Microalbuminuria, renal function and development of sustained hypertension: a longitudinal study in the early stage of hypertension

OBJECTIVE: Microalbuminuria (MA) is a marker of adverse outcome in hypertension. The aim of this study was to investigate the association of MA with cardiovascular risk factors and glomerular hyperfiltration in the early stage of hypertension and to assess its predictive value for the development of sustained hypertension requiring antihypertensive treatment. DESIGN AND PARTICIPANTS: We studied 1041 young stage 1 hypertensive subjects. Study variables were 24-h ambulatory blood pressure and heart rate, anthropometric measures, metabolic variables, creatinine clearance and lifestyle factors analyzed as a function of ascending urinary albumin measured from 24-h collections. Subjects were followed until they developed sustained hypertension and were eligible for antihypertensive medication according to current guidelines. SETTING: Seventeen outpatient clinics in Italy. RESULTS: Eighty-five percent of the subjects were normoalbuminuric, 9% had borderline MA, and 6% had overt MA. No between-group differences were found for age, body mass index, heart rate, lifestyle factors and biochemistry in both genders. Creatinine clearance was greater in the subjects with overt MA and borderline MA than in the normoalbuminuric subjects (P = 0.003 and 0.011, respectively). In a two-way ANCOVA, microalbuminuric subjects both with hyperfiltration (P < 0.001) and with normal filtration (P = 0.04) had higher 24-h systolic blood pressure than subjects with normoalbuminuria and normal filtration. In a Cox analysis, neither MA nor hyperfiltration were significant predictors of development of sustained hypertension. CONCLUSION: MA is not associated with an adverse metabolic risk profile in the early stage of hypertension. MA is associated with greater hemodynamic load and with glomerular hyperfiltration in this clinical setting, but does not help in predicting those subjects destined to develop sustained hypertension requiring antihypertensive therapy.     

Task Force I: methodological aspects of blood pressure measurement

OBJECTIVE: To reach a consensus on important methodological aspects of blood pressure measurement. METHODS: A Task Force on the methodological aspects of blood pressure measurement wrote this review after the Eighth International Consensus Conference on Blood Pressure Monitoring, in Sendai, Japan (28-31 October 2001). This consensus paper is based on the papers presented by Task Force I and on the discussion sessions, and is therefore representative of a broad spectrum of expert opinion. POINTS OF CONSENSUS: Consensus was reached on the following five issues: (1) there is an urgent need for a simplified protocol for the validation of blood pressure measuring devices; (2) there is a need for a means of updating the "state of the market" for validated devices so that users can have easy access to this information; (3) new devices must be validated independently, and existing devices that have not been validated must be reappraised; (4) manufacturers should confirm when new models use algorithms which have been validated previously; (5) the Food and Drug Administration now accepts that when ambulatory blood pressure measurement is used in clinical short-term trials in which side-effects are not being assessed, a placebo arm is not required.     

Genetic contribution to the variance in left ventricular mass: the Tecumseh Offspring Study.

OBJECTIVE: To estimate the contribution of heredity to the variance in left ventricular mass (LVM), and to ascertain whether genetic factors may interact with non-genetic factors in promoting LVM growth. SUBJECTS AND SETTING: The study population consisted of 290 healthy parents and 251 healthy children living in Tecumseh, Michigan, USA. MAIN OUTCOME MEASURE: Correlation of parents' LVM with offspring's LVM adjusting for a number of clinical variables. METHODS: LVM in parents and offspring was measured with M-mode echocardiography by the same investigators. RESULTS: Parents unadjusted LVM was unrelated to offspring unadjusted LVM, but after removing the confounding effect of age, sex, anthropometric measurements, systolic blood pressure, plasma insulin and urinary sodium excretion, parent-child correlation for LVM was 0.28 (P = 0.006). The relative contribution of parental-adjusted LVM and of several offspring phenotypic and environmental variables on offspring LVM was evaluated by multivariable regression analysis. When age, gender, anthropometric measurements and systolic blood pressure were accounted for, adjusted LVM of parents explained only 1.6% of the total variance in offspring LVM. However, after inclusion of insulin and urinary sodium in the model heredity explained 7.6% of the total variance in offspring LVM, and its predictive power was second only to that of child's height. Furthermore, an interactive effect of parental LVM with offspring systolic blood pressure was found on child's left ventricular mass. CONCLUSION: Heredity can explain a small, but definite proportion of the variance in LVM. Higher blood pressure favors the phenotypic expression of the genes that regulate LVM growth.     

Ambulatory versus clinic blood pressure for the assessment of anti hypertensive efficacy in clinical trials: insights from the Val-Syst Study

BACKGROUND: Several studies have found that measurement of blood pressure (BP) in the clinical setting may lead to overestimation of hypertension and may yield inaccurate assessments of the efficacy of antihypertensive treatment. OBJECTIVE: The aim of this study was to determine whether the use of clinic BP in the Valsartan and Amlodipine for the Treatment of Isolated Systolic Hypertension in the Elderly (Val-Syst) study accurately identified those elderly outpatients with systolic hypertension who had true 24-hour elevations in BP, as well as those who required dose increases in antihypertensive therapy during follow-up. METHODS: In Val-Syst, patients aged between 60 and 80 years with a clinic sitting systolic BP (SBP) of 160 to 220 mm Hg and a diastolic BP <90 mm Hg after a 2-week placebo washout period were randomized to receive valsartan 80 mg or amlodipine 5 mg once daily (level 1). In those with a trough SBP > or =140 mm Hg after 8 weeks of double-blind treatment, doses were titrated upward to valsartan 160 mg or amlodipine 10 mg once daily (level 2). If clinic SBP was > or =140 mm Hg after a further 8 weeks, hydrochlorothiazide 12.5 mg was added for an additional 8 weeks (level 3). Clinical decisions during the active-treatment period were based on clinic BP measurements. Thirteen of the 35 participating centers assessed ambulatory BP as well as clinic BP at baseline and the end of the treatment, making it possible to compare the results of the 2 modes of measurement. The Student test was used to compare drug-induced changes in clinic and ambulatory BP in individual patients. Differences between the decreases in clinic and ambulatory BP at the 3 treatment levels were tested using repeated-measures analysis of covariance (ANCOVA), with baseline as the covariate. RESULTS: One hundred sixty-four elderly patients (age range, 60-80 years; 85 men, 79 women) were included in the study (79 valsartan, 85 amlodipine), and valsartan and amlodipine were reported to have comparable effects on the level and rhythm of 24-hour BP In the present study, 22 of 164 patients had white-coat hypertension at baseline (clinic SBP > or =160 mm Hg and mean 24-hour SBP <130 mm Hg). For both treatments combined, the mean (SD) decreases in clinic SBP were inversely proportional to the treatment level (level 1 = -33.2 (7.9) mm Hg; level 2 = -31.6 (11.8) mm Hg; level 3 = -29.3 (11.6) mm Hg; P = 0.001, overall ANCOVA). In contrast, after adjusting for baseline values, the decreases in mean 24-hour SBP did not differ between treatment levels (level 1 = -10.8 [10.4] mm Hg; level 2 = -13.0 [11.2] mm Hg; level 3 = -16.4 [13.8] mm Hg). The decrease in clinic BP during therapy was similar in patients with white-coat hypertension and sustained hypertension (clinic SBP > or 160 mm Hg and mean 24-hour SBP > or =130 mm Hg), whereas 24-hour and 8- to 9-am SBP decreased significantly only in patients with sustained hypertension (P < 0.001). At the end of the study, mean 24-hour SBP continued to be uncontrolled (> or =130 mm Hg) in 16 of 53 patients (30.2%) at treatment level 1, 27 of 62 (43.5%) at level 2, and 19 of 49 (38.8%) at level 3 (P = NS). CONCLUSION: Based on the findings in this population of elderly patients with systolic hypertension, the management of hypertension may vary depending on whether decisions concerning the selection of patients for clinical trials and treatment adjustments during follow-up are made using clinic or ambulatory BP measurement.     

Cytochrome P450 1A2 is a major determinant of lidocaine metabolism in vivo: effects of liver function

OBJECTIVES: This study was designed (1) to evaluate the effect of a cytochrome P450 (CYP) 1A2 inhibitor, fluvoxamine, on the pharmacokinetics of intravenous lidocaine and its 2 pharmacologically active metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX), to confirm recent in vitro results indicating that CYP1A2 is the main isoform responsible for lidocaine biotransformation and (2) to assess whether liver function has any influence on the fluvoxamine-lidocaine interaction. METHODS: The study was carried out in 10 healthy volunteers and 20 patients with cirrhosis, 10 with mild (Child grade A) and 10 with severe (Child grade C) liver dysfunction, according to a randomized, double-blind, 2-phase, crossover design. In one phase all participants received placebo for 6 days; in the other phase they received 50 mg fluvoxamine for 2 days and 100 mg fluvoxamine for the next 4 days. On day 6, a 1-mg/kg lidocaine dose was administered intravenously 2 hours after the last dose of fluvoxamine or placebo. Plasma concentrations of lidocaine, MEGX, GX, and fluvoxamine were measured up to 12 hours after lidocaine injection. RESULTS: The effects of fluvoxamine coadministration were dependent on liver function. Lidocaine clearance was decreased on average by 60% (from 12.1 mL/min.kg to 4.85 mL/min.kg, P <.001) in healthy subjects and by 44% (from 9.83 mL/min.kg to 5.06 mL/min.kg, P <.001) in patients with mild liver dysfunction, with proportional increases in terminal half-lives, whereas virtually no effect was produced in patients with severe liver dysfunction (4.21 mL/min.kg versus 3.65 mL/min.kg, P >.05). Analogous effects were observed on MEGX and GX formation kinetics, which were drastically impaired in healthy subjects and patients with mild liver cirrhosis but virtually unaffected in patients with severe cirrhosis. CONCLUSION: CYP1A2 is the enzyme principally responsible for the metabolic disposition of lidocaine in subjects with normal liver function. The extent of fluvoxamine-lidocaine interaction decreases as liver function worsens, most likely because of the concomitant decrease in the hepatic level of CYP1A2. These observations indicate that results obtained in healthy subjects cannot be extended a priori to patients with liver dysfunction, but the clinical consequences of inhibition of drug metabolism must also be assessed in such patients.     

G-protein beta3-subunit gene 825T allele and hypertension: a longitudinal study in young grade I hypertensives

The 825T allele of the GNB3 gene has been associated with essential hypertension and obesity in cross-sectional studies. We have therefore planned a longitudinal cohort study to assess whether the GNB3 825T allele is predictive of blood pressure increase in young subjects with grade I hypertension. We genotyped at the GNB3 825 locus 461 participants of the Hypertension and Ambulatory Recording Venetia Study (HARVEST) study (age, 18 to 45 years) at low cardiovascular risk, according to 1999 ISH/WHO criteria. The study end point was eligibility for antihypertensive medication, that is, progression to grade II hypertension during the first year of observation or office systolic blood pressure > or =150 mm Hg and/or office diastolic blood pressure > or =95 mm Hg in two later consecutive visits during follow-up. At baseline, there was no statistically significant difference among genotypes with respect to body mass index, blood pressure, and heart rate. During follow-up (mean, 4.7 years), 113 (51.1%) patients with CC genotype and 145 (60.4%) patients with TT/TC genotype reached the end point. According to survival analysis, the patients carrying the 825T allele had an increased risk of reaching the blood pressure end point (CI, 1.108 to 1.843; P=0.006). In young patients with grade I hypertension, the 825T allele is associated with increased risk of progression to more severe hypertension requiring antihypertensive therapy. The GNB3 825T allele may be considered a genetic marker of predisposition for hypertension.     

Comparison of C‐reactive Protein and Albumin Excretion as Prognostic Markers for 10‐Year Mortality After Myocardial Infarction

Background

C‐reactive protein (CRP) is an established prognostic marker in the setting of acute coronary syndromes. Recently, albumin excretion rate also has been found to be associated with adverse outcomes in this clinical setting. Our aim was to compare the prognostic power of CRP and albumin excretion rate for long‐term mortality following acute myocardial infarction (AMI).

Hypothesis

To determine whether albumin excretion rate is a better predictor of long‐term outcome than CRP in post‐AMI patients.

Methods

We prospectively studied 220 unselected patients with definite AMI (median [interquartile] age 67 [60–74] y, female 26%, heart failure 39%). CRP and albumin‐to‐creatinine ratio (ACR) were measured on day 1, day 3, and day 7 after admission in 24‐hour urine samples. Follow‐up duration was 10 years for all patients.

Results

At survival analysis, both CRP and ACR were associated with increased risk of 10‐year all‐cause mortality, also after adjusting for age, hypertension, diabetes mellitus, prehospital time delay, creatine kinase‐MB isoenzyme peak, heart failure, and creatinine clearance. CRP and ACR were associated with nonsudden cardiovascular (non‐SCV) mortality but not with sudden death (SD) or noncardiovascular (non‐CV) death. CRP was not associated with long‐term mortality, while ACR was independently associated with outcome both in short‐ and long‐term analyses. At C‐statistic analysis, CRP did not improve the baseline prediction model for all‐cause mortality, while it did for short‐term non‐SCV mortality. ACR improved all‐cause and non‐SCV mortality prediction, both in the short and long term.

Conclusions

ACR was a better predictor of long‐term mortality after AMI than CRP. Copyright © 2010 Wiley Periodicals, Inc. This work was supported by grants from the University of Padova, Padova, Italy, for the collection, management, and analysis of the data. The authors have no other funding, finan‐ cial relationships, or conflicts of interest to disclose.