Matthias R.W. Langenfeld

Pioglitazone Decreases Carotid Intima-Media Thickness Independently of Glycemic Control in Patients With Type 2 Diabetes Mellitus Results From a Controlled Randomized Study

Background—Patients with type 2 diabetes mellitus are at high risk of cardiovascular disease. Carotid intima-media thickness (IMT) is a strong predictor of myocardial infarction and stroke. Methods and Results—We compared the effects of pioglitazone-based therapy (45 mg/d) and glimepiride-based treatment (2.7±1.6 mg/d) for 12 and 24 weeks on metabolic control (HbA1c), insulin resistance (homeostasis model assessment), and carotid IMT (B-mode ultrasonography) in a randomized controlled study in 173 orally treated patients with type 2 diabetes (66 women, 107 men; mean±SD age, 62.6±7.9 years; body mass index, 31.8±4.6 kg/m2; HbA1c, 7.5±0.9%). Treatment was generally well tolerated in both groups. Despite similar improvements in metabolic control (HbA1c) after 24 weeks (−0.8±0.9% [pioglitazone] versus −0.6±0.8% [glimepiride]; P=NS), carotid IMT was reduced only in the pioglitazone group after 12 weeks (−0.033±0.052 versus −0.002±0.047 mm [glimepiride]; P<0.01 between groups) and 24 weeks (−0.054±0.059 versus −0.011±0.058 mm [glimepiride]; P<0.005 between groups). Insulin resistance was also improved only in the pioglitazone group (homeostasis model assessment, −2.2±3.4 versus −0.3±3.3; P<0.0001 between groups). Reduction of IMT correlated with improvement in insulin resistance (r=0.29, P<0.0005) and was independent of improvement in glycemic control (r=0.03, P=0.68). Conclusions—We found a substantial regression of carotid IMT, independent of improved glycemic control, after 12 and 24 weeks of pioglitazone treatment. This finding may have important prognostic implications for patients with type 2 diabetes mellitus.

Does Lipoprotein(a) Impair Endothelial Function

OBJECTIVES This study was undertaken to test the hypothesis that lipoprotein(a) [Lp(a)] impairs endothelial function. BACKGROUND Elevated Lp(a) plasma levels have been demonstrated to be associated with an increased risk of coronary heart disease. In atherosclerosis, endothelial dysfunction is known to be an early indicator of vascular changes. However, the effect of Lp(a) on nitric oxide (NO)-dependent vasodilator response has not yet been determined. We therefore examined the influence of Lp(a) on basal and stimulated NO-mediated vasodilator response in the forearm vascular bed. METHODS Strain gauge plethysmography was used to measure changes in forearm blood flow produced by intraarterial infusion of increasing doses of acetylcholine (3, 12, 24 and 48 microg/min), sodium nitroprusside (200, 800 and 3,200 ng/min) and N-monomethyl L-arginine (L-NMMA) (1, 2 and 4 micromol/min) in 57 white subjects (mean age +/- SD 37 +/- 14 years). Lp(a) plasma concentrations were determined by rocket immunoelectrophoresis. RESULTS Endothelium-dependent vasodilation tested by intraarterial acetylcholine and endothelium-independent vascular relaxation tested by intraarterial sodium nitroprusside were not correlated with Lp(a). Similarly, no significant differences in forearm blood flow changes were observed when patients were classified into tertiles according to their individual Lp(a) concentration. In contrast, changes in forearm blood flow after intraarterial L-NMMA indicating basal production and release of NO differed significantly among tertiles. Patients in the highest Lp(a) tertile (49.2 +/- 20.3 mg/dl) had a much greater vasoconstrictive response to L-NMMA than patients in the lowest Lp(a) tertile (4.8 +/- 2.5 mg/dl): 2 micromol/min of L-NMMA, -23.6 +/- 22.5% vs. -10.4 +/- 9.1% (p < 0.02); 4 micromol/min of L-NMMA, -27.8 +/- 10.3% vs. -17.6 +/- 9.9% (p < 0.03). Lp(a) plasma level consistently correlated negatively with the forearm blood flow responses to 4 micromol/min of intraarterial L-NMMA (r = -0.38, p < 0.01). Multiple stepwise regression analysis of variables, including total and high and low density lipoprotein cholesterol, further confirmed that plasma Lp(a) remained a significant independent determinant of forearm blood flow changes in response to L-NMMA (p < 0.02). CONCLUSIONS The endothelium-dependent vasoconstrictive response to L-NMMA was enhanced in subjects with relatively high Lp(a) plasma levels, suggesting an increased basal production and release of NO. This response seemed to reflect a compensatory mechanism of the endothelium to yet unknown Lp(a)-induced atherosclerotic effects.

1166 A/C Polymorphism of the Angiotensin II Type 1 Receptor Gene and the Response to Short-Term Infusion of Angiotensin II

BACKGROUND Previous studies reported an association of the 1166 A/C polymorphism of the angiotensin II (Ang II) type 1 receptor gene with high blood pressure and cardiovascular disease. We tested the hypothesis that this polymorphism affects the blood-pressure, renal hemodynamic, and aldosterone response to infused Ang II. METHODS AND RESULTS Young, male, white volunteers (n = 116) with normal (n = 65) or mildly elevated (n = 51) blood pressure on a high salt intake were genotyped for the 1166 A/C polymorphism. Two doses of Ang II (0.5 and 3 ng x kg(-1) x min(-1) over 30 minutes each) increased blood pressure, plasma aldosterone, glomerular filtration rate, and filtration fraction and decreased renal blood flow. The blood-pressure, renal hemodynamic, and aldosterone responses were not significantly different between subjects homozygous for the A allele (n = 56) and heterozygous subjects (n = 47) or subjects homozygous for the C allele (n = 13). Comparison of A allele homozygotes with all C allele carriers pooled (n = 60) or restriction of the analysis to normotensive volunteers also revealed no significant differences between genotypes. CONCLUSIONS The 1166 C variant of the Ang II type 1 receptor does not lead to a greater blood-pressure, aldosterone, or renal vascular response to infused Ang II in young, male, white subjects. We conclude that the 1166 A/C polymorphism does not have a major effect on these actions of Ang II.

Treatment and post-treatment effects of α- versus β-receptor blockers on left ventricular structure and function in essential hypertension

Abstract This study was undertaken to compare the effects of α-receptor blockade and β-receptor blockade on left ventricular structure and function in essential hypertension. The increase in left ventricular mass in patients with essential hypertension is at least partly induced by the sympathetic nervous system. We conducted a double-blind, randomized, controlled clinical trial to compare the effects of α-blockers and β-blockers on left ventricular structure and function. Forty-three patients with mild to moderate essential hypertension were randomly allocated to receive antihypertensive therapy with either the α-blocker bunazosin ( n = 23) or the β-blocker metoprolol ( n = 20). Twenty-four—hour blood pressure measurements and echocardiographic measurements of left ventricular structure and function were performed before therapy, after 6 months of therapy, and 4 weeks after discontinuation of therapy. Bunazosin and metoprolol led to similar reductions in systolic/diastolic blood pressure (−11 ± 11−9 ± 8 mm Hg vs −11 ± 12−8 ± 9 mm Hg, respectively) and left ventricular mass (−25 ± 42 gm vs −28 ± 44 gm, respectively) ( p = no significant difference, bunazosin vs metoprolol). Neither metoprolol nor bunazosin significantly affected left ventricular systolic function. Diastolic left ventricular filling, however, was increased with β-blocker medication, as indicated by a decrease in atrial filling fraction (39% ± 5% to 34% ± 5%; p

Impaired Sodium Excretion During Mental Stress in Mild Essential Hypertension

In hypertensive rats, environmental stress causes sodium retention by an exaggerated increase in renal sympathetic nerve activity, which is modulated by angiotensin II. We tested whether similar effects can be observed in humans. In 66 normotensive subjects (half of them with a family history of hypertension) and 36 subjects with mild essential hypertension, urinary sodium excretion and renal hemodynamics were examined at rest and during mental stress treated either with placebo or ACE inhibition in a double-blind, randomized, cross-over design. Despite a marked increase in glomerular filtration rate in response to mental stress (&Dgr;glomerular filtration rate, 4.3±7.7 mL/min in normotensives without versus 5.6±8.4 mL/min in normotensives with a family history versus 10.1±5.7 mL/min in patients with mild essential hypertension;P <0.002), the increase in urinary sodium excretion was blunted in patients with mild essential hypertension (&Dgr;urinary sodium excretion, 0.12±0.17 mmol/min versus 0.10±0.14 mmol/min versus 0.05±0.14 mmol/min;P <0.05). ACE inhibition corrected the natriuretic response to mental stress in subjects with mild essential hypertension (&Dgr;urinary sodium excretion, 0.05±0.14 mmol/min with placebo versus 0.13±0.19 mmol/min with ACE inhibition;P <0.01); thus, after ACE inhibition, urinary sodium excretion increased similarly in all 3 groups. In conclusion, impaired sodium excretion occurs during mental stress in human essential hypertension but not in subjects with positive family history of hypertension. This abnormality in sodium handling during activation of the sympathetic nervous system appears to be mediated by angiotensin II.

Endogenous erythropoietin correlates with blood pressure in essential hypertension

Patients on maintenance hemodialysis with a family history of essential hypertension are at higher risk for increased arterial blood pressure when treated with erythropoietin than patients without family history. This study was performed to elucidate the role of endogenous erythropoietin in essential hypertension. We conducted a study in 42 untreated patients (mean age, 51 +/- 9 years) with essential hypertension World Health Organization stages I or II. Ambulatory 24-hour blood pressure (Spacelab 90207), cardiac output (2D guided M-mode echocardiography and CW Doppler sonography), renal hemodynamics (para-aminohippurate and inulin clearance), and endogenous erythropoietin (radioimmunoassay) together with erythrocyte count, hemoglobin, and hematocrit were measured in parallel. Mean 24-hour systolic blood pressure was 145 +/- 13 mm Hg, and mean diastolic blood pressure was 93 +/- 8 mm Hg. The average erythropoietin concentration was 15.3 +/- 3.7 mU/mL and within the normal range. We found that the higher erythropoietin concentrations, the more elevated was both 24-hour ambulatory systolic (r = 0.51, P < 0.005) and diastolic blood pressure (r = 0.49, P < 0.005). Also, the concentration of endogenous erythropoietin was correlated with total peripheral resistance as noninvasively determined by echocardiographic and Doppler sonographic measurements (r = 0.40, P < 0.02 and r = 0.49, P < 0.02, respectively). With increasing erythropoietin concentrations, renal plasma flow and renal blood flow were found to be progressively reduced (r = -0.32, P < 0.05 and r = -0.35, P < 0.05, respectively) and renal vascular resistance increased (r = 0.41, P < 0.01). Neither hematocrit nor hemoglobin nor erythrocyte count were related to endogenous erythropoietin concentrations. In human essential hypertension, the level of arterial blood pressure is related to endogenous erythropoietin, which is hemodynamically mediated by an increase of total peripheral resistance. Because erythropoietin has shown proliferative and vasoconstricting effects on the endothelium in experimental studies, we suggest that endogenous erythropoietin might be an aggravating or even a promoting factor in the pathogenesis of essential hypertension.

Impact of α- Versus β-Blockers on Hypertensive Target Organ Damage: Results of a Double-Blind, Randomized, Controlled Clinical Trial

Abstract In hypertensive disease, the extent of target organ damage determines the prognosis. We conducted a 6-month, double-blind randomized study to compare the effects of an α1-adrenoreceptor blocker (bunazosin) with those of a β1-adrenoreceptor blocker (metoprolol) on early hypertensive target organ damage at a similar level of blood pressure reduction. The study consisted of 43 patients (29 men and 14 women) of varying ages (mean age 52 ± 9 years) with essential hypertension World Health Organization stage I–II. Both the α- and the β-blocker lowered blood pressure to a similar extent measured by 24-h blood pressure monitoring. The left ventricular mass was comparably reduced in both cohorts (α-blocker 284 ± 80 v 259 ± 67 g, P

Enhanced antinatriuresis in response to angiotensin II in essential hypertension

Angiotensin II regulates sodium homeostasis by modulating aldosterone secretion, renal vascular response, and tubular sodium reabsorption. We hypothesized that the antinatriuretic response to angiotensin II is enhanced in human essential hypertension. We therefore studied 48 white men with essential hypertension (defined by ambulatory blood pressure measurement) and 72 normotensive white control persons, and measured mean arterial pressure, sodium excretion, renal plasma flow, glomerular filtration rate, and aldosterone secretion in response to angiotensin II infusion (0.5 and 3.0 ng/kg/min). Hypertensive subjects exhibited a greater increase of mean arterial pressure (16.7+/-8.2 mm Hg v 13.4+/-7.1 mm Hg in normotensives, P < .05) and a greater decrease of renal plasma flow (-151.5+/-73.9 mL/ min v -112.6+/-68.0 mL/min in controls, P < .01) when 3.0 ng/kg/min angiotensin II was infused. The increase of glomerular filtration rate and serum aldosterone concentration was similar in both groups. Sodium excretion in response to 3.0 ng/kg/min angiotensin II was diminished in both groups (P < .01). However, the decrease in sodium excretion was more pronounced in hypertensives than in normotensives (-0.18+/-0.2 mmol/min v -0.09+/-0.2 mmol/min, P < .05), even if baseline mean arterial pressure and body mass index were taken into account (P < .05). We conclude that increased sodium retention in response to angiotensin II exists in subjects with essential hypertension, which is unrelated to changes in glomerular filtration rate and aldosterone concentration. Our data suggest a hyperresponsiveness to angiotensin II in essential hypertension that could lead to increased sodium retention.

Hyper-responsiveness to angiotensin Ii is related to cardiac structural adaptation in hypertensive subjects

BACKGROUND Angiotensin II has been found to be a growth stimulating factor for myocardial cells. In humans, angiotensin II infusion causes vasoconstriction in systemic and renal vasculature and leads to aldosterone secretion. Our hypothesis was that hyper-responsiveness to angiotensin II is related to left ventricular mass in human essential hypertension. METHODS AND RESULTS In 30 normotensive individuals and 30 subjects with mild essential hypertension (white men, mean age 26+/-3 years), the responsiveness to angiotensin II was assessed by measuring changes in mean arterial pressure, renal blood flow, glomerular filtration rate and aldosterone secretion in response to i.v. angiotensin II infusion (0.5 and 3.0 ng/kg per min). The provoked changes to angiotensin II infusion were similar in the normotensive and hypertensive group with the exception of an exaggerated increase in mean arterial pressure in hypertensives (14+/-5 versus 10+/-5 mm Hg, P<0.001 at 3.0 ng/kg per min angiotensin II). The increase in mean arterial pressure was correlated with left ventricular mass in hypertensive subjects (angiotensin II 0.5 ng/kg per min: r = 0.49, P<0.005; angiotensin II 3.0 ng/kg per min: r = 0.35, P<0.05); no such correlation was found in the normotensive group. After taking into account baseline mean arterial pressure and body mass index, the increase in mean arterial pressure to angiotensin II 0.5 ng/kg per min was still correlated with left ventricular mass (partial r = 0.50, P<0.01). Similarly, the change of glomerular filtration rate but not of renal blood flow in response to angiotensin II 0.5 ng/kg per min was correlated with left ventricular mass, (r = 0.42, P<0.02) in the hypertensive group but not in the normotensive one. This relationship remained significant even after taking baseline glomerular filtration rate, mean arterial pressure and body mass index into account (partial r = 0.43, P<0.05). CONCLUSION Hyper-responsiveness to angiotensin II is related to an increased left ventricular mass in hypertensive subjects independent of blood pressure.