 89 OLT explants and 2 patients in pre-transplant, the degree of severe inflammation (A3F4, 0.0%) was significantly less frequent than in patients with minimal and moderate degree of inflammation (≤ A2F4, 16.2%) P = 0.048, in patients carrying the APOE4 allele when compared to non-APOE4. In addition, a significant difference was also found (≤ A2F4, 64.4% vs A3F4, 0.0%; P = 0.043) and (A1F4, 57.4% vs A3F4, 0.0%; P = 0.024) in APOE4 patients when compared to APOE3 carriers. The fibrosis degree of the liver graft in 8 of 91 patients and the lack of the E4 allele was associated with more moderate fibrosis (F2) (P = 0.006). CONCLUSIONOur results suggest that the E4 allele protects against progression of liver fibrosis and degree of inflammation in HCV-infected patients.     

Increased postprandial lipemia in patients with normolipemic peripheral arterial disease

Methods We evaluated the postprandial lipid metabolism in patients with normolipemic peripheral arterial disease (PAD) after the administration of an oral fat load. Total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), HDL₂ and HDL₃ subfractions, triglycerides (TGs), lipoprotein(a), and LDL size were determined at baseline and for 8 hours after the meal. Results In patients with PAD, TGs increased significantly at the 4th, 6th, and 8th hours postprandially; in control subjects, TGs increased at the 4th and 6th hours. HDL decreased significantly at the 4th, 6th, and 8th hours in patients with PAD and at the 6th hour in control subjects. The magnitude of postprandial lipemia, expressed as “the area under the incremental curve for TGs,” was higher in patients with PAD than in control subjects (770 ± 476 vs 391 ± 195 mg/dL at 8 hours, P < .05). Multiple-regression analysis showed that baseline TGs were positively related to the magnitude of postprandial lipemia (P = .01) and that LDL size was negatively related (P = .05). Conclusions This is the first documentation of postprandial behavior in patients with normolipemic PAD, suggesting the relevance of postprandial lipoprotein metabolism in the pathogenesis of peripheral atherosclerosis. (Am Heart J 2002;143:733-8.)     

The APOE ɛ2 allele is associated with increased plasma apolipoprotein E levels in patients with coronary artery disease

AimsWe sought to evaluate the influence of APOE polymorphisms (ɛ2-rs7412, ɛ4-rs429358) on plasma levels of apolipoprotein E in patients with confirmed coronary artery disease.MethodsA total of 94 patients with coronary artery disease were included in our study. Genotypisation for rs429358 and rs7412 in APOE was performed and plasma levels of apolipoprotein E, lipids, and hs-CRP were measured.ResultsSignificantly higher plasma levels of APOE were found in the ɛ2 carriers compared to the normal ɛ3/ɛ3 genotype (40.4 mg/mL vs. 22.9 mg/mL, P = 0.018). There was no difference in APOE levels between the ɛ4 allele and ɛ3/ɛ3 allele carriers. Significantly higher HDL cholesterol levels (1.55 mmol/L vs. 1.16 mmol/L, P = 0.001) were found in the ɛ2 carriers, and significantly lower levels of hs-CRP (1.07 mg/L vs. 2.14 mg/L, P = 0.035) in the ɛ4 carriers compared to the normal ɛ3/ɛ3 genotype.ConclusionsIn CAD patients, the ɛ2 APOE allele is associated with significantly higher plasma levels of APOE and HDL cholesterol, whereas the ɛ4 allele is associated with significantly lower levels of hsCRP.     

Reference limits of serum TSH and free T4 are significantly influenced by race and age in an urban outpatient medical practice

Objective The suitability of TSH reference limits derived from national databases to outpatient practices has not been established. We aimed to determine whether race and age influence the distribution of TSH and free T4 (fT4). Design A cross‐sectional study of an urban outpatient medical practice. Participants Patients (n = 22 116) without clinical evidence of thyroid disease or use of thyroid‐specific medications. Measurements Comparison of TSH and fT4 distributions in specific racial and age groups including blacks, whites and Hispanics. Results TSH was distributed at higher concentrations, without skew, in whites compared to blacks (median, 1·54 mIU/l vs. 1·18 mIU/l, P < 0·001) and in old (>80 years old) compared to young (20–29 years old) (median, 1·61 mIU/l vs. 1·13 mIU/l, P < 0·001). In all patients, blacks and whites, 3%, 8% and 5%, respectively, of those aged > 80 years were misclassified as having high TSH compared to those aged 20–29 years (P < 0·001). Using TSH limits from national databases resulted in significant misclassification of patients with raised or lowered TSH. Mean fT4 was significantly lower in blacks than whites (17·5 ± 4·38 pmol/l vs. 18·3 ± 3·99 pmol/l, P < 0·001), did not differ between young and old, but decreased progressively (average 7%) as TSH increased to > 4·5 mIU/l. Conclusions Reference limits for TSH differ between races and with age. Use of race‐ and age‐specific reference limits decreases misclassification of patients with lowered or raised TSH in an urban practice. The unique fT4:TSH relationships of blacks and whites may be genetically determined. The implications of the small decrement in fT4 as TSH increases remain to be explored.