[Comparison of preventive effect of "new" and "old" antihypertensive agents]. / Sammenlikning av forebyggende effekt av "nye" og "gamle" blodtrykksmedisiner.

BACKGROUND: Until recently no morbidity-mortality study had examined the effects of newer drugs like angiotensin-converting enzyme inhibitors, calcium-antagonists and alpha-blockers compared to "old" but well-proven thiazide diuretics and beta-blockers in the treatment of essential hypertension. MATERIAL AND METHODS: The prospective and randomized clinical trials CAPPP, STOP-2, NORDIL, INSIGHT and one arm of ALLHAT, with a total of approximately 58,000 middle-aged or elderly hypertensive patients have been assessed. RESULTS: The primary outcome, composite cardiovascular (CV) death, cerebral stroke and myocardial infarction, in one study with heart failure, or composite fatal coronary heart disease and myocardial infarction, was equal in all trials. INTERPRETATION: According to current evidence, prevention of cardiovascular disease in hypertension is the same irrespective of the class of drug.

[Are newer antihypertensive agents better than the older ones? Results of trials (CAPPP, STOP-2, NORDIL, INSIGHT and ALLHAT) with newer antihypertensive agents]. / Er de nye antihypertensiva bedre end de gamle? Resultater fra hypertensions-studier (CAPPP, STOP-2, NORDIL, INSIGHT og ALLHAT) med nyere medikamenter.

Until recently, no morbidity-mortality study had examined the effects of "newer" drugs, like angiotensin-converting enzyme inhibitors, calcium antagonists, and alpha-blockers compared to "old", but well-proven, thiazide diuretics, and beta-blockers in the treatment of essential hypertension. The prospective and randomised clinical trials, CAPPP, STOP-2, NORDIL, INSIGHT, and one arm of ALLHAT, with a total of about 58,000 middle-aged or elderly hypertensive patients have now been published. The primary outcome, composite cardiovascular (CV) death, cerebral stroke, and myocardial infarction, or composite fatal coronary heart disease and myocardial infarction, was the same, irrespective of the drug in all trials. Thus, prevention of CV complications depends on the lowering of blood pressure with well-tolerated medication, irrespective of class.

Randomised trial of effects of calcium antagonists compared with diuretics and beta-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study.

BACKGROUND: Calcium antagonists are a first-line treatment for hypertension. The effectiveness of diltiazem, a non-dihydropyridine calcium antagonist, in reducing cardiovascular morbidity or mortality is unclear. We compared the effects of diltiazem with that of diuretics, beta-blockers, or both on cardiovascular morbidity and mortality in hypertensive patients. METHODS: In a prospective, randomised, open, blinded endpoint study, we enrolled 10,881 patients, aged 50-74 years, at health centres in Norway and Sweden, who had diastolic blood pressure of 100 mm Hg or more. We randomly assigned patients diltiazem, or diuretics, beta-blockers, or both. The combined primary endpoint was fatal and non-fatal stroke, myocardial infarction, and other cardiovascular death. Analysis was done by intention to treat. FINDINGS: Systolic and diastolic blood pressure were lowered effectively in the diltiazem and diuretic and beta-blocker groups (reduction 20.3/18.7 vs 23.3/18.7 mm Hg; difference in systolic reduction p<0.001). A primary endpoint occurred in 403 patients in the diltiazem group and in 400 in the diuretic and beta-blocker group (16.6 vs 16.2 events per 1000 patient-years; relative risk 1.00 [95% CI 0.87-1.15], p=0.97). Fatal and non-fatal stroke occurred in 159 patients in the diltiazem group and in 196 in the diuretic and beta-blocker group (6.4 vs 7.9 events per 1000 patient-years; 0.80 [0.65-0.99], p=0.04) and fatal and non-fatal myocardial infarction in 183 and 157 patients (7.4 vs 6.3 events per 1000 patient-years; 1.16 [0.94-1.44], p=0.17). INTERPRETATION: Diltiazem was as effective as treatment based on diuretics, beta-blockers, or both in preventing the combined primary endpoint of all stroke, myocardial infarction, and other cardiovascular death.

Long-term central hemodynamic effects at rest and during exercise of losartan in essential hypertension.

BACKGROUND: Losartan reduces blood pressure in patients with essential hypertension, but the long-term central hemodynamic effects at rest and during exercise are not known. METHODS AND RESULTS: After 8 months of losartan treatment (50 to 100 mg daily, mean 82 mg), intra-arterial pressure was reduced from 165/102 mm Hg to 145/91 mm Hg at rest and from 193/104 mm Hg to 179/96 mm Hg during 100 W exercise in 28 patients with essential hypertension. Cardiac index and heart rate remained unchanged, but total peripheral resistance index was reduced 12% to 15%. Stroke index was unchanged at rest but increased 7% to 9% during exercise. Twenty-four-hour ambulatory blood pressure was reduced 10% to 13%. Left ventricular mass was reduced 27% in patients with left ventricular hypertrophy (n = 18). CONCLUSION: Losartan lowers blood pressure by reducing total peripheral resistance at rest and during exercise but cardiac pump function is unchanged or slightly improved. In patients with left ventricular hypertrophy, losartan induces a sizeable reduction in left ventricular mass.

Reproducibility of salt sensitivity testing using a dietary approach in essential hypertension.

To investigate the reproducibility of salt sensitivity testing using a dietary approach, 30 essential hypertensive patients underwent salt sensitivity testing on an outpatient basis twice with a 6 month interval. At both tests casual and 24-h ambulatory blood pressure (24-h BP) was recorded on habitual diet, then after a 6-day period on a low salt diet (aiming at 50 mmol/day), and finally after a 6-day period on a high salt diet (supplementation with sodium chloride tablets aiming at 250 mmol/day). Subjects showing > or =10% increase in mean BP when changing from low to high dietary salt intake were classified as salt sensitive. Dietary salt intake was assessed as 24-h urinary sodium excretion. Based on 24-h BP recordings eight patients were characterised as salt sensitive (SS) and 22 as salt resistant (SR) in the first test, and three of the initial SS and 15 of the initial SR patients maintained their salt sensitivity status at the second test. Based on casual BP recordings 13 patients were characterised as SS and 17 as SR in the first test, and three of the initial SS and 13 of the initial SR patients maintained their salt sensitivity status at the second test. Thus, salt sensitivity status was reproducible in 60% when using 24-h BP, and in 53% when using casual BP measurements. There was no difference in baseline BP in dietary salt intake between the two tests. In the total study population, no significant correlation was found between the change in casual or 24-h BP during salt repletion in the first and second test. In conclusion casual and 24-h BP response to a 200 mmol/24h change in dietary salt intake is highly individual and varies over time. Characterisation of salt sensitivity using a dietary approach in out-patients is reproducible in only 53-60% of the patients.

Similar central hemodynamics in salt-sensitive and salt-resistant hypertensive patients.

Salt may be involved in the pathogenesis of essential hypertension but no agreement has been reached on how salt might exert its blood pressure control. One reason for the conflicting results could be differences in response to changes in salt intake--i.e. between salt-sensitive and salt-resistant subjects. Hypertension reflects a hemodynamic disturbance: mainly an increase in total peripheral resistance. In order to determine whether central hemodynamics is different in salt-sensitive and salt-resistant essential hypertension, a study was carried out on 37 patients aged 31-63 years with mean casual blood pressure 165/104 mmHg. Based on an increase in ambulatory 24-h mean blood pressure of > or = 10% after one week of dietary salt loading (260 mmol NaCl/24 h) following a one-week salt depletion period (60 mmol NaCl/24 h), 7 patients (19%) were classified as salt sensitive and 30 patients (81%) as salt resistant. Before the salt-sensitivity test, while patients were on their habitual salt intake (160 mmol NaCl/24 h), central hemodynamics (intra-arterial pressure, cardiac output by dye dilution, heart rate by electrocardiogram, and total peripheral resistance) was examined at rest and during bicycle exercise. None of the central hemodynamic variables were different between the two groups, despite a marked difference in blood pressure response to one week of salt loading between the salt-sensitive and the salt-resistant groups (27/9 mmHg vs -2/1 mmHg). Furthermore, no statistically significant differences were observed in neurohumoral variables or echocardiographic indices of left ventricular dimensions between the two groups. Owing to the invasive hemodynamic procedure, central hemodynamics was not restudied during high- or low salt intake. It is concluded that there is no difference in central hemodynamics in salt-sensitive and salt-resistant hypertensive patients when they are on their habitual salt diet.

Factors influencing left ventricular mass in salt sensitive and salt resistant essential hypertensive patients.

UNLABELLED: To investigate whether salt sensitivity is associated with differences in left ventricular mass or geometry, salt sensitivity testing and Doppler echocardiography was performed in 30 essential hypertensive patients (7 women and 23 men) with mean age 43+/-9 years. Salt sensitivity was defined as a 10% increase or more in 24-h blood pressure (24hBP) when going from low to high dietary sodium intake based on a single test. Eight patients were characterized as salt sensitive and 22 as salt resistant. At baseline, there was no difference in casual blood pressure (156/103+/-17/9 vs 158/100+/-18/11 mmHg) or 24hBP (152/ 90+/-25/15 vs 159/89+/-19/8 mmHg), in duration of hypertension (5+/-4 vs 4+/-3 years), daily sodium excretion (144+/-68 vs 171+/-68 mmol), left ventricular mass (LVM) (212+/-45 vs 246+/-52 g) or left ventricular relative wall thickness (RWT) between the salt sensitive and salt resistant groups of patients. In the total study population, increased RWT was found in 17 patients, and increased LVM in 10 patients. In only 10 patients were both these variables normal. Left ventricular geometric pattern did not differ between the salt sensitive and salt resistant groups. LVM and RWT were significantly correlated with 24hBP (r = 0.57 and 0.51, respectively; both p < 0.01). Significant correlation was also found between LVM and casual blood pressure, blood volume, body surface area, serum creatinine and albuminuria (r = 0.53, 0.60, 0.54, 0.54 and 0.43, respectively; all p < 0.01). In multiple regression analysis, 24hBP and blood volume were identified as independent predictors of LVM (R = 0.51, p < 0.001). CONCLUSIONS: increased RWT or LVM is common in both salt sensitive and salt resistant essential hypertensive patients. Salt sensitivity status based on a single test does not influence left ventricular hypertrophy or geometry. Twenty-four-hour blood pressure is related to increased RWT and LVM.

Factors influencing reduction in blood pressure and left ventricular mass in hypertensive type-1 diabetic patients using captopril or doxazosin for 6 months.

The effect of doxazosin versus captopril on blood pressure, albuminuria, and left ventricular mass was studied in 33 hypertensive type-1 diabetic patients randomized to 6 months treatment with captopril (17 patients, mean daily dose 100 mg) or doxazosin (16 patients, mean daily dose 9 mg). Casual and 24-h ambulatory blood pressure (24hBP) were reduced from 163/95 to 144/83 mm Hg and 152/86 to 145/81 mm Hg, respectively, in the captopril group, and from 160/93 to 145/86 mm Hg and 156/86 to 147/79 mm Hg in the doxazosin group (all P < .05). The achieved 24hBP on treatment was positively associated with pretreatment levels of glycosylated hemoglobin (HbA1c) and plasma atrial natriuretic peptide (r = 0.53 and 0.59, respectively, both P < .01). Albuminuria did not change significantly in either group. Left ventricular hypertrophy was present in 13 patients (7 in the captopril and 6 in the doxazosin group). Left ventricular mass was reduced by an average of 27% and 23%, respectively, in these patients (both P < .01), but did not change significantly in patients without left ventricular hypertrophy. The reduction in left ventricular mass was positively associated with the presence of baseline left ventricular hypertrophy and inversely with dietary sodium intake and achieved casual blood pressure on treatment (R2 = 0.59, P < .001). We conclude that doxazosin and captopril used for 6 months are equally effective in reducing blood pressure and left ventricular hypertrophy in hypertensive type-1 diabetic patients; the antihypertensive effect is closely related to glycemic control; and dietary sodium intake and achieved casual blood pressure after treatment are independent determinants of the reduction in left ventricular mass seen in these patients.

Beta-2 adrenoceptor genetic variation is associated with genetic predisposition to essential hypertension: The Bergen Blood Pressure Study.

We tested the hypothesis that genetic variation in the beta-2 adrenoceptor gene is associated with a genetic predisposition to hypertension. Offspring of two hypertensive parents were compared with offspring of two normotensive parents. The subjects were participants of the Bergen Blood Pressure Study, where couples were recruited in 1963 to 1964 and re-examined in 1990. We studied offspring of those couples in which both partners were either hypertensive or normotensive in both examinations. Twenty-three hypertensive and 22 normotensive families met the inclusion criteria. DNA samples from the first born of hypertensive family-history offspring and normotensive family-history offspring were analyzed. We used multiplex sequencing and specifically examined the promoter and the N-terminal portion of the beta-2 adrenoceptor gene. We found four genetic variants: at position -47, a C-->T substitution in the 5' leader cistron causing an Arg-->Cys exchange, at -20, a T-->C substitution, at +46 an A-->G substitution leading to an Arg16-->Gly exchange, and at +79, a C-->G substitution leading to a Gln27-->Glu exchange. The frequency of the Arg16 allele was significantly higher in the hypertensive family-history offspring compared to normotensive family-history offspring (58% vs. 28% P < 0.011). We constructed haplotypes for the four intragenic variants and found significant linkage dysequilibrium. In particular, the 5' leader cistron mutant with the wild type alleles at the other loci was significantly more frequent in offspring of hypertensive parents, compared to offspring of normotensive parents. We also performed a relative risk analysis comparing the Gly/Gly, Arg/Gly, and Arg/Arg alleles, which implicated the Arg-containing allele. Finally, we analyzed the effect of genotype on blood pressure in the offspring. We found a significant step-wise effect for all four polymorphisms examined. Our data suggest that the Arg variant of the Arg-->Gly exchange is associated with parental hypertension and higher blood pressure values in this northern European population.

Factors influencing LVM in hypertensive type-1 diabetic patients.

Diabetes mellitus is associated with a high prevalence of hypertension and left ventricular hypertrophy (LVH), and a causative relationship with abnormal sodium metabolism in diabetic patients has been suggested. Factors influencing left ventricular mass (LVM) were assessed in 30 hypertensive type-1 diabetic patients, mean age 46 +/- 9 (range 24-67) years, with a mean duration of diabetes and hypertension of 19 +/- 10 and 6 +/- 5 years, respectively. In the total study population, casual blood pressure was 163/94 +/- 24/10 mmHg and 24 h blood pressure was 155/87 +/- 17/8 mmHg. Twenty-four-hour urine samples were obtained to measure daily albumin excretion (0.77 +/- 1.06 g) and dietary sodium intake was assessed as 24 h sodium excretion (173 +/- 77 mmol). Creatinine clearance averaged 1.41 +/- 0.53 ml/s. LVM determined by echocardiography was 221 +/- 74 g (range 104-408 g) and 33% of the patients had LVH. Multiple regression analysis identified dietary sodium intake and plasma atrial natriuretic peptide as independent predictors of LVM (R2 = 0.52, p < 0.001). No significant association was found between LVM and blood pressure or albuminuria. The results propose dietary sodium intake as an important factor in the development of LVH in hypertensive type-1 diabetic patients.

Salt sensitivity in hypertensive type-1 diabetes mellitus.

UNLABELLED: As sodium retention has been proposed as a causal factor in the development of hypertension in diabetic patients, a high incidence of salt sensitivity has been suggested. To evaluate the influence of dietary sodium intake on blood pressure, casual and 24-h blood pressure was measured in 30 hypertensive type-1 diabetic patients aged 24-67 (mean 46) years while they were on habitual diet, after 6 days of low-sodium diet (50 mmol/day), and after 6 days of high-sodium diet (250 mmol/day). Nine patients (30%) who increased their 24-h mean blood pressure by more than 10% when going from low- to high-sodium intake were classified as salt sensitive; the others as salt resistant. The salt sensitive group had a significantly lower urinary excretion of dopamine at baseline, and a higher diuresis and a more pronounced decrease in 24-h blood pressure during salt depletion (all p < 0.01). Low-sodium diet reduced casual and 24-h blood pressure by 4% in the total study population compared with 9% in the salt sensitive group (p < 0.01). There was no difference in glomerular filtration rate, filtration fraction, proteinuria or urinary sodium excretion between the groups. CONCLUSIONS: Sodium restriction more effectively reduces blood pressure in the salt sensitive minority of hypertensive type-1 diabetic patients irrespective of renal function. The incidence of salt sensitivity is not increased in hypertensive type-1 diabetic patients compared with essential hypertensive patients.

[Status of ongoing controlled clinical trials on hypertension]. / Status for pågående kontrollerte kliniske hypertensjonsforsøk.

Antihypertensive treatment with diuretics and/or beta-blockers lowers stroke and coronary heart disease morbidity and mortality. However, although the newer antihypertensives induce effective control of blood pressure and regression of hypertensive organ damage, it has not been proven whether they reduce mortality. Ongoing clinical trials such as STOP II, CAPPP, NORDIL, INSIGHT, ALLHAT and LIFE test whether antihypertensive regimens with ACE-inhibitor, calcium-blocker, alpha-blocker and Angiotensin II-antagonist are equally good or possibly even better than diuretics and beta-blockers in preventing cardiovascular complications. The HOT trial clarifies how much the diastolic blood pressure should be lowered, and whether a small dose of aspirin has a protective effect when combined with optimal control of blood pressure. These studies should give better guidelines for the treatment of hypertension.

The Bergen blood pressure study: offspring of two hypertensive parents have significantly higher blood pressures than offspring of one hypertensive and one normotensive parent.

OBJECTIVE: To study blood pressure and antihypertensive drug treatment in subjects with contrasting family histories of hypertension. SUBJECTS AND METHODS: We grouped 520 offspring examined in 1990 (mean +/- SD age 36 +/- 7 years) according to their parents' blood pressure screened in 1963-1964 as offspring of two normotensive (systolic/diastolic blood pressure < 135/70 mmHg) parents (group 1); offspring of one hypertensive (> or = 145/95 mmHg) and one normotensive (<135/70 mmHg) parent (group 2); and offspring of two hypertensive (> or = 140/90 mmHg) parents (group 3). Offspring blood pressure was measured with a conventional mercury sphygmomanometer by one observer. The mean of the last two of three seated measurements was used for analyses. Drug treatment was determined by interview. RESULTS: Mean +/- SD blood pressure was lowest in group 1 (121 +/- 12/72 +/- 10 mmHg), intermediate in group 2 (125 +/- 12/76 +/- 9 mmHg) and highest in group 3 (135 +/- 15/85 +/- 11 mmHg), P<0.01 for each. Of the subjects in groups 1, 2 and 3, 1.3, 2.4 and 11.7%, respectively, were taking antihypertensive drugs (P<0.01). CONCLUSIONS: Screening blood pressure in parents has implications for offspring blood pressure almost 30 years later. Offspring of hypertensive parents have higher blood pressure and are given antihypertensive drugs at higher rates than the offspring of normotensive parents. Also, substantial differences were seen between the offspring of one and of two hypertensive parents. Thus, risk associated with a family history of hypertension varies with the definition of the family history. To obtain maximum contrast in the predisposition to high blood pressure, comparative studies in offspring of hypertensive and normotensive families should be based on blood pressure data from both parents.

Current issues in the control of hypertension.

The controversies surrounding population-based hypertension studies compared with controlled clinical trials are discussed. The results of non-pharmacological trials based on life-style changes vs. drug treatment are presented. The ultimate goal of anti-hypertensive therapy is to prevent and reverse target organ damage.

The Bergen Blood Pressure Study: prehypertensive changes in cardiac structure and function in offspring of hypertensive families.

Cardiac morphology and function were determined by echocardiography in normotensive offspring of 23 hypertensive and 22 normotensive families. The family histories of hypertension or normotension were based on 27 years' observation of parental blood pressure. Pulsed Doppler and M-mode echocardiography were performed in standard views. Out of the total 109 offspring, 94 participated in the present study (age (mean +/- SD) 36 +/- 7 years). Left ventricular posterior wall thickness was higher in offspring of hypertensive than normotensive families (10.1 +/- 1.7 vs. 9.3 +/- 1.5 mm; p < 0.05). Offspring of hypertensive families had lower transmitral early/late peak flow velocities (p < 0.001) and higher transmitral late peak flow velocities (p < 0.001) than offspring of normotensive families, but the differences between groups became inconsistent after adjustment for confounding variables (including left ventricular structural parameters). On the other hand, the family history of hypertension was consistently associated with increased transmitral early peak flow velocity and increased transmitral acceleration and deceleration slopes p < 0.05), a pattern suggesting increased left ventricular stiffness. Increased posterior wall thickness and diastolic functional changes may indicate cardiac hypertrophy and decreased left ventricular compliance and precede the development of hypertension in offspring of hypertensive families.

The relationships between casual and ambulatory blood pressure measurements and central hemodynamics in essential human hypertension.

OBJECTIVE: To determine the association between ambulatory blood pressure (ABP) and central hemodynamics in hypertensive patients and between the area under the 24-h blood pressure curve and the hemodynamic indexes. PATIENT POPULATION: Forty untreated essential hypertensive patients (28 previously untreated, 12 withdrawn from therapy for > 12 weeks). METHODS: Patients underwent casual and 24-h ABP monitoring and invasive measurements of central hemodynamics. Central measures of ABP included 24-h mean, awake, and sleep values guided by activity journals. The ABP data were modeled by Fourier series and the ability of the smoothed and unsmoothed data to predict hemodynamics was compared. Individual blood pressure curves were analyzed by calculating the area under the curve using different threshold awake and sleep values to test the correlations between this form of blood pressure load and hemodynamics. RESULTS: Hemodynamic measures were not predicted by casual blood pressure but were related to ABP. Total peripheral resistance was strongly predicted by the area under the diastolic blood pressure (DBP) curve using an awake threshold of 90 mmHg and a sleep threshold of 80 mmHg (r = 0.56, P < 0.001). Data smoothing using Fourier transformation did not alter any correlations between ABP and hemodynamics. Exercise stroke index, an indicator of cardiac function impaired in early hypertensive heart disease, was also best predicted by area under the DBP curve using the same thresholds as above (r = -0.56, P < 0.001). CONCLUSIONS: These data imply that integrated areas under the ABP curve are related to hemodynamic hypertensive indexes and could be used to assess the extent of hypertensive burden in clinical trials.