Markus P. Schlaich

Renin-angiotensin system and cardiovascular risk

The renin-angiotensin system is a major regulatory system of cardiovascular and renal function. Basic research has revealed exciting new aspects, which could lead to novel or modified therapeutic approaches. Renin-angiotensin system blockade exerts potent antiatherosclerotic effects, which are mediated by their antihypertensive, anti-inflammatory, antiproliferative, and oxidative stress lowering properties. Inhibitors of the system-ie, angiotensin converting enzyme inhibitors and angiotensin receptor blockers, are now first-line treatments for hypertensive target organ damage and progressive renal disease. Their effects are greater than expected by their ability to lower blood pressure alone. Angiotensin receptor blockers reduce the frequency of atrial fibrillation and stroke. Renin-angiotensin system blockade delays or avoids the onset of type 2 diabetes and prevents cardiovascular and renal events in diabetic patients. Thus, blockade of this system will remain a cornerstone of our strategies to reduce cardiovascular risk.

Increased Wall:Lumen Ratio of Retinal Arterioles in Male Patients With a History of a Cerebrovascular Event

Arterial hypertension is a major risk factor for stroke, and retinal vessels can be regarded as a mirror of the cerebral vasculature. Whether vascular remodeling of retinal arterioles with ageing and hypertension plays a role in cerebrovascular risk stratification has not yet been adequately addressed. In study 1, retinal arteriolar structure was assessed in 182 normotensive volunteers and 117 patients with essential hypertension. In study 2, we compared retinal arteriolar structure among 74 normotensive volunteers, 47 patients with treated essential hypertension, and 18 subjects with a history of a cerebrovascular event. Retinal arteriolar structure was assessed using scanning laser Doppler flowmetry and automatic full-field perfusion imaging analysis. In study 1, wall:lumen ratio of retinal arterioles revealed a significant correlation with age (r=0.198; P=0.001). In study 2, wall:lumen ratio was highest in patients with a history of a cerebrovascular event compared with treated hypertensive and normotensive subjects (0.46±0.08, 0.36±0.14, and 0.35±0.12; P=0.007). When the treated group with hypertension was divided into 2 subgroups according to the quality of blood pressure control, patients with poor blood pressure control showed higher wall:lumen ratio than subjects with good blood pressure control (0.40±0.13 versus 0.31±0.13; P=0.025). Thus, assessment of wall:lumen ratio of retinal arterioles emerged as an attractive tool to identify treated patients with hypertension with increased cerebrovascular risk.

Rapid improvement of nitric oxide bioavailability after lipid-lowering therapy with cerivastatin within two weeks

OBJECTIVES We investigated whether improvement of endothelial dysfunction in hypercholesterolemia can be achieved with short-term lipid-lowering therapy. BACKGROUND Impaired endothelium-dependent vasodilation plays a pivotal role in the pathogenesis of atherosclerosis and acute coronary syndromes. METHODS In a randomized, double-blind, placebo-controlled trial, we studied 37 patients (52 +/- 11 yrs) with low density lipoprotein cholesterol > or = 160 mg/dl (196 +/- 44 mg/dl) randomly assigned to either cerivastatin (0.4 mg/d) or placebo. Endothelium-dependent vasodilation of the forearm vasculature was measured by plethysmography and intra-arterial infusion of acetylcholine (ACh 12, 48 microg/min) and endothelium-independent vasodilation by intra-arterial infusion of nitroprusside (3.2, 12.8 microg/min). RESULTS Low density lipoprotein cholesterol decreased after two weeks of treatment (cerivastatin -33 +/- 4% vs. placebo + 2 +/- 4%, x +/- SEM, p < 0.001). Endothelium-dependent vasodilation improved after two weeks of therapy with cerivastatin compared with baseline (ACh 12 microg/min: + 22.3 +/- 5.2 vs. + 11.2 +/- 1.9 ml/min/100 ml, p < 0.01; ACh 48 microg/min: +31.2 +/- 6.3 vs. +19.1 +/- 3.1 ml/min/100 ml, p < 0.05). In contrast, changes in forearm blood flow to ACh were similar before and after therapy in the placebo group (ACh 12 microg/min: + 12.9 +/- 3.6 vs. + 9.0 +/- 1.9 ml/min/100 ml, NS; ACh 48 microg/min: +20.7 +/- 3.7 vs. 19.4 +/- 2.9 ml/min/100 ml, NS). Endothelium-dependent vasodilation improved in comparison with placebo (ACh 48 microg/min: +203 +/- 85% [cerivastatin] vs. -26 +/- 71% [placebo], p < 0.05). This improvement in endothelium-dependent vasodilation was no longer observed when the nitric oxide-synthase inhibitor N(G)-monomethyl-L-arginine was coinfused (ACh 48 microg/min + N(G)-monomethyl-L-arginine 4 micromol/min -48 +/- 85% [cerivastatin]). CONCLUSIONS Short-term lipid-lowering therapy with cerivastatin can improve endothelial function and NO bioavailability after two weeks in patients with hypercholesterolemia.

Rapid Nongenomic Effects of Aldosterone on the Renal Vasculature in Humans

There is increasing evidence for the importance of rapid nongenomic effects of aldosterone on the human vasculature. In vitro animal experiments in renal arterioles also suggest the presence of such effects on the renal vasculature. We conducted a clinical study to explore these effects in vivo in humans. Thirteen healthy male volunteers were examined. Aldosterone (500 &mgr;g) or placebo was injected intravenously with or without coinfusion of N(G) monomethyl-l-arginine (l-NMMA) in a randomized, double-blinded 4-fold crossover design. Renal plasma flow and glomerular filtration rate were measured by constant infusion clearance technique using inulin and para-aminohippuric acid. Injection of aldosterone without concomitant infusion of l-NMMA changed the renal plasma flow and glomerular filtration rate not statistically significant compared with placebo. Coinfusion of l-NMMA unmasked the effect of aldosterone: aldosterone with l-NMMA decreased the glomerular filtration rate slightly (−1.4±6.2 mL/min), whereas infusion of l-NMMA alone increased the glomerular filtration rate (8.3±9.8 mL/min; P=0.004). l-NMMA alone decreased renal plasma flow by 58.2±97.5 mL/min, and aldosterone with l-NMMA decreased renal plasma flow by 190.0±213.7 mL/min (P=0.074). Accordingly, Aldosterone with l-NMMA increased renal vascular resistance much more than l-NMMA alone (1588±237 versus 614±240 dyn×s×cm−5; P=0.014). These data indicate that aldosterone acts via rapid nongenomic effects in vivo in humans at the renal vasculature. Antagonizing the endothelial NO synthase unmasks these effects. Therefore, rapid nongenomic aldosterone effects increase renal vascular resistance and thereby mediate arterial hypertension if endothelial dysfunction is present.

Impact of Aldosterone on Left Ventricular Structure and Function in Young Normotensive and Mildly Hypertensive Subjects

Left ventricular (LV) hypertrophy is an independent risk factor for cardiovascular morbidity and mortality. Experimental data revealed that elevated circulating aldosterone is associated with increased collagen accumulation resulting in myocardial fibrosis. To analyze whether aldosterone is also associated with cardiac structural and functional changes in humans, we examined the effects of aldosterone on LV structure and function before and after suppression of aldosterone by increasing oral salt intake. The study group comprised 26 normotensive male white healthy control subjects (age 26 +/- 3 years) and 31 male white subjects (age 25 +/- 3 years) with mild essential hypertension (World Health Organization stages I to II). Two-dimensional-guided M-mode echocardiography and 24-hour ambulatory blood pressure (BP) monitoring was performed in each subject. Simultaneously, we measured 24-hour urinary sodium excretion, 24-hour urinary aldosterone, and serum aldosterone concentration at baseline and after increasing oral salt intake to suppress aldosterone secretion. In all subjects LV mass correlated with body mass index (r = 0.42, p <0.001) and both 24-hour ambulatory systolic (r = 0.28, p <0.05) and diastolic (r = 0.25, p <0.05) BP. Changes in urinary sodium excretion correlated inversely with changes in serum aldosterone concentration (r = -0.28; p <0.05). Urinary aldosterone concentration after salt loading decreased in normotensive (10.98 vs 7.44 microg/24 hours; p <0.02) but not in hypertensive (9.34 vs 10.51 microg/24 hours; p = NS) subjects. Serum and urinary aldosterone levels at baseline were not related to LV structure or function. In contrast, after increasing oral salt intake, urinary aldosterone concentration was related to LV mass (r = 0.43; p <0.01) and impaired midwall fractional fiber shortening (r = -0.33; p <0.02) in all subjects, independent of 24-hour ambulatory BP. Subgroup analysis revealed that this was significant only in hypertensive (r = 0.46; p <0.01 and r = -0.44; p <0.02, respectively) but not in normotensive (r = 0.28 and -0.16; p = NS for both, respectively) subjects. Consistently, the greater serum aldosterone remained after increasing oral salt intake, the greater was LV mass (r = 0.35; p <0.01). The latter was found in hypertensive subjects (r = 0.44; p <0.02), independent of 24-hour ambulatory BP, but not in normotensive subjects (r = 0.025; p = NS). Inadequate suppression of aldosterone in response to an increase in oral salt intake is related to LV structural and functional changes in hypertensive subjects. Thus, our results support experimental data indicating that aldosterone affects LV structure and function in humans and that this effect is BP independent.

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.

Left Ventricular Hypertrophy and its Regression: Pathophysiology and Therapeutic Approach Focus on Treatment by Antihypertensive Agents

In numerous studies, left ventricular hypertrophy (LVH) has been clearly established to be a strong blood pressure (BP) independent risk factor for cardiovascular morbidity and mortality. In fact, increased echocardiographic left ventricular mass (LVM) has been shown to predict cardiovascular complications not only in patients with arterial hypertension, but also in the general population. Preliminary data revealed that regression of LVH reduced cardiovascular complications. As a consequence, regression of LVH emerged as a desirable goal in patients with echocardiographically determined LVH. These findings raised the question of whether certain antihypertensive drugs differ in their ability to reduce LVM. To resolve this issue, several comparative studies and some metaanalyses have been carried out. Regarding the available data until the end of 1996 including only double-blind, randomized, controlled clinical studies with parallel group design, we found that angiotensin converting enzyme (ACE) inhibitors reduced LVM by 12% (95% CI, 9.0-14.5%), calcium channel blockers by 11% (95% CI, 7.8-13.7%), beta-blockers by 5% (95% CI, 1.2-7.3%), and diuretics by 8% (95% CI, 3.9-11.1%) (overall: P < .01). A similar reduction was found for posterior and septal wall thickness. Thus, ACE inhibitors and calcium channel blockers seemed to be more potent than beta-blockers in their ability to reduce LVH, with diuretics in the intermediate range. The role of new antihypertensive agents such as AT-receptor antagonists cannot be conclusively answered, because the available data source is too small at this time. In addition to the drug class, reduction of LVH seems to be determined by pretreatment LVM, decline in BP, and duration of drug treatment. Further prospective controlled trials will be required to finally evaluate whether the excellent reduction of LVH with ACE inhibitors and calcium channel blockers can be transferred into improved cardiovascular prognosis.

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.

Assessment of endothelial function of the renal vasculature in human subjects.

BACKGROUND L-Arginine, the substrate of nitric oxide (NO) synthase, and N(G)-monomethyl-L-arginine (L-NMMA), a competitive inhibitor of endothelial NO synthase, are used to analyze endothelial function of the renal vasculature. However, little is known about the appropriate dose of L-arginine to be used and the duration of action of L-arginine and L-NMMA. METHODS Twenty-nine healthy male subjects (age, 27+/-1 years) were examined. In protocol 1 (N = 17), L-arginine at low (100 mg/kg) and high dose (250 mg/kg), and high-dose L-arginine combined either with L-NMMA (total dose, 4.25 mg/kg; N = 9) or placebo (N = 8) were given. In protocol 2 (N = 12), L-NMMA was given before L-arginine infusion (100 mg/kg). Glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured at rest and at the end of each infusion step. RESULTS In protocol 1, L-arginine dose dependently increased RPF and GFR (RPF: 599+/-19 v 630+/-18 v 690+/-24 mL/min, P <.05; GFR: 111+/-3 v 115+/-3 v 121+/-3 mL/min, P <.01; for baseline, L-arginine 100 mg/kg and 250 mg/kg, respectively). However, these changes could not be antagonized by coinfusion of L-NMMA to L-arginine 250 mg/kg: RPF and GFR remained unchanged in both the placebo and the L-NMMA group. In protocol 2, L-NMMA decreased RPF (492+/-18 v 567+/-27 mL/min, P <.01) and increased GFR (122+/-4 v 118+/-3 mL/min, P <.05). These changes could only be partially reversed by subsequent infusion of L-arginine (RPF: 533+/-15 mL/min; GFR: 121+/-4 mL/min; both parameters P = NS v L-NMMA and v baseline). CONCLUSIONS L-arginine at a dose of 100 mg/kg is sufficient to analyze endothelial function of the renal vasculature. The prolonged effect of L-NMMA and L-arginine must be taken into account in study protocols using both substances. Thus, stimulation and blockade of NO synthase cannot be examined in the same protocol.

Renal Vascular Endothelial Function in Hypertensive Patients With Type 2 Diabetes Mellitus

BACKGROUND Basal nitric oxide (NO) activity has a pivotal role in the regulation of glomerular hemodynamics, and in animal experiments, its alteration has been associated with morphological changes characteristic of diabetic nephropathy. STUDY DESIGN Prospective observational-study during a mean follow-up of 2.1 years. SETTING & PARTICIPANTS 66 hypertensive patients (aged 30 to 80 years) with type 2 diabetes and estimated glomerular filtration rate (GFR) greater than 80 mL/min/1.73 m(2) with normoalbuminuria or microalbuminuria. PREDICTOR Mean arterial pressure during follow-up during treatment with telmisartan or ramipril for 9 weeks, followed by treatment according to the discretion of the individual primary care physician. OUTCOMES & MEASUREMENTS Renal vascular resistance, renal plasma flow, GFR, and change in renal plasma flow in response to infusion of the NO synthase inhibitor N-monomethyl-L-arginine as an indicator of basal NO activity in the renal vasculature. RESULTS 50 of 66 patients could be reexamined. At follow-up, mean arterial pressure decreased from 106 +/- 9.1 to 100 +/- 11 mm Hg (P < 0.001). Body mass index and hemoglobin A(1c) levels were unaltered. Renal vascular resistance decreased (from 128 +/- 44 to 103 +/- 30 mm Hg/mL/min/1.73 m(2); P < 0.001), renal plasma flow increased (from 490 +/- 133 to 589 +/- 154 mL/min/1.73 m(2); P < 0.001), and GFR did not change (113 +/- 22 versus 116 +/- 26 mL/min/1.73 m(2); P = 0.4) during follow-up. The decrease in renal plasma flow in response to N-monomethyl-l-arginine infusion was more pronounced at follow-up (-56.7 +/- 39 versus -73.4 +/- 48 mL/min/1.73 m(2); P = 0.02), indicating improved basal NO activity. After adjustment for possible confounders, patients with a marked decrease in mean arterial pressure showed more improved basal NO activity during follow-up than those with a less pronounced decrease in mean arterial pressure (P = 0.04). LIMITATIONS Patients were treated according to the discretion of the individual primary care physician. CONCLUSIONS During follow-up, renal vascular resistance, renal plasma flow, and renal endothelial function (indicated by basal NO activity) improved. Better blood pressure control was associated with improved endothelial function of the renal vasculature, thereby potentially mediating the changes in renal hemodynamics.