Ove K. Andersson

Survival in treated hypertension: follow up study after two decades

Abstract Objective: To compare survival and cause specific mortality in hypertensive men with non-hypertensive men derived from the same random population, and to study mortality and morbidity from cardiovascular diseases in the hypertensive men in relation to effects on cardiovascular risk factors during 22-23 years of follow up. Design: Prospective, population based observational study. Subjects and methods: 686 hypertensive men aged 47-55 at screening compared with 6810 non-hypertensive men. The hypertensive men were having stepped care treatment with eitherβ adrenergic blocking drugs, thiazide diuretics, or combination treatment. Mortality, morbidity, and adverse effects were registered at yearly examinations and from death certificates. Main outcome measures: All cause mortality and cause specific mortality. Results: Treated hypertensive men had significantly impaired probability of total survival as well as survival from coronary heart disease and stroke. All cause mortality as well as coronary heart disease and stroke mortality were very similar in hypertensive men and normotensive men during the first decade, but increased steadily thereafter despite continuous good blood pressure control. Smoking, signs of target organ damage, and high serum cholesterol levels, but not blood pressure at screening, were significantly related to the incidence of coronary heart disease during follow up. In time dependent Coxs regression analysis, the incidence of coronary heart disease was significantly related only to serum cholesterol concentrations in the study. Cancer mortality was almost similar in treated hypertensive men (61/686, 8.9%) and non-hypertensive men (732/6810, 10.8%). Conclusion: Treated hypertensive men had impaired survival and increased mortality from cardiovascular disease compared with non-hypertensive men of similar age. These differences were observed during the second decade of follow up. During an observation period of 22-23 years —about 15 000 patient years—hypertensive men receiving diuretics and β blockers had no increased risk of cancer or non-cardiovascular disease.

Diabetes in treated hypertension is common and carries a high cardiovascular risk: results from a 28-year follow-up.

Objective The objective of this study was to analyse predictive factors for development of type 2 diabetes during life-long therapy for hypertension and the alleged additional cardiovascular risk this constitutes. Methods The study group (n = 754) comprised the hypertensive subgroup of a randomized population sample of 7500 men, aged 47–54 years, screened for cardiovascular risk factors and followed for 25–28 years. The patients were treated with thiazide diuretics and beta-adrenergic blocking drugs with the addition of hydralazin during the first decade. Calcium antagonists were substituted for hydralazin and, if needed, angiotensin-converting enzyme inhibitors were added when these drugs became available. Results A total of 148 (20.4%) treated hypertensive patients developed diabetes during 25 years, and in multivariate Cox regression analysis body mass index, serum triglycerides and treatment with beta-blockers were positively related with this complication. New-onset diabetes implied a significantly increased risk for stroke [hazard ratio (HR): 1.67; 95% confidence interval (95% CI): 1.1–2.6; P < 0.05], myocardial infarction (OR: 1.66; 95% CI: 1.1–2.5; P < 0.05) and mortality (OR: 1.42; 95% CI: 1.1–1.9; P < 0.05). The greatest risk for stroke was new-onset diabetes, followed by smoking (OR: 1.46; 95% CI: 1–2.2; P = 0.07) and the greatest risk for myocardial infarction was new-onset diabetes, followed by smoking (HR: 1.64; 95% CI: 1.1–2.4; P < 0.01). The greatest risk for mortality was smoking (HR: 1.73; 95% CI: 1.3–2.2; P < 0.005). Achieved systolic and diastolic blood pressure were not predictive of cardiovascular complications or death. The mean observation time from onset of diabetes mellitus to a first stroke was 9.1 years and to a first myocardial infarction 9.3 years. Conclusion Diabetes in treated hypertensive patients is alarmingly common and carries a high risk for cardiovascular complications and mortality.

Enhanced left ventricular endocardial border delineation with an intravenous injection of SonoVue, a new echocardiographic contrast agent : A European multicenter study.

The safety and efficacy of SonoVue (also referred to as BR1), a new contrast agent for delineating endocardial border of the left ventricle after intravenous administration, was assessed. Two hundred and eighteen patients with suspected coronary artery disease undergoing fundamental echocardiography for the assessment of left ventricle were enrolled in a prospective multicenter, single blind, cross‐over study with random sequence allocation of four different doses of SonoVue. Endocardial border definition in the apical and parasternal views was scored as O = not visible, 1 = barely visible, and 2 = well visualized before and after contrast enhancement. Analysis was performed by two pairs of off‐site observers. Safety of SonoVue was also assessed. Results of our study indicated that the mean improvements in the endocardial border visualization score were as follows: 3.1 ± 7.8 (95% CI, 2.5 and 3.7) for 0.5 ml, 3.4 ± 8.0 (95% CI, 2.8 and 4.0) for 1 ml, 3.4 ± 7.9 (95% CI, 2.8 and 4.0) for 2 ml, and 3.7 ± 8.0 (95% CI, 3.1 and 4.3) for 4 ml (P < 0.05 for all doses from baseline). Changes from baseline in endocardial visualization scores were also seen in the apical views (P < 0.05) and they were dose‐dependent (P < 0.001). Similar enhancements of endocardial visualization scores were observed in the apical views in patients with suboptimal baseline echocardiographic images. Diagnostic confidence for assigning a score and image quality also were significantly better following contrast enhancement. No significant changes in the laboratory parameters and vital signs were noted following contrast enhancement, and the side effects were minimal. It was concluded that SonoVue is safe and effective in delineating endocardial border, including in patients with suboptimal baseline images.

Diabetes mellitus and raised serum triglyceride concentration in treated hypertension--are they of prognostic importance? Observational study.

Abstract Objective: To analyse whether metabolic changes during long term treatment with antihypertensive drugs are associated with an increased risk of coronary heart disease. Design: Observational study. Setting: Gothenburg, Sweden. Subjects: 686 middle aged hypertensive men, recruited after screening of a random population sample, and followed for 15 years during treatment with predominantly β adrenoceptor blockers or thiazide diuretics, or both. Coronary heart disease and diabetes mellitus were registered at yearly patient examinations. Entry characteristics, as well as within study serum concentrations of cholesterol and triglycerides and the development of diabetes mellitus, were related to the incidence of coronary heart disease in a time dependent Coxs regression analysis. Main outcome variable: Coronary heart disease morbidity. Results: Diabetes mellitus, raised serum cholesterol and triglyceride concentrations present at the beginning of the study were all significantly predictive of coronary heart disease in univariate analysis. The relative risk of diabetes mellitus and of a 1 mmol/l increase in the cholesterol and triglyceride concentrations was 2.12 (95% confidence interval 1.11 to 4.07), 1.21 (1.05 to 1.39), and 1.21 (1.03 to 1.43) respectively. However, when the within study metabolic variables were analysed, only the serum cholesterol concentration was significantly and independently associated with coronary heart disease (relative risk 1.07 (1.02 to 1.13)). Although the triglyceride concentrations increased slightly during the follow up, the within study serum triglyceride concentrations were not associated with the incidence of coronary heart disease (1.04 (0.96 to 1.10)). New diabetes mellitus—that is, onset during follow up—was not significantly associated with an increased risk for coronary heart disease (1.48 (0.37 to 6.00)). Conclusions: Metabolic disturbances such as diabetes mellitus and hyperlipidaemia presenting before the start of antihypertensive treatment have a prognostic impact in middle aged, treated hypertensive men. Moreover, while within study cholesterol concentration was an independent predictor of coronary heart disease, drug related diabetes mellitus and raised serum triglyceride concentrations that are associated with treatment do not seem to have any major impact on the coronary heart disease prognosis in this category of patients. Key messages The issue of “newer” versus “older” antihypertensive agents is an important one in the treatment of hypertension This study shows that diabetes mellitus and raised serum triglyceride concentrations occurring during long term treatment of middle aged hypertensive men taking β blockers or thiazide diuretics, or both, have no major impact on the prognosis for coronary heart disease Until the outcome of controlled trials comparing “metabolically neutral” drugs with β blockers and thiazide diuretics, β blockers or thiazide diuretics, either alone or combined, should continue to be used as major first line drugs in the treatment of hypertension

Cardiovascular effects of weight reduction versus antihypertensive drug treatment: a comparative, randomized, 1-year study of obese men with mild hypertension.

The aim of the study was to compare cardiovascular effects of weight reduction and sodium restriction with antihypertensive drug treatment in obese middle-aged men with mild hypertension in an open randomized trial lasting for 1 year, preceded by a 6-week run-in period. In the diet group (n = 31), weight decreased by 7.8 kg and salt intake by 2 g/day. In the other group (n = 30), treatment was structured with atenolol as the first line drug. The differences in antihypertensive response were highly significant when measured as casual blood pressure, with drug treatment being favoured. Echocardiographic estimations of left ventricular morphology and function showed no difference in effects between the two treatment modalities. Further analyses showed that the presence of previous antihypertensive treatment was modulating the effect of intervention on left ventricular mass. The response to treatment in plethysmographic estimations of resistance at maximal dilatation in the forearm did not differ between the groups. We conclude that drug treatment was superior to the diet regimen in controlling hypertension, that no differences were observed in effects on cardiovascular structure and that previous antihypertensive treatments seems to be a potent confounding factor that should be taken into consideration in future studies.

Resting and volume-stimulated circulating atrial natriuretic peptide in young normotensive men with positive family histories of hypertension

Normotensive young men (36 +/- 5 years old) with positive family histories of hypertension (n = 11) and age-matched controls (n = 21) with negative family histories of hypertension were examined. The control group was divided into one group matched for body mass index with those subjects with positive family histories (n = 10) and one group with normal body mass index (n = 11). Blood pressure, central venous pressure (CVP), plasma atrial natriuretic peptide (ANP) and serum aldosterone were examined at a baseline and during an acute volume load with 1000 ml saline solution. Subjects with positive family histories and controls matched for body mass index had a higher blood pressure at baseline than controls with normal body mass index. CVP and serum aldosterone did not differ between the three groups, while sodium intake and plasma concentrations of ANP were significantly higher in subjects with positive family histories. During volume loading, CVP increased significantly more in subjects with positive family histories as compared with the two control groups. A blunted response to ANP was observed during volume loading in subjects with positive family histories, while subjects in the two control groups demonstrated comparable and significant increases in circulating ANP. Serum aldosterone, however, decreased during volume loading in all three groups, with no difference between the groups. We conclude that normotensive subjects with positive family histories are characterized by increased basal concentrations of ANP and exhibit a blunted response to an acute volume load.(ABSTRACT TRUNCATED AT 250 WORDS)

Candesartan Cilexetil in Hypertension: Effects of Six Weeks' Treatment on Haemodynamics, Baroreceptor Sensitivity and the Renin-angiotensin-aldosterone System

The effects of the angiotensin II receptor blocker candesartan cilexetil on systemic and forearm haemodynamics and baroreceptor sensitivity were evaluated in this randomized, placebo-controlled, double-blind, crossover study. After a 4-week placebo run-in period, 22 patients with essential hypertension (diastolic blood pressure 100-114 mmHg) were randomized to receive either candesartan cilexetil 16 mg or placebo once daily for 6 weeks. At the end of each period, 24 h after the last dose, invasive haemodynamic assessments were performed. Simultaneously, the plasma renin activity and plasma concentrations of angiotensin II, aldosterone and catecholamines were measured. Compared to placebo, candesartan cilexetil significantly reduced mean arterial pressure by 8 mmHg (95% CI: 2.6; 12.3), while cardiac output, stroke volume and heart rate were unchanged. Forearm vascular resistance was reduced by 1 mmHg x ml(-1) x L x min (CI: 0.3; 2.3). The baroreceptor sensitivity was not influenced, but a change in the set-point was noted. Plasma renin activity and angiotensin II concentrations were increased, while the aldosterone concentration was significantly reduced. Plasma catecholamine concentrations were unaffected. In conclusion, 6 weeks treatment with candesartan cilexetil 16 mg o.d. induced systemic and forearm vasodilatation and a reduction in blood pressure without compromising cardiac performance. The plasma concentration of aldosterone was reduced.

Influence of AT1 receptor blockade on blood pressure, renal haemodynamics and hormonal responses to intravenous angiotensin II infusion in hypertensive patients.

The aim of this study was to investigate blood pressure, renal haemodynamics, hormone secretion and the responses to angiotensin II infusion during candesartan cilexetil (candesartan), losartan potassium (losartan) and valsartan treatment in patients with essential hypertension. In this double-blind, randomized, crossover study, 24 patients (mean blood pressure of 163/97 mmHg), received candesartan 16 mg, losartan 50 mg and valsartan 80 mg once daily (o.d.) for 4 weeks after a placebo run-in period. At the end of each period, angiotensin II (0.5, 1.0 and 1.5 ng/min/kg) was infused 24 h after the previous drug administration. Each dose of angiotensin II was infused for 45 min. Before infusion and at the end of each infusion step, blood pressure and renal haemodynamics were assessed and plasma renin activity and plasma concentrations of angiotensin II and aldosterone were measured. During treatment with candesartan, resting mean arterial pressure (mean - SEM, 106 - 2 mmHg) was significantly decreased compared with treatment with losartan (110 - 2 mmHg) and valsartan (109 - 2 mmHg). Candesartan inhibited the angiotensin II induced increase in filtration fraction (0.8 - 0.4%) significantly more than losartan (1.5 - 0.4%) and valsartan (1.6 - 0.4%) and reduced the increase in aldosterone secretion (17 - 5 pg/ml/) significantly more than losartan (74 - 17 pg/ml/) and valsartan (82 - 19 pg/ml/). In conclusion, candesartan 16 mg o.d. reduced resting blood pressure significantly more than losartan 50 mg o.d. and valsartan 80 mg o.d. Candesartan almost completely inhibited the exogenous angiotensin II induced renal vasoconstriction, effectively inhibited the increase in filtration fraction and significantly blunted aldosterone secretion compared with losartan and valsartan, indicating a more effective AT 1 receptor blockade with candesartan.

Vasoconstriction during acute hypervolemic hemodilution in hypertensive patients is not prevented by calcium blockade.

The reduction of blood viscosity by moderate acute hypervolemic hemodilution in untreated hypertensives can be associated with a secondary vasoconstriction. The aim of this study was to examine whether a vasodilating therapy prevents this hemodynamic reaction. Twelve hypertensive patients (WHO stage II) were treated with the vasoselective calcium channel blocker isradipine in a placebo-controlled, double-blind, crossover study. Acute hypervolemic hemodilution was performed twice: at the end of the placebo period and after two months of treatment. Hemodilution was achieved by the intravenous infusion of 1000 mL saline over a 10- to 15-minute period. Arterial blood pressure, heart rate, cardiac output (dye dilution), renal blood flow, glomerular filtration, natriuresis, hemat ocrit, whole blood, and plasma viscosity were assessed before and after infusion. Flow resis tance and vascular hindrance in the central and renal circulation were calculated. Acute hemodilution associated with a significant reduction of blood (P<0.01) and plasma (P<0.01) viscosity did not influence the mean arterial pressure and cardiac output. Consequently, the total flow resistance remained unchanged. However, as a result of hemodilution, the calculated vascular hindrance index in the systemic circulation increased, indicating a vasoconstrictive reaction, both with placebo (from 5.22 to 6.07 U x mPa-1 x s-1, P < 0.05) and during chronic treatment with calcium blockade (from 3.75 to 4.22 U x mPa-1 x s-1, P<0.02). Vasoconstriction was not observed in the renal circula tion, either during the placebo or active treatments. The results of this study indicate that the systemic vasoconstriction evoked by the acute moderate hypervolemic hemodilution in hypertensive patients was not prevented by a calcium channel blockade.

Central hemodynamics and brachial artery compliance during therapy with isradipine, a new calcium antagonist

Seventeen middle-aged males with sustained essential hypertension (WHO stage II) and diastolic blood pressures (BP) exceeding 100 mm Hg during a placebo run-in period completed a trial to assess the hemodynamic effects of isradipine, a new dihydropyridine calcium antagonist. The study was double-blind and placebo-controlled with a crossover design. Brachial artery compliance was assessed as the ratio of stroke volumes and simultaneous pulse pressure. During therapy with isradipine (all patients received 7.5 mg b.i.d.), highly significant reductions in supine systolic BP [from 184 ± 16 to 162 ± 20 mm Hg (mean ± S.D.)] and diastolic BP (from 96 ± 8 to 83 ± 8 mm Hg) were observed. Heart rate was unchanged (69 ± 3 vs. 73 ± 2 beats/min) during chronic therapy. Total peripheral resistance was significantly reduced (from 24.8 ± 9 to 17.4 ± 5 units) while cardiac output was unchanged (6.0 ± 1.9 vs. 7.2 ± 1.8 L/min). Stroke volume was unchanged (92 ± 25 vs. 100 ± 25 ml/beat), and a significant (p < 0.05) increase in brachial artery compliance (from 1.05 ± 0.25 to 1.26 ± 0.35 ml/mm Hg) was observed.