Pp van Geel

Angiotensin II Type 1 Receptor A1166C Gene Polymorphism Is Associated With an Increased Response to Angiotensin II in Human Arteries

An adenine/cytosine (A/C) base substitution at position 1166 in the angiotensin II type 1 receptor (AT(1)R) gene is associated with the incidence of essential hypertension and increased coronary artery vasoconstriction. However, it is still unknown whether this polymorphism is associated with a difference in angiotensin II responsiveness. Therefore, we assessed whether the AT(1)R polymorphism is associated with different responses to angiotensin II in isolated human arteries. Furthermore, we evaluated whether inhibition of the renin-angiotensin system modifies the effect of the AT(1)R polymorphism. One hundred twelve patients who were undergoing coronary artery bypass graft surgery were prospectively randomized to receive an ACE inhibitor or a placebo for 1 week before surgery. Excess segments of the internal mammary artery were exposed to angiotensin II (0.1 nmol/L to 1 micromol/L) and KCl (60 mmol/L) in organ bath experiments. Patients homozygous for the C allele (n=17) had significantly greater angiotensin II responses (percentage of this maximal KCl-induced response) than did patients genotyped with AA+AC (n=95, P<0.05). Although ACE inhibition increased the response to angiotensin II, the difference in the response to angiotensin II, between CC and AA+AC patients remained intact in ACE inhibitor-treated patients. These results indicate increased responses to angiotensin II in patients with the CC genotype. The mechanism is preserved during ACE inhibition, which in itself also increased the response to angiotensin II. This reveals that the A1166C polymorphism may be in linkage disequilibrium with a functional mutation that alters angiotensin II responsiveness, which may explain the described relation between this polymorphism and cardiovascular abnormalities.

Angiotensin-(1–7) Is a Modulator of the Human Renin-Angiotensin System

The renin-angiotensin system is important for cardiovascular homeostasis. Currently, therapies for different cardiovascular diseases are based on inhibition of angiotensin-converting enzyme (ACE) or angiotensin II receptor blockade. Inhibition of ACE blocks metabolism of angiotensin-(1-7) to angiotensin-(1-5) and can lead to elevation of angiotensin-(1-7) levels in plasma and tissue. In animal models, angiotensin-(1-7) itself causes or enhances vasodilation and inhibits vascular contractions to angiotensin II. The function of angiotensin-(1-5) is unknown. We investigated whether angiotensin-(1-7) and angiotensin-(1-5) inhibit ACE or antagonize angiotensin-induced vasoconstrictions in humans. ACE activity in plasma and atrial tissue was inhibited by angiotensin-(1-7) up to 100%, with an IC(50) of 3.0 and 4.0 micromol/L, respectively. In human internal mammary arteries, contractions induced by angiotensin I and II and the non-ACE-specific substrate [Pro(11),D-Ala(12)]-angiotensin I were antagonized by angiotensin-(1-7) (10(-5) mol/L) in a noncompetitive way, with a 60% inhibition of the maximal response to angiotensin II. Contractions to ACE-specific substrate [Pro(10)]-angiotensin I were also inhibited, an effect only partly accounted for by antagonism of angiotensin II. Angiotensin-(1-5) inhibited plasma ACE activity with a potency equal to that of angiotensin I but had no effect on arterial contractions. In conclusion, angiotensin-(1-7) blocks angiotensin II-induced vasoconstriction and inhibits ACE in human cardiovascular tissues. Angiotensin-(1-5) only inhibits ACE. These results show that angiotensin-(1-7) may be an important modulator of the human renin-angiotensin system.

Increased risk for ischaemic events is related to combined RAS polymorphism

OBJECTIVE To determine whether the angiotensin converting enzyme (ACE) and the angiotensin II type 1 receptor (AT1R A1166C) gene polymorphism interact to increase the risk of ischaemic events, and whether this can be explained by the progression of angiographically defined coronary atherosclerosis. DESIGN Prospective defined substudy of the lipid lowering regression trial (REGRESS). SETTING University hospital. PATIENTS 885 male patients with stable coronary artery disease. MAIN OUTCOME MEASURES Incidence of ischaemic events during a two year follow up; serial quantitative coronary arteriography (mean segment diameter and minimum obstruction diameter) at baseline and after two years. RESULTS Patients who carried both the ACE-DD and AT1R-CC genotype had significantly more ischaemic events during the two year follow up than those carrying other genotype combinations (p = 0.035, Mantel-Haenszel test for linear association). There was no association between the two genotypes and mean segment diameter or minimum obstruction diameter at baseline or after two years. CONCLUSIONS The suggestion that ACE-DD and AT1R-CC genotypes interact to increase the risk of ischaemic events is confirmed. However, this increased risk was not accompanied by increased progression of angiographically defined coronary atherosclerosis.

Long term angiotensin converting enzyme-inhibition in patients after coronary artery bypass grafting reduces levels of soluble intercellular cell adhesion molecule-1

OBJECTIVE to examine the effect of angiotensin converting enzyme inhibition (ACEI) on soluble intercellular adhesion molecule 1 (sICAM-1) and C-reactive protein (CRP) in patients requiring coronary artery bypass grafting (CABG). METHOD subgroup analysis of 42 patients randomised to Quinapril (40 mg daily determined) and 45 to placebo. sICAM-1 and CRP were > or = 4 weeks before and 1 year after surgery. RESULTS there was no difference in sICAM-1 at baseline (142.2 microg/L vs 136.6 microg/L). There was significant reduction in s-ICAM-1 in patients receiving quinapril (142.2+/-10.8 microg/L vs 125.6+/-9.4 microg/L, p<0.05) but not placebo (136.6+/-10.2 microg/L vs 131.2+/-11.7 microg/L, p=NS). Levels of C-reactive protein remained unchanged in both groups (3.70+/-0.85 vs 2.73+/-0.32 mg/L, 2.85+/-0.48 vs 3.16+/-0.50 mg/L). CONCLUSIONS ACEI reduces sICAM-1 in patients undergoing CABG. The benefits of ACEI may partly be due to a reduction of the vascular inflammatory response.

DD ACE gene polymorphism is associated with increased coronary artery endothelial dysfunction: the PREFACE trial

Endothelial dysfunction is an early event in atherogenesis and is associated with the propensity to cause future cardiovascular events. The amelioration of endothelial dysfunction has been a research target for some years now, and success has been reported with, for example, the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. Research has also identified the homozygous deletion (DD) subset of the angiotensin converting enzyme (ACE) insertion(I)/deletion(D) polymorphism to be associated with deteriorated endothelial function. The results, however, are conflicting. In a substudy of the PREFACE (pravastatin-related effects following angioplasty on coronary endothelium) trial1 we assessed ACE polymorphism, coronary endothelial function, and the influence of the HMG-CoA reductase inhibitor pravastatin. PREFACE1 was a randomised, double blinded, placebo controlled, multicentre study designed to assess the effect of three months of treatment with pravastatin (40 mg, once daily) on the endothelial function of native and dilated coronary arteries in non-smoking, non-hypercholesterolaemic patients. Coronary endothelium dependent vasomotion at three months was assessed by serial, two minute, intracoronary infusions of acetylcholine with the final intracoronary concentrations estimated to be 10-8, 10-7, and 10-6 M. Hereafter …

Mycotic Aneurysm of the Aorta as an Unusual Complication of Coronary Angiography

INTRODUCTION Mycotic aneurysm of the aorta is a rare diagnosis with high mortality. REPORT Percutaneous coronary intervention was complicated by bacteraemia with Staphylococcus aureus and a mycotic aortic aneurysm, an unusual complication of coronary angiography. Combining CT and PET scan showed a hotspot in the thoracic aorta. After six months of antibiotic treatment she fully recovered. Repeated CT/PET scanning revealed complete abolishment of the aortic abnormalities. DISCUSSION This report suggests that diagnosing and follow-up of aortitis is feasible with combined CT/PET scan and may help in determining choice and duration of therapy.

The use of the gastroepiploic artery for peripheral revascularisation. A study in pigs

OBJECTIVES To use the autologous gastroepiploic artery (GEA) as arterial bypass graft for peripheral revascularisation. We compared the development of intimal hyperplasia and nitric oxide (NO) capacity in GEA and internal jugular vein (IJV) implanted as peripheral grafts. MATERIALS AND METHODS In pigs the GEA was implanted into the right peripheral circulation as a femoropopliteal bypass graft. In the left peripheral circulation the IJV was implanted as a femoropopliteal graft. After 21 days all grafts were harvested. Vascular rings of each graft before and after operation were studied for NO capacity. The distal half of each graft was prepared for histomorphometric studies. RESULTS Administration of bradykinin to IJV and GEA induced relaxation. After implantation bradykinin resulted in contraction in IJV grafts, whereas in GEA grafts relaxation was reduced. In IJV grafts extensive intimal hyperplasia was formed, whereas in GEA grafts only small areas of intimal hyperplasia were formed. CONCLUSIONS The functional studies lost NO capacity in IJV grafts, whereas NO capacity in GEA grafts remained intact. Intimal hyperplasia in IJV grafts was extensive, whereas GEA grafts demonstrated preservation of pre-existent intimal architecture. These results may encourage the application of the human GEA as bypass graft for reconstruction of arteries in the lower limb or foot.