Abstract-The risk for an adverse pregnancy outcome is markedly higher in women with history of preeclampsia. This may stem from impaired placentation in early gestation and from high impedance to flow in uteroplacental circulation. The renin-angiotensin system is one of the mediators of the remodeling of spiral arteries throughout pregnancy. The D allele of the Insertion/Deletion (I/D) polymorphism in the ACE gene has been associated with higher ACE activity, accounting for 47% of the total phenotypic variance of serum enzyme levels. To investigate whether the ACE I/D polymorphism affects maternal uteroplacental and fetal umbilical circulation and the pregnancy outcome in women with a history of preeclampsia, 106 women underwent Doppler examination of uterine arteries resistance index and umbilical artery pulsatility index at the 16th, 20th, and 24th weeks of gestation and were genotyped for the I/D polymorphism. This study found a difference in genotype distribution (Pϭ0.0002) and allele frequency (PϽ0.0001) between women with and those without preeclampsia recurrence and fetal growth restriction as well as an association (Pϭ0.0007) between DD genotype and risk of recurrent preeclampsia or fetal growth restriction. At the 16th, 20th, and 24th weeks, uterine artery resistance indexes were significantly lower in II, higher in DD, and intermediate in ID genotype carriers, whereas the umbilical artery pulsatility index values were significantly higher in the DD group in comparison to ID and II genotypes. Key Words: angiotensin-converting enzyme Ⅲ polymorphism Ⅲ preeclampsia Ⅲ pregnancy T he risk for an adverse pregnancy outcome in women who have previously had preeclampsia is markedly higher (from 20% to 40%) 1,2 in comparison to women with history of normal pregnancy, but the mechanisms involved have not yet been identified. The maternal syndrome of preeclampsia (PE) and the fetal syndrome of fetal growth restriction (FGR) during the latter half of pregnancy are believed to result from impaired placentation in early gestation. 3,4 Deficient placentation is characterized by inadequate trophoblast invasion into the maternal spiral arteries and a failure to develop lowresistance uteroplacental circulation. 3 Doppler ultrasonographic studies of uteroplacental 5 and fetal umbilical circulation 6 have shown that high impedance to flow is associated with subsequent PE, FGR, and related complications.Previous experimental studies 7 suggested that the "physiological remodeling" of spiral arteries throughout pregnancy is mediated by the renin-angiotensin system (RAS), which is one of the main factors regulating blood pressure, and fluid and electrolyte balance. 8 Throughout normal pregnancy, the RAS is stimulated; plasma renin activity, angiotensinogen, angiotensin II, and aldosterone levels are all increased. 9 At the same time, pregnancy induces a refractoriness to the pressor effects of angiotensin II. 10 In patients with PE, a significant association between the T235 molecular variant of the angiotensinogen (AGT) gene, ...

Abstract-Data from literature report that angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism affects the recurrence of preeclampsia and that low-molecular-weight heparin (LMWH) prevents adverse outcomes in thrombophilic women. We investigated the effect of LMWH on the pregnancy outcome, on maternal blood pressure values, and on uteroplacental flow in ACE DD nonthrombophilic women with history of preeclampsia. Eighty nonthrombophilic ACE DD women were randomized in 2 groups: 41 treated with dalteparin 5000 IU/day and 39 untreated (control group). Women underwent 24-hour automated blood pressure monitoring in the preconceptional period and every 2 weeks from weeks 8 to 36 and transabdominal color flow/pulsed Doppler examination at weeks 16, 20, and 24. LMWH reduced the risk of clinical negative outcomes (74.1% reduction of preeclampsia and 77.5% reduction of fetal growth restriction) and the severity (88.3% reduction of early onset of preeclampsia and 86.4% reduction of early onset of fetal growth restriction). In treated women, the relative risk for preeclampsia was 0.26 (Pϭ0.02), and the relative risk for fetal growth restriction was 0.14 (PϽ0.001). Systolic (Pϭ0.002) and diastolic (Pϭ0.002) blood pressures, as well as awake (Pϭ0.04) and asleep (Pϭ0.01) period values, and the resistance indexes of both uterine arteries (Pϭ0.002) were lower in the treated group. LMWH reduces the recurrence of preeclampsia, of negative outcomes, and the resistance of uteroplacental flow, and also prevents maternal blood pressure increase in ACE DD homozygote women with a previous history of preeclampsia.

Complications of pregnancy have been found to be related with thrombophilic polymorphisms that explain about 30% of obstetric complications. We evaluated the angiotensin converting enzyme (ACE) and the angiotensin type 1 receptor (AT1R) gene polymorphisms in the renin-angiotensin system (RAS) as possible risk factors for fetal loss. Fifty-nine women with a history of three or more first-trimester fetal losses and 70 healthy women with a history of normal pregnancies were enrolled in this study. Thrombophilic factors, ACE insertion/deletion (I/D) and AT1R A1166C polymorphisms, prothrombin G20210A and factor V Leiden mutations were analyzed. At univariate and multivariate analysis, a significant association between ACE DD and AT1R CC genotype and fetal loss was observed. The effect of the ACE DD genotype on the risk of fetal loss was higher in AT1R C allele carriers. The prevalence of hyperhomocysteinemia (Hcy) (defined as baseline plasma levels higher than the 95% percentile; cut-off, 10.5 micromol/l per l) was significantly higher in women with fetal loss, and an association between Hcy and fetal loss was detected. All patients showed normal antithrombin, protein C, protein S, and plasminogen activator inhibitor-1 (PAI-1) values. The presence of one risk factor not associated with others was found in 33 out of 59 patients (56%); ACE DD genotype was the most prevalent risk factor. Our results identify new possible predictive markers for fetal loss in RAS polymorphisms and Hcy. Large-scale studies are warranted to attribute clinical relevance to these polymorphisms as risk factors for complicated pregnancies.

Our report indicates the increased risk of coronary artery disease in the presence of ACE DD and AT1R CC genotypes independent of other risk factors, in Italian patients. The present study stresses the relevance of screening for genetic risk factors.

Our findings document that ACE DD genotype represents a susceptibility factor for AAA.

Our findings suggest a role for minK and eNOS genes as predisposing factors to NVAF.

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Aims: In atrial fibrillation (AF) patients, age z75 years is one of the major risk factors for stroke. However, it is not clear if an upper limit for the indication to OAT exists. Methods and results: For this reason, we performed a prospective study on 290 AF patients on OAT aged z75 years (median age 82 years, total follow-up period 814 pt/ years) followed by our Anticoagulation Clinic. Seventeen major bleeding events were recorded (rate 2.1 × 100 pt/years), 11 of which cerebral (1.35 × 100 pt/years). The occurrence of major bleedings was associated with history of previous TIA or stroke [OR 3.4 (1.1-12.5), p = 0.01] and with diabetes .7) p = 0.01]. We found a trend to a progressive increase in the rate of bleeding risk with the increase of the CHADS 2 score: patients with score 4-6 showed a rate of 3.4 × 100 pt/years with respect to 1.5 × 100 pt/years of patients with lower score. Number Needed to Harm (NNH) was calculated in relation to different classes of age (75-89, 80-84, z85 years) and to CHADS 2 score. For patients in CHADS 2 score 1-3 NNH remained stable across the different age classes. Instead for patients in CHADS 2 score 4-6, NNH varied among the 3 groups of ages, reaching a value of 10 in patients ≥ 85 years. Conclusion: Our data suggest that: 1) in AF patients older than 75 years with CHADS 2 score 1-3 the risk of bleeding is low, 2) in AF patients N85 years with CHADS 2 4-6 the risk of bleeding is high so that the use of OAT should be highly individualised.