Anders Hägg

Regression of left ventricular hypertrophy in human hypertension with irbesartan

Background The Swedish irbesartan left ventricular hypertrophy investigation versus atenolol (SILVHIA). Objective Angiotensin II induces myocardial hypertrophy. We hypothesized that blockade of angiotensin II subtype 1 (AT1) receptors by the AT1-receptor antagonist irbesartan would reduce left ventricular mass (as measured by echocardiography) more than conventional treatment with a beta blocker. Design and methods This double-blind study randomized 115 hypertensive men and women with left ventricular hypertrophy to receive either irbesartan 150 mg q.d. or atenolol 50 mg q.d. for 48 weeks. If diastolic blood pressure remained above 90 mmHg, doses were doubled, and additional medications (hydrochlorothiazide and felodipine) were prescribed as needed. Echocardiography was performed at weeks 0, 12, 24 and 48. Results Baseline mean blood pressure was 162/104 mmHg, and mean left ventricular mass index was 157 g/m2 for men and 133 g/m2 for women. Systolic and diastolic blood pressure reductions were similar in both treatment groups. Both irbesartan (P < 0.001) and atenolol (P < 0.001) progressively reduced left ventricular mass index, e.g. by 26 and 14 g/m2 (16 and 9%), respectively, at week 48, with a greater reduction in the irbesartan group (P = 0.024) . The proportion of patients who attained a normalized left ventricular mass (i.e. ⩽ 131 g/m2 for men and ⩽ 100 g/m2 for women) tended to be greater with irbesartan (47 versus 32%, P = 0.108). Conclusions Left ventricular mass was reduced more in the irbesartan group than in the atenolol group. These results suggest that blocking the action of angiotensin II at AT1-receptors may be an important mechanism, beyond that of lowering blood pressure, in the regulation of left ventricular mass and geometry in patients with hypertension.

Angiotensin converting enzyme gene polymorphism predicts blood pressure response to angiotensin II receptor type 1 antagonist treatment in hypertensive patients

Objectives To determine whether polymorphisms in the renin–angiotensin system can predict blood pressure-lowering response to antihypertensive treatment; more specifically, in response to treatment with irbesartan or atenolol. Design and methods Eighty-six patients with hypertension were randomized to double-blind treatment with either the angiotensin II type 1 receptor antagonist irbesartan or the β1 adrenergic receptor blocker atenolol and followed for 3 months. We analysed angiotensinogen T174M and M235T, angiotensin converting enzyme (ACE) I/D and angiotensin II type 1 receptor A1166C polymorphisms and related them to blood pressure reduction. Results The mean reductions in blood pressure were similar for both treatments. In the irbesartan group, individuals homozygous for the ACE gene I allele showed a greater reduction in diastolic blood pressure, exceeding those with the D allele (− 18 ± 11 SD versus − 7 ± 10 mmHg, P = 0.0096). This was not the case during treatment with atenolol, and the interaction term between type of treatment and ACE II genotype was significant (P = 0.0176). The angiotensinogen and angiotensin II type 1 receptor polymorhisms were not related to the response to treatment. Conclusions ACE genotyping predicted the blood pressure-lowering response to antihypertensive treatment with irbesartan but not atenolol. Thus, specific genotypes might predict the response to specific antihypertensive treatment.

Hydrochlorothiazide, but not Candesartan, aggravates insulin resistance and causes visceral and hepatic fat accumulation : the mechanisms for the diabetes preventing effect of Candesartan (MEDICA) Study

Treatment with angiotensin II receptor blockers is associated with lower risk for the development of type 2 diabetes mellitus compared with thiazide diuretics. The Mechanisms for the Diabetes Preventing Effect of Candesartan Study addressed insulin action and secretion and body fat distribution after treatment with candesartan, hydrochlorothiazide, and placebo. Twenty-six nondiabetic, abdominally obese, hypertensive patients were included in a multicenter 3-way crossover trial, and 22 completers (by predefined criteria; 10 men and 12 women) were included in the analyses. They underwent 12-week treatment periods with candesartan (C; 16 to 32 mg), hydrochlorothiazide (H; 25 to 50 mg), and placebo (P), respectively, and the treatment order was randomly assigned and double blinded. Intravenous glucose tolerance tests and euglycemic hyperinsulinemic (56 mU/m2 per minute) clamps were performed. Intrahepatic and intramyocellular and extramyocellular lipid content and subcutaneous and visceral abdominal adipose tissue were measured using proton magnetic resonance spectroscopy and MRI. Insulin sensitivity (M-value) was reduced following H versus C and P (6.07±2.05, 6.63±2.04, and 6.90±2.10 mg/kg of body weight per minute, mean±SD; P≤0.01). Liver fat content was higher (P<0.05) following H than both P and C. The subcutaneous to visceral abdominal adipose tissue ratio was reduced following H versus C and P (P<0.01). Glycosylated hemoglobin, alanine aminotransferase, aspartate aminotransferase, and high-sensitivity C-reactive protein levels were higher (P<0.05) after H, but not C, versus P. There were no changes in body fat, intramyocellular lipid, extramyocellular lipid, or first-phase insulin secretion. Blood pressure was reduced similarly by C and H versus P. In conclusion, visceral fat redistribution, liver fat accumulation, low-grade inflammation, and aggravated insulin resistance were demonstrated after hydrochlorothiazide but not candesartan treatment. These findings can partly explain the diabetogenic potential of thiazides.

A Prospective Comparison of Duplex Ultrasonography, Captopril Renography, MRA, and CTA in Assessing Renal Artery Stenosis

Purpose: To prospectively compare the diagnostic accuracy of duplex ultrasonography, captopril renography, computed tomography angiography (CTA), and 3D Gd magnetic resonance angiography (MRA) in diagnosing hemodynamically significant renal artery stenosis (RAS). Material and Methods: The standard of reference was measurement of transstenotic pressure gradient. Fifty-eight hypertensive patients with suspicion of RAS were evaluated, when possible, by all five techniques. Sensitivity and specificity to detect RAS were compared for each technique on both a patient and kidney basis. Discrepancies were evaluated separately and classified as borderline, method dependent, or operator dependent. Results: The prevalence of RAS was 77%. The sensitivity/specificity of ultrasonography, captopril renography, CTA, and MRA in detecting kidneys with RAS was 73/71%, 52/63%, 94/62%, and 93/91%, respectively. Ultrasonography had a significantly lower sensitivity than CTA and MRA (P<0.001) but higher than captopril renography (P = 0.013). Borderline RAS was the main cause for discrepancies. Conclusion: MRA and CTA were significantly better than duplex ultrasonography and captopril renography in detecting hemodynamically significant RAS. The ultrasonography criteria for RAS based on the evaluation of renal peak systolic velocity and renal/aortic ratio are questionable. Captopril renography cannot be recommended for assessing RAS.

Polymorphisms in the angiotensinogen and angiotensin II type 1 receptor gene are related to change in left ventricular mass during antihypertensive treatment: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial.

Background Our aim was to determine if gene polymorphisms in the renin–angiotensin–aldosterone system (RAAS) were related to the degree of change in left ventricular hypertrophy (LVH) during antihypertensive treatment. Methods and results Patients with essential hypertension and echocardiographically diagnosed LVH were included in a double-blind study to receive treatment with either the angiotensin II type 1 receptor (AT1-receptor) antagonist irbesartan (n = 41), or the beta-1 adrenergic receptor blocker atenolol (n = 43) as monotherapy for 3 months. The angiotensinogen T174M and M235T, the angiotensin-converting enzyme I/D, the AT1-receptor A1166C and the aldosterone synthase (CYP11B2) -344 C/T polymorphisms were analysed and related to the change in left ventricular mass (LVM). Patients with the angiotensinogen 174 TM genotype treated with irbesartan responded with the greatest reduction in LVM (−23 ± 31SD g/m2 for TM and +0.5 ± 18 g/m2 for TT, P = 0.005), independent of blood pressure reduction. Both the angiotensinogen 235 T-allele (P = 0.02) and the AT1-receptor 1166 AC genotype responded with the greatest reduction in LVM when treated with irbesartan (−0.1 ± 19 g/m2 for AA and –18 ± 30 g/m2 for AC, P = 0.02), independent of blood pressure reduction. These polymorphisms were not associated with the change in LVM during treatment with atenolol. Discussion The angiotensinogen T174M and M235T and the AT1-receptor A1166C polymorphisms were related to the change in LVH during antihypertensive treatment with an AT1-receptor antagonist; of these angiotensinogen T174M was the most powerful. This highlights the role of the RAAS for left ventricular hypertrophy and the potential of pharmacogenetics as a tool for guidance of antihypertensive therapy.

Aldosterone synthase (CYP11B2) -344 C/T polymorphism is related to antihypertensive response : Results from the Swedish Irbesartan left ventricular hypertrophy investigation versus atenolol (SILVHIA) trial

BACKGROUND Our aim was to determine whether the aldosterone synthase (CYP11B2) -344 C/T polymorphism was associated with the blood pressure (BP)-lowering response to antihypertensive treatment. METHODS Patients with mild-to-moderate primary hypertension and left ventricular hypertrophy were randomized in a double-blind study to receive treatment with either the angiotensin II type 1 (AT1) receptor antagonist irbesartan (n = 43), or the beta1-adrenergic receptor blocker atenolol (n = 43). The aldosterone synthase (CYP11B2) -344 C/T polymorphism was analyzed using solid-phase minisequencing and related to BP reduction after 3 months treatment. Serum aldosterone levels were measured. RESULTS After 3 months treatment the mean reductions in BP were similar for both treatment groups. When assessing the systolic BP reduction in the irbesartan group, patients with the TT variant had a more pronounced reduction (-21 +/- 19 SD mm Hg, n = 17) than both the TC (-14 +/- 18 mm Hg, n= 18) and CC (0 +/- 17 mm Hg, n = 8) genotypes (P = .04). There was no association between this polymorphism and the diastolic BP response. The -344 C/T polymorphism was not associated with the BP response to atenolol. Nor was it related to the baseline serum aldosterone level. CONCLUSIONS The aldosterone synthase -344 C/T polymorphism was related to the BP-lowering response in hypertensive patients treated with the AT1-receptor antagonist irbesartan.

Treatment with irbesartan or atenolol improves endothelial function in essential hypertension

Objectives To investigate if antihypertensive treatment could improve endothelium-dependent vasodilatation in hypertensive patients, and whether the angiotensin II subtype-1 (AT1)-receptor antagonist irbesartan and the β1-receptor antagonist atenolol would differ in this respect. Subjects and methods Thirty-four patients (28 men and six women) with mild-to-moderate essential hypertension (diastolic blood pressure 90–120 mmHg) were randomized to once daily 150–300 mg irbesartan or 50–100 mg atenolol in a double-blind fashion, preceded by a placebo run-in period. Forearm blood flow (FBF) was assessed by venous occlusion plethysmography during local intra-arterial infusions of methacholine and sodium nitroprusside, to evaluate endothelium-dependent and endothelium-independent vasodilatation, respectively. Measurements of FBF were undertaken at the end of the run-in placebo period and repeated after 3 months of active antihypertensive treatment. Results Irbesartan and atenolol induced a similar decline in blood pressure (from 171/107 to 158/98 mmHg, P < 0.05), and improved endothelium-dependent vasodilatation (e.g. an increase in FBF response to 4 μg/min methacholine from 325 ± 29% to 411 ± 41%, P < 0.05), with no difference between the two study drugs. No significant changes in endothelium-independent vasodilatation were induced by irbesartan or by atenolol. Conclusions The present study shows that 3 months of antihypertensive therapy with irbesartan or atenolol improves endothelium-dependent vasodilatation.

Blood viscosity and peripheral vascular resistance in patients with untreated essential hypertension

Objectives: The viscosity of blood is increased in patients with essential hypertension. The aim of the present study was to investigate the importance of the different variables of blood rheology to total peripheral resistance, and to elucidate whether inappropriate regulation of the formation of erythropoietin could be important. Design: Nineteen consecutive patients with untreated essential hypertension were examined and compared with a group of matched healthy volunteers. Methods: The haemorheologic variables were assessed by rotational viscometry and the haemodynamic variables by bioimpedance cardiography. The serum concentrations of erythropoietin were determined by radioimmunoassay. Results: The whole blood viscosity and peripheral resistance index were elevated in the hypertensive group. The two variables were positively correlated with each other (r=0.68, P=0.0015). The plasma viscosity and erythrocyte aggregation tendency were increased and the erythrocyte deformability, measured as fluidity, was decreased in the hypertensive patients. In the male subpopulation (n=12) the aggregation tendency was positively, and the deformability negatively, correlated with body mass index. The serum concentrations of erythropoietin were equal in the two groups. Conclusions: The increased total peripheral resistance in patients with essential hypertension may in part be explained by an increased blood viscosity, but the possibility of an opposite cause-effect relationship must also be taken into consideration. The haemorheological abnormalities observed in the present patients cannot be explained by high serum levels of erythropoietin.

Captopril, but not nifedipine, improves endothelium-dependent vasodilation in hypertensive patients

The present study aimed to investigate the influence of the angiotensin-converting enzyme (ACE)-inhibitor captopril and the Ca-antagonist nifedipine on endothelium-dependent vasodilation (EDV) in the forearm of hypertensive patients. Twenty-three middle-aged untreated hypertensive patients underwent evaluation of EDV and endothelium-independent vasodilation (EIDV) in the forearm, by means of local intra-arterial infusions of methacholine (MCh, evaluating EDV) and sodium-nitroprusside (SNP, evaluating EIDV), before and 1 h after intake of either captopril (25 mg) or nifedipine (10 mg) in a randomised, double-blind fashion. A matched normotensive control group was investigated at baseline conditions only. Five of the hypertensives were also evaluated after 3 months of treatment with captopril 25 mg twice daily in an open pilot study.First, the vasodilation induced by methacholine (MCh), but not SNP, was significantly attenuated in the hypertensive patients compared to the normotensive controls (P < 0.001 at mch 4 μg/min).Second, although the two drugs induced a similar decline in blood pressure (BP) 1 h after administration (−11 to 10 mm Hg/−8 to 7 mm Hg), captopril significantly potentiated the vasodilator response to MCh (+32 ± 13%, MCh 4 μg/min, P < 0.01) but not snp, while nifedipine did not significantly alter the response to either mch or snp. the improvement in vasodilator response to mch induced by captopril was closely related to the reduction in bp (r = 0.72, P < 0.01).Third, in the pilot study, 3 months of captopril treatment induced a significant potentiation of the vasodilator response to MCh (+34 ± 17%, MCh 4 μg/min, P < 0.05) in parallel with a significant bp reduction (−22 ± 24/13 ± 13 mm hg, P < 0.05), while the response to snp was unchanged.In conclusion, the present study confirmed that essential hypertension is associated with a defect in EDV. Furthermore, an improvement in EDV was seen in hypertensive patients shortly after administration of captopril, but not nifedipine. In addition, a significant beneficial effect on EDV was seen in a small pilot study during long-term treatment with captopril.

Continuous recording of muscle nerve sympathetic activity during percutaneous transluminal angioplasty in renovascular hypertension in man.

We have previously shown that during percutaneous transluminal renal angioplasty (PTRA) there is a transient increase in plasma renin activity (PRA) that is partly mediated by adrenergic beta-receptors. Despite a concomitant increase in plasma aldosterone, no increase in blood pressure occurred. The aim of this study was to record sympathetic outflow in man during PTRA as reflected by muscle nerve sympathetic activity and arterial plasma noradrenaline. Nine patients with hypertension and unilateral renal artery stenosis underwent PTRA by the Grüntzig technique and simultaneous microelectrode recording of muscle nerve sympathetic activity in the peroneal nerve. Blood pressure and heart rate were recorded and blood specimens were drawn for determination of noradrenaline and PRA. During total occlusion of the renal artery, muscle nerve sympathetic activity and the heart rate were unchanged. In the first 6 min after occlusion PRA increased transiently, but there was no significant change in muscle nerve sympathetic activity, arterial noradrenaline, heart rate or blood pressure. From 10 min after PTRA, muscle nerve sympathetic activity was significantly increased and after 40 min there was a significant increase in noradrenaline. The heart rate remained unchanged throughout the procedure, but the blood pressure decreased progressively and the diastolic blood pressure was significantly reduced at 40 min, indicating successful dilation. Despite activation of the renin-angiotensin-aldosterone system and the sympathetic nervous system, two strong pressor systems, the only circulatory reaction was a decrease in diastolic blood pressure. These findings indicate simultaneous activation of a potent depressor mechanism during PTRA.