Showing papers by "Roland E. Schmieder published in 1999"

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

Abstract: 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 · kg−1 · 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.

825T allele of the G-protein β3 subunit gene (GNB3) is associated with impaired left ventricular diastolic filling in essential hypertension

Abstract: OBJECTIVE Recently, a novel C825T polymorphism in the gene (GNB3) encoding for the G-protein beta3 subunit was identified. The 825T allele is associated with the generation of a novel splice variant, enhanced intracellular signal transduction, and arterial hypertension. In this study, we investigated the impact of the 825T allele on left ventricular structure and function in mild to moderate essential hypertensive subjects. METHODS In 34 white patients with established mild to moderate essential hypertension (World Health Organization stage I or II, mean age 52 +/- 9 years) genotype analysis of GNB3 C825T polymorphism, insertion/deletion polymorphism of the ACE gene and 1166 A/C polymorphism of the AT1 receptor gene was performed. In each patient, 24 h ambulatory blood pressure measurement (SpaceLabs 90207) and two-dimensional guided M-mode echocardiography combined with Doppler sonography were performed. RESULTS In our homogenous study group, the GNB3 825T allele was not associated with casual and 24 h ambulatory blood pressure (CC versus TC/TT 144 +/- 13/92 +/- 8 versus 151 +/- 14/97 +/- 7 and 143 +/- 11/92 +/- 7 versus 150 +/- 16/ 96 +/- 9 mmHg, respectively) or parameters of left ventricular structure (relative wall thickness: CC versus TC/TT, 0.48 +/- 0.1 versus 0.46 +/- 0.1; left ventricular mass: CC versus TC/TT, 281 +/- 65 versus 299 +/- 80 g). However, transmitral flow variables reflecting left ventricular diastolic filling were impaired in patients expressing the TC/TT genotype (ratio of peak late (A) to early (E) velocities: CC versus TC/TT, 0.95 +/- 0.24 versus 1.2 +/- 0.26, P< 0.02; velocity time integrals A/E: CC versus TC/TT, 0.57 +/- 0.16 versus 0.76 +/- 0.23, P< 0.01) while all co-variables such as age, body mass index, ambulatory blood pressure, heart rate and end-diastolic volume were similar between the two groups. If patients were stratified according to the I/D polymorphism of the ACE gene and the A1166C polymorphism of the AT1 receptor gene, no differences in blood pressure, left ventricular structure or systolic and diastolic function of the left ventricle were found between different genotypes. CONCLUSION The GNB3 825T allele was associated with impaired left ventricular diastolic filling in hypertensive subjects in this study. Since alterations in left ventricular filling have been identified as an early marker of hypertensive heart disease, the GNB3 C825T polymorphism may influence cardiac adaptation to increased afterload.

Low-density lipoprotein-cholesterol determines vascular responsiveness to angiotensin II in normocholesterolaemic humans.

Abstract: Objective Both LDL-cholesterol and angiotensin II have been shown to increase the risk for and severity of cardiovascular disease. In hypercholesterolaemia, experimental studies have demonstrated an increased angiotensin type 1 (AT 1 ) receptor expression on vascular smooth muscle cells and an increased vascular responsiveness to vasopressors has been documented in humans. We investigated in a normocholesterolaemic young population whether vascular responsiveness to angiotensin II (Ang II) infusion depends on LDL-cholesterol serum levels in the systemic and renal circulation. Design and methods Changes in systolic and diastolic blood pressure (ΔBP) to Ang II infusion (0.5 and 3.0 ng/kg per min) were investigated in 103 normocholesterolaemic (LDL-cholesterol 111 mg/dl). Results Blood pressure (BP) responses to Ang II infusion 3.0 ng/kg per min were enhanced in the group with the highest LDL-cholesterol levels (A systolic BP: +12.8 ± 6.7, +13.2 ± 8.6, +17.9 ± 9.6, P< 0.02; A diastolic BP: +11.1 ± 5.8, +11.5 ± 6.5, +16.5 ± 8.3, P<0.01, for the lower, middle and upper tertiles, respectively). This holds true when baseline BP was taken into account as a confounding covariable (P < 0.015). BP responses to Ang II infusion were related to LDL-cholesterol serum levels (A systolic BP: r = 0.26, p = 0.01; A diastolic BP: r = 0.32, p = 0.001). In multiple stepwise regression analysis, LDL-cholesterol emerged as the strongest determinant of vascular responsiveness to Ang II (A systolic BP: P< 0.01; A diastolic BP: P<0.001). Conclusion In young male subjects, responsiveness to Ang II is determined by the LDL-cholesterol serum level even in the normal range of LDL-cholesterol, thereby potentially contributing to the cardiovascular risk of LDL-cholesterol even within the so-called normal range.

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

Abstract: Background Angiotensin II has been found to be a growt 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 ir the normotensive and hypertensive group with the exception of an exaggerated increase in mean arterial pressure in hypertensives (14 ± 5 versus 10 ± 5 mmHg, 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.

Not all left ventricular hypertrophy is created equal

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Behandlung der Hypertonie mit AT1-Rezeptorantagonisten

Abstract: Unkonstrollierte persistierende Blutdruckerhohungen stellen einen der wichtigsten unabhangigen Hauptrisikofaktoren fur zerebrovaskulare Schadigungen, kardiale Komplikationen und fortgeschrittene Nierenerkrankung dar. Eine adaquate medikamentose Behandlung des Bluthochdrucks fuhrte zu einer deutlichen Reduktion der kardiovaskularen Mortalitat und Morbiditat [14, 30]. Neue Ergebnisse der Framingham-Studien von mittlerweile uber 20 Jahre „follow-up“ weisen darauf hin, das eine Langzeitbehandlung mit Andhypertensiva noch viel mehr gegen kardiovaskulare Morbiditat und Mortalitat schutzt, als es fruhere Ergebnisse aus klinischen Untersuchungen haben vermuten lassen [36]. Die hochste Gesamtuberlebenszeit war bei Mannern mit einem systolischen Blutdruck von weniger als 134 mg unter antihypertensiver Behandlung assoziiert, bei Frauen von weniger als 149 mg systolisch und fur beide Geschlechter mit einem diastolischen Blutdruck von weniger als 95 mg [6]. Die Hypertension-Optimal-Treatment (HOT)-Studie hat weiterhin gezeigt, das eine Blutdrucksenkung unter 90 mg diastolisch moglich und sicher ist und das der optimale Blutdruck unter Behandlung mit der geringsten kardiovaskularen Morbiditat bei 139/83 mg liegt [31]. Eine Metaanalyse von 14 randomisierten klinischen Studien konnte eine 42%ige Reduktion der Inzidenz fur Schlaganfalle bei einer Abnahme des diastolischen Blutdrucks von 5–6 mg feststellen [14]. Die Abnahme der Schlaganfallsrate war in einem vergleichbaren Umfang ubereinstimmend in Langzeit- beobachtungsstudien festgestellt worden, in denen bei einer entsprechenden Blutdruckabnahme eine 35–40%ige Abnahme der Schlaganfallereignisse zu verzeichnen war. Zusammenfassend unterstreichen die dargestellten Ergebnisse die Notwendigkeit, eine antihypertensive Therapie konsequent durchzufuhren.

Nephroprotektion durch Antihypertensiva

Abstract: Trotz enormer technischer Fortschritte und optimierter Therapiemoglichkeiten stellt die chronisch progrediente Niereninsuffizienz ein zunehmendes globales, soziookonomisches und medizinisches Problem dar, da Erkrankungshaufigkeit und Sterblichkeitsrate stetig ansteigen. Die arterielle Hypertonie ist nach dem Diabetes mellitus die zweithaufigste Ursache fur ein chronisches Nierenversagen. In Anbetracht der Tatsache, das beide Erkrankungen effektiv behandelt werden konnen, stellt sich die Frage nach einer Verbesserung und intensiveren Ausschopfung der zur Verfugung stehenden Behandlungsstrategien. In diesem Zusammenhang konnte gezeigt werden, das eine medikamentose Blutdrucksenkung unterhalb des klassischen Zielwerts von 140/90 mmHg zu einer Verlangsamung der Progression des Nierenfunktionsverlusts beitragt. Dieser Zielblutdruck kann primar durch alle derzeit verfugbaren Hochdruckmedikamente erreicht werden. Der wesentliche Unterschied zwischen den Vertretern der verschiedenen Substanzklassen begrundet sich in den von der Blutdrucksenkung unabhangigen nephroprotektiven Eigenschaften. Insbesondere die Klasse der ACE-Hemmer und Angiotensin II-AT1-Rezeptorantagonisten fuhren blutdruckunabhangig zu einer gunstigen Beeinflussung der renalen Hamodynamik und der Nierenfunktion, wahrend Diuretika und s-Blocker in aquipotent blutdrucksenkender Dosis die Nierenfunktion eher verschlechtem. Die Datenlage zur nephroprotektiven Potenz der Kalziumantagonisten ist kontrovers, insbesondere wenn man nach harten Endpunkten sucht. Fur die ACE-Hemmer dagegen gibt es mehrere prospektive Studien, in denen eine uber die Blutdrucksenkung hinausgehende Verhinderung des Nierentodes dokumentiert wurde. Inwieweit sich Angiotensin II-AT1-Rezeptorantagonisten in ihrer Langzeitwirkung auf die Nierenfunktion von der Klasse der ACE-Hemmer unterscheiden, wird sich erst im Rahmen placebokontrollierter, prospektiver Langzeitstudien erweisen.