Hydrochlorothiazide and atenolol combination antihypertensive therapy: effects of drug initiation order.

For combination antihypertensive therapy with thiazide diuretics and beta-blockers, the effect of the order of initiation of the drugs on the outcome has not been tested. Patients with uncomplicated hypertension were randomized to receive either hydrochlorothiazide (HCTZ) or atenolol monotherapy, followed by addition of the alternative drug. Blood pressure (BP) responses were evaluated by race and order of drug initiation. A total of 368 participants received combination therapy. Among the participants, blacks showed a greater BP-lowering effect than whites did with HCTZ monotherapy (-13.0/-7.4 mm Hg vs. -8.0/-4.2 mm Hg, P < 0.001) but a smaller BP-lowering effect than did whites with atenolol monotherapy (-1.1/-2.9 mm Hg vs. -9.9/-9.2 mm Hg, P < 0.0001). These differences were not evident during combination therapy. However, both groups showed greater response to HCTZ + atenolol than to atenolol + HCTZ (-19.1/-14.2 mm Hg vs. -15.6/-11.3 mm Hg, P < 0.0001). Despite optimal dosing of HCTZ + atenolol, only two-thirds of the participants achieved BP control. In HCTZ/atenolol combination antihypertensive therapy, the order in which the drugs are initiated affects total BP lowering during the first 4-6 months of therapy.

Multilocus effects of the renin-angiotensin-aldosterone system genes on blood pressure response to a thiazide diuretic.

BACKGROUND: The renin-angiotensin-aldosterone (RAA) system regulates blood pressure (BP) levels and influences responses to antihypertensive medications. Variation in RAA system genes has been reported to influence interindividual differences in BP levels and the occurrence of hypertension (HTN). METHODS: We evaluated the relationship between variation in genes of the RAA system and interindividual differences in BP response to a thiazide diuretic. Analyses were carried out in a race- and gender-specific manner in 255 unrelated hypertensive African-Americans (125 men and 130 women) and 246 unrelated hypertensive non-Hispanic Whites (133 men and 113 women). RESULTS: The angiotensin II receptor (AT(1)R) A1166C and angiotensinogen G-6A polymorphisms had a significant effect on systolic BP response to the diuretic in African-American women. Multilocus analyses indicated that the effects of these genes combined additively to influence response. Results of a permutation test to adjust for multiple comparisons and the possible nonindependence among genotypes remained significant at the P=0.003 level. CONCLUSIONS: Among African-American women, particular gene variations in the RAA system have additive effects on BP response to a thiazide diuretic.

Use of gene markers to guide antihypertensive therapy.

Sequencing of the human genome has elevated the potential for genetic information to aid in the prevention, diagnosis, and treatment of common chronic diseases. One beneficial application of genetic information is the identification of variants that influence response to pharmaceutical agents used to lower blood pressure and prevent target organ complications of hypertension. Knowledge of genetic variants that influence blood pressure response to antihypertensive drugs may allow more individualized tailoring of antihypertensive drug therapy, and provide greater insight into the molecular mechanisms regulating blood pressure levels and causing hypertension.

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.

Are aneroid sphygmomanometers accurate in hospital and clinic settings?

BACKGROUND: The aneroid sphygmomanometer is commonly used for the indirect measurement of blood pressure despite significant concerns about its accuracy. Although the mercury sphygmomanometer is highly accurate, there are concerns about the environmental toxicity of mercury. In response to various external pressures to become essentially mercury free, the Mayo Clinic, Rochester, Minn, has replaced many mercury sphygmomanometers with aneroid devices. Since 1993, a maintenance protocol has been in place to ensure proper function and accuracy of these devices. METHODS: We assessed the accuracy of 283 aneroid devices using as the reference standard a digital pressure and vacuum meter that was calibrated using a mercury sphygmomanometer. RESULTS: The mean +/- SD values from the aneroid device in millimeters of mercury at each reference point (at 20-mm Hg intervals from 60 to 240 mm Hg defined by the reference device) were 59.9 +/- 1.9 at 60; 79.9 +/- 1.9 at 80; 100.0 +/- 1.8 at 100; 120.3 +/- 1.8 at 120; 140.7 +/- 1.4 at 140; 160.7 +/- 1.7 at 160; 180.9 +/- 1.3 at 180; 200.7 +/- 5.0 at 200; 221.0 +/- 1.3 at 220; and 240.8 +/- 1.6 at 240 (r = 0.99; P<.001). The values from the aneroid device underestimated those of the reference device by a mean of 0.5 mm Hg (95% confidence interval, 0.3-0.7). Virtually 100% of the values from the aneroid device were within the 4-mm Hg range recommended by the Association for the Advancement of Medical Instrumentation. CONCLUSION: Aneroid sphygmomanometers provide accurate pressure measurements when a proper maintenance protocol is followed.

C825T polymorphism of the G protein beta(3)-subunit and antihypertensive response to a thiazide diuretic.

The T allele of the C825T polymorphism of the gene encoding the beta(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 beta(3)-subunit may help identify patients with essential hypertension who are more responsive to diuretic therapy.

Association of atrial fibrillation and aortic atherosclerosis: a population-based study.

OBJECTIVE: To examine the association between atrial fibrillation (AF) and aortic atherosclerosis in the general population. SUBJECTS AND METHODS: Transesophageal echocardiography was performed in 581 subjects, a random sample of the adult Olmsted County, Minnesota, population (45 years of age or older) participating in the Stroke Prevention: Assessment of Risk in a Community (SPARC) study. The frequency of aortic atherosclerosis was determined in 42 subjects with AF and compared with that in 539 subjects without AF (non-AF group). RESULTS: Subjects with AF were significantly older than non-AF subjects (mean +/- SD age, 82+/-10 vs 66+/-13 years, respectively; P<.001) and more commonly had hypertension (28 [66.7%] vs 288 [53.4%], respectively; P=.10). The 2 groups were similar in sex and frequency of diabetes mellitus, hyperlipidemia, or smoking history (P>.10). The odds of aortic atherosclerosis (of any degree) were 2.87 times greater (95% confidence interval [CI], 1.41-5.83; P=.004) and the odds of complex atherosclerosis (protruding atheroma >4 mm thick, mobile debris, or plaque ulceration) were 2.71 times greater (CI, 1.13-6.53; P=.03) in the AF group than in the non-AF group. Age was a significant predictor of aortic atherosclerosis (P<.001). After adjusting for age, the odds of atherosclerosis and complex atherosclerosis were not significantly different between the 2 groups (P=.13 and P=.75, respectively). CONCLUSIONS: In the general population, AF is associated with aortic atherosclerosis, including complex atherosclerosis. This association is related to age since both AF and aortic atherosclerosis are more frequent in the elderly population.

Antihypertensive pharmacogenetics: getting the right drug into the right patient.

Pharmacogenetic investigation seeks to identify genetic factors that contribute to interpatient and interdrug variation in responses to antihypertensive drug therapy. Classical studies have characterized single gene polymorphisms of drug metabolizing enzymes that are responsible for large interindividual differences in pharmacokinetic responses to several antihypertensive drugs. Progress is being made using candidate gene and genome scanning approaches to identify and characterize many additional genes influencing pharmacodynamic mechanisms that contribute to interindividual differences in responses to antihypertensive drug therapy. Knowledge of polymorphic variation in these genes will help to predict individual patients' blood pressure responses to antihypertensive drug therapy and may also provide new insights into molecular mechanisms responsible for elevation of blood pressure.

Step care therapy for hypertension in diabetic patients.

For diabetic patients, a goal blood pressure lower than 130/80-85 mm Hg is strongly supported by clinical trial results. We review the agents, sequence, and dosing used in clinical trials and propose a treatment algorithm. Multiagent antihypertensive therapy is required to attain goal blood pressure in most patients. Step sequences to obtain this goal are suggested. In general, we favor initial therapy with an angiotensin-converting enzyme inhibitor, followed by the addition of a diuretic. The presence of comorbid conditions may dictate variation from this scheme. The effect of antihypertensive agents on established cardiovascular diseases, proteinuria, renal function, and metabolic factors is discussed. Tailored recommendations for specific clinical scenarios are described.

Effect of time of day on intraindividual variability in ambulatory blood pressure.

The aim of this study was to determine whether intraindividual blood pressure (BP) variability, measured by noninvasive ambulatory monitoring, differs between the active (daytime) and inactive (nighttime) periods of the day. We obtained ambulatory BP recordings in 143 healthy adults (95 men, 48 women) from Rochester, Minnesota. Readings were obtained every 10 min for a 24-h period. We calculated the standard deviation of each individual's BP readings about the means for the active period and for the inactive period as measures of intraindividual BP variability. In men, mean within-individual standard deviations for both systolic (SBP) and diastolic blood pressure (DBP) were significantly greater during the inactive period than during the active period (for SBP: 10.3 +/- 2.1 v 11.9 +/- 2.7, P < .0001; for DBP: 8.8 +/- 2.0 v 9.7 +/- 2.5, P = .0027). In women, the mean within-individual standard deviation for SBP did not differ significantly between the active and inactive periods (9.7 +/- 2.2 v 10.3 +/- 2.4, P = 0.225) but for DBP was significantly greater during the inactive period than during the active period (8.1 +/- 2.0 v 9.2 +/- 2.3, P = .020). Statistically significant predictors of intraindividual BP variability included measures of age and body size, metabolic traits, neuroendocrine traits, erythrocyte cation traits, and renal function traits. This study demonstrates that intraindividual BP variability, as measured by noninvasive ambulatory monitoring, is as great or greater during the inactive period as during the active period of the day.

Left atrial appendage flow velocities in subjects with normal left ventricular function.

The objectives of this study were to establish reference values and define the determinants of left atrial appendage (LAA) flow velocities in the general population. LAA flow velocities (contraction and filling velocities) were assessed by transesophageal echocardiography in 310 subjects aged > or = 45 years, sampled from the population-based Stroke Prevention: Assessment of Risk in a Community study. All subjects were in sinus rhythm, with preserved left ventricular systolic function (ejection fraction > or = 50%), and without valvular disease. Values of LAA contraction and filling velocities were established for various age groups in the population. Age was negatively associated with LAA contraction and filling velocities, which decreased by 4.1 cm/s (p < 0.001) and 2.0 cm/s (p < 0.01) for every 10 years of age, respectively. Contraction velocities were 5 cm/s higher in men than in women (p < 0.05). After adjusting for age and sex, heart rate was independently associated with LAA contraction velocities (p < 0.001; nonlinear association). Body surface area, left atrial size, left ventricular mass index, and a history of previous cardiac disease or hypertension showed no significant association with LAA flow velocities (p > 0.05). Furthermore, detailed analysis of 24-hour ambulatory blood pressure data (available in 253 subjects) showed no association between various blood pressure parameters (systolic and diastolic blood pressure, out-of-bed and in-bed measurements) and LAA flow velocities (all p > 0.05). In summary, the present study establishes the reference values for LAA flow velocities in a large sample of the general population. LAA flow velocities progressively decline with age in subjects with preserved left ventricular systolic function.

Independent association of high blood pressure and aortic atherosclerosis: A population-based study.

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:

Predictors of interindividual variation in ambulatory blood pressure and their time or activity dependence.

The objectives of this study were to determine whether total interindividual variation in blood pressure (BP) differs between inactive and active hours of the day, to identify predictors of interindividual variation in BP, and to assess whether variation associated with any of these identified predictors is greater (or less) during inactive hours than during active hours of the day. We obtained ambulatory BP recordings over 20 consecutive hours (12 active, out of bed [daytime]; and 8 inactive, in bed [nighttime]) in a sample of 240 unrelated, non-Hispanic white adults (138 men; 102 women). We estimated total interindividual variation in BP, and the percentage of interindividual variation associated with measures of age and body size, metabolic traits, catecholamines, erythrocyte cation transport, and renal function. We used linear regression to assess changes in the hourly estimates of total interindividual variation and in variation attributable to each set of predictor traits over the 20 h. In both men and women, total interindividual variation in systolic BP was significantly greater (not less) during inactive hours than during active hours. In addition, in women, total interindividual variation in diastolic BP was as great during inactive hours as during active hours. Each set of traits considered predicted a statistically significant percentage of interindividual variation in BP. None of the sets of traits predicted a greater percentage of interindividual variation during the inactive hours than during the active hours. Measures of age and body size, catecholamines, cation transport and renal function traits predicted significantly less interindividual variation during inactive hours than during active hours of the day. That total interindividual variation in BP is as great or greater during inactive hours than during active hours of the day emphasizes the potential for differences in nighttime BP to contribute to the development of cardiovascular disease. In as much as the predictors of interindividual variation in BP differ between the daytime and nighttime, the causes of variation during these two times may also differ.

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.

A review of the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.

Hypertension is a major modifiable risk factor for cardiovascular diseases. After decades of improvement, population surveys demonstrate disturbing downward trends in the rates of awareness, treatment, and control of this disorder in recent years. Over this same time period, there has been a slight increase in the incidence of strokes, and a steady rise in the incidence of end-stage renal disease and the prevalence of congestive heart failure, conditions in which hypertension plays a prominent role. Results of recent studies support the possibility that lifestyle modifications may be effective for prevention of hypertension. Treatment of established hypertension involves lifestyle modifications and drug therapies designed to control blood pressure and reduce overall cardiovascular risk. Both threshold blood pressure levels for initiating drug therapy and goal blood pressure levels with treatment are individually determined based on the presence or absence of additional cardiovascular risk factors and hypertension target organ injury or clinical cardiovascular disease. Recent clinical trials support the value of lower goal blood pressures for patients with diabetes, heart failure, and renal disease. The presence or absence of comorbid conditions often determines specific drug choices. Diuretics and beta-blockers remain the drugs of choice in uncomplicated hypertension. Additional studies confirm the benefits of treating isolated systolic hypertension in the elderly. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure provides a practical, evidence-based resource to help health care providers meet the public health challenges of preventing and controlling hypertension.

Association of genetic variation with interindividual variation in ambulatory blood pressure.

OBJECTIVE: To determine whether genetic and non-genetic components of interindividual variation in systolic and diastolic blood pressure are constant throughout the day or are time or activity dependent. METHODS: We obtained 24 h ambulatory blood pressure recordings in 263 members of 68 unrelated nuclear families (i.e. parents and their offspring) representative of the Caucasian population of Rochester, MN, USA. Using the time each patient got into bed as a reference point, we identified 198 records in which this reference point was preceded by eight consecutive active hours (out of bed) and followed by four consecutive inactive hours (in bed) in which four or more blood pressure readings taken each hour were judged to be technically satisfactory. For each hourly mean for systolic and diastolic blood pressure, we estimated total interindividual variance, variance associated with concomitant variables (generation; sex within generation strata; and age, height, weight, body mass index, and abdomen-to-hip ratio within generation and sex strata), and variance associated with additive genetic effects (i.e. the chief cause of resemblance between relatives). To assess trends in each component of interindividual blood pressure variance over the 12 h period, we estimated the slope of the linear regression line fit to the hourly estimates. RESULTS: For systolic blood pressure, total interindividual variance did not change significantly (slope of regression line = -0.23, P = 0.717). In contrast, total interindividual variance for diastolic blood pressure was greater during active hours than inactive hours (slope of regression line = -5.53, P < 0.001). For both systolic and diastolic blood pressure, variance associated with the concomitant variables was greater during active hours than during inactive hours (for systolic blood pressure slope of regression line = -2.98, P = 0.001; for diastolic blood pressure slope of regression line = -6.14, P < 0.001). Likewise, for both systolic and diastolic blood pressure, variance associated with additive genetic effects was also greater during active hours than during inactive hours (for systolic blood pressure slope of regression line = -1.65, P = 0.090; for diastolic blood pressure slope of regression line = -1.47, P = 0.018). CONCLUSIONS: This study demonstrates that components of interindividual variation in blood pressure are not constant, but are time or activity dependent.

Twenty-four-hour blood pressure profiles in normotensive sons of hypertensive parents.

We investigated whether blood pressures are higher in normotensive offspring of hypertensive parents than in normotensive offspring of normotensive parents outside the physician's office and, if so, whether these higher blood pressures are dependent on the level of dietary sodium intake. We compared 24-hour ambulatory blood pressure profiles between 11 normotensive sons of two hypertensive parents and 11 normotensive sons of two normotensive parents; profiles were recorded after 1 week of a low sodium diet (10 meq/day) and after 1 week of a high sodium diet (200 meq/day). The sons of hypertensive parents were on average 6 years older than the sons of normotensive parents (47 +/- 5 [SD] versus 41 +/- 4 years, p < 0.05). The shift from low to high sodium diet did not significantly change the magnitude of differences in office or ambulatory blood pressures between the groups (i.e., no group-by-diet interaction); thus, we assessed group effects by contrasting blood pressure means for each group pooled across diets. Age-adjusted office blood pressure was higher in sons of hypertensive parents than in sons of normotensive parents (116 +/- 7/80 +/- 6 versus 111 +/- 7/75 +/- 6 mm Hg; p = 0.020 for systolic and p = 0.003 for diastolic blood pressure).(ABSTRACT TRUNCATED AT 250 WORDS)

Diagnosis, pathogenesis, and management of essential hypertension.

Hypertension, defined as systemic blood pressure equal to or exceeding 140/90 mm Hg, is a common health problem afflicting approximately 20% of the adult population of the United States. Ninety-five percent have "essential hypertension" for which the pathogenesis is unknown, although both genetic and environmental factors probably are important. Using proper technique, multiple blood pressure determinations made both inside and outside the physician's office are used to diagnose hypertension and assess the effects of treatment. The goal of therapy is to reduce the morbidity and mortality attributable to high blood pressure, which is accomplished by reducing blood pressure to below 140/90 mm Hg. Treatment involves both nonpharmacologic and pharmacologic modalities. Because noncompliance remains a major problem, proper selection of therapy is important. Cooperation of all health care professionals who deal with hypertensive patients is important to ensure control of this common health problem.