J. Munjal

Endothelial Nitric Oxide Synthase T-786C Mutation, A Reversible Etiology of Prinzmetal's Angina Pectoris

Because the endothelial nitric oxide synthase (eNOS) T-786C polymorphism is associated with reduced nitric oxide production and coronary artery spasm in Japanese patients, we speculated that it might be reversibly associated with Prinzmetals variant angina in white Americans. Polymerase chain reaction analyses of eNOS T-786C and stromelysin 5A6A polymorphisms were done in 31 women and 12 men (42 white and 1 black American, median age 50 years), with well-documented Prinzmetals variant angina. We matched each case with 1 healthy control by race and gender. Of the 43 cases, 21 (49%) were homozygous for wild-type normal eNOS, 19 (44%) were T-786C heterozygotes, and 3 (7%) were T-786C homozygotes. Of the 43 controls, 31 (72%) were homozygous for wild-type normal eNOS, 12 (28%) were T-786C heterozygotes, and 0 (0%) were T-786C homozygotes (p = .013). The mutant eNOS T-786C allele frequency in patients was 25 (29%) of 86 vs 12 (14%) of 86 in the controls (p = 0.016). Patients did not differ from controls for the distribution of the stromelysin 6A mutation (p = 0.66) or for the mutant 6A allele frequency (53% in cases, 50% in controls; p = 0.65). Nineteen patients took nitric oxide-elevating l-arginine (9.2 g/day, orally). Of these 19 patients, 10 (53%) became free of angina, 3 (16%) were improved but not angina free, and 6 (32%) had no change in their angina. Using l-arginine, the physical ability score (Seattle Angina Questionnaire) increased from a median of 42 to 72 of a total possible score of 100 (p = 0.011), satisfaction with symptom reduction increased from 53 to 61 (p = 0.004), and the perception of quality of life as acceptable increased from 29 to 50 (p = 0.001). In conclusion, the eNOS T-786C mutation appears to be a reversible etiology of Prinzmetals variant angina in white Americans whose angina might be ameliorated by l-arginine.

55 UNEXPLAINED SPORADIC FIRST-TRIMESTER MISCARRIAGE: FACTOR V LEIDEN GENE MUTATION.

Background The propensity to form thrombi is physiologically increased in normal pregnancy secondary to reduction in naturally occurring anticoagulants, an increase in coagulation factors, and a reduction in fibrinolysis. We hypothesized that when the physiologic hypercoagulability of pregnancy is superimposed on the thrombophilic G1691A factor V Leiden mutation, sporadic first-trimester miscarriage and repetitive pregnancy loss are promoted. We hypothesized that the thrombophilic G1691A factor V Leiden gene mutation was a common, significant, treatable cause of sporadic first-trimester miscarriage. Methods We compared the frequency of the G1691A factor V Leiden mutation in women with ≥ 1 pregnancy and 1 miscarriage with women having ≥ 1 pregnancy and 0 miscarriages. In 848 Caucasian women with consecutive measures of the factor V Leiden mutation, we compared the frequency of the V Leiden mutation in 136 women with ≥ 1 pregnancy and 1 miscarriage (260 live births, 136 miscarriages), 50 women with ≥ 1 pregnancy and 2 miscarriages (83 live births, 100 miscarriages), 53 women with ≥ 1 pregnancy and ≥ 3 miscarriages (recurrent pregnancy loss) (109 live births, 227 miscarriages), and 609 women with ≥ 1 pregnancy and 0 miscarriages (1,473 live births). We used PCR techniques to characterize the thrombophilic G1691A V Leiden [FV] gene mutation. Results Of the 609 controls, 41 (6.7%) had FV heterozygosity versus 15 heterozygous and 2 homozygous FV cases (17 of 136, 12.5%) with 1 sporadic miscarriage, Χ3 = 5.2, p = .023, vs 8 of 53 (15%, 7 heterozygous and 1 homozygous) with ≥ 3 miscarriages, Fishers p = .048, vs 2 of 50 (4%) with 2 miscarriages. The V Leiden frequency in cases with 1 sporadic miscarriage (17 of 136, 12.5%) did not differ from recurrent pregnancy loss cases with ≥ 3 miscarriages (8 of 53, 15%), Χ2 = 0.22, p = .64. Conclusions After unexplained sporadic first-trimester miscarriage, as well as after recurrent pregnancy loss, to provide the option to prospectively optimize subsequent live birth outcomes with low molecular weight heparin throughout pregnancy, we suggest that measurements be done of the FV mutation, a treatable etiology for sporadic miscarriage, as well as for recurrent pregnancy loss.

54 MYOCARDIAL INFARCTION-ANGIOPLASTY-CORONARY ARTERY BYPASS GRAFTS ≤ AGE 45: ATHEROTHROMBOSIS.

Although heritable thrombophilias and hypofibrinolysis predominantly cause venous thrombosis, they may also promote arterial thrombosis, synergistic with atherosclerosis, producing atherothrombotic cardiovascular (ATCVD) events. In 70 men and 16 women with ≥ 1 premature myocardial infarction (n = 60)-angioplasty (n = 52)-coronary artery bypass grafts (n = 33) (≤ age 45 years), we assessed whether and to what degree heritable thrombophilia-hypofibrinolysis contributed to 145 ATCVD events ≤ age 45. Hereditary thrombophilias studied by PCR included the G1691A factor V Leiden, G20210A prothrombin, MTHFR C677T-A1298C, and platelet glycoprotein PL A1/A2 mutations, with serologic studies of ACLA IgG and IgM, the lupus anticoagulant, proteins C and S, antithrombin III, homocysteine, and factors VIII and XI. Hypofibrinolysis studies included the 4G4G plasminogen activator inhibitor 1 mutation (PAI), PAI activity (PAI-Fx), and Lp(a). Cases were compared with healthy normal controls (149 men for PCR, 40 for serologic tests, 109 women for PCR and for serologic tests). At entry, hypertension was present in 46% of men and 31% of women, diabetes in 19% and 13%, and cigarette smoking in 26% and 13%, respectively. In the 70 male cases, mean ± SD age was 49 ± 11, BMI 29.5 ± 4.2, LDLC 102 ± 45, HDLC 41 ± 15, and TG 204 ± 229 mg/dL. In 16 female cases, mean ± SD age was 43 ± 7, BMI 28.1 ± 5.5, LDLC 103 ± 32, HDLC 45 ± 11, and TG 191 ± 170 mg/dL. Male cases were more likely than male controls to have factor V Leiden (6 of 60, 10% vs 4 of 149, 3%, p = .035), high Lp(a) (≥ 35 mg/dL) (25 of 69, 36% vs 7 of 40, 18%, p = .039), high PAI-Fx (> 21.1 U/mL) (15 of 61, 25% vs 3 of 39, 8%, p = .036), high (> 150%) factor VIII (15 of 57, 26% vs 1 of 38, 3%, p = .003), and high (> 150%) factor XI (9 of 55, 16% vs 0 of 38, 0%, p = .0096). Female cases were more likely then female controls to have high factor VIII (5 of 14, 36% vs 13 of 109, 12%, p = .033) and were more likely to have low free protein S (3 of 14, 21% vs 3 of 107, 3%, p = .02). In patients sustaining MI-angioplasty-CABG events ≤ age 45, we speculate that hereditary thrombophilias (factor V Leiden, factor VIII, factor XI, low free protein S) and hypofibrinolysis (PAI-Fx, Lp(a)) promote arterial thrombosis that may be synergistic with atherosclerotic endothelial injury. In patients with MI-angioplasty-CABG events ≤ age 45 and concurrent hereditary thrombophilia, we speculate that thromboprophylaxis may have value in secondary prevention of subsequent ATCVD.

41 ROSUVASTATIN ACCEPTABILITY, EFFICACY, AND SAFETY IN HYPERCHOLESTEROLEMIC PATIENTS UNABLE TO TOLERATE OTHER STATINS.

Statins as a class are well tolerated. We assessed acceptability, efficacy, and safety of rosuvastatin in 57 euthyroid patients with primary high LDL cholesterol (LDLC) who, serially, could not tolerate most other statins or cholesterol-lowering drugs, primarily because of myocitis. Of the 57 patients, 44 could not tolerate atorvastatin, 27 simvastatin, 15 pravastatin, 7 fluvastatin, 2 lovastatin, 1 Vytorin, 10 WelChol, 5 Zetia, 2 TriCor, and 2 Niaspan. Rosuvastatin (5 mg/day)-diet was given to 24 patients (3 men, 21 women, 21 white, 3 black, 3 type 2 diabetics, mean ± SD age 61 ± 9 years, BMI 31.7 ± 4.2, LDLC 179 ± 32 mg/dL). On rosuvastatin 5 mg-diet for a median of 5 months, weight fell 3.0 ± 7.7 lb (p = .016), LDLC fell 76 ± 35 mg/dL (p < .0001) to 103 ± 31 mg/dL, with median percent change -47%. Adjusted for changes in body weight, decrements in LDLC remained significant, LS mean ± SE -75 ± 8 mg/dL, p < .0001. None of the 24 patients discontinued the 5 mg rosuvastatin, muscle symptoms were minor to absent, and there were no untoward changes in liver function tests (

74 METFORMIN-DIET AMELIORATES CORONARY HEART DISEASE RISK FACTORS AND FACILITATES RESUMPTION OF REGULAR MENSES IN ADOLESCENTS WITH POLYCYSTIC OVARY SYNDROME.

3 times the laboratory upper normal limit), or in CPK (

40 HEREDITARY THROMBOPHILIAS MEDIATING ARTERIAL THROMBOTIC EVENTS.

10 times the laboratory upper normal limit). Rosuvastatin (10 mg/day) was given to 33 patients, 16 men, 17 women, 31 white, 1 black, 1 other, 9 smokers, 4 type 2 diabetics, mean ± SD age 59 ± 10 years, BMI 31.1 ± 5.2, and LDLC 178 ± 53 mg/dL. On therapy for a median of 11 months, body weight fell 3.1 ± 6.8 lb (p = .014), LDLC fell 80 ± 49 mg/dL (p < .0001) to 96 ± 38 mg/dL, median percent change -48%. Adjusted for body weight change, decrements in LDLC remained significant, LS mean ± SE -82 ± 11 mg/dL, p < .0001. None of the 33 patients discontinued the 10 mg rosuvastatin, muscle symptoms were minor to absent, and there were no untoward changes in liver function tests (

Rosuvastatin 5 and 10 mg/d: A pilot study of the effects in hypercholesterolemic adults unable to tolerate other statins and reach ldl cholesterol goals with nonstatin lipid-lowering therapies

3 times the laboratory upper normal limit), or in CPK (

Factor V Leiden mutation: a treatable etiology for sporadic and recurrent pregnancy loss

10 times the laboratory upper normal limit). Since rosuvastatin is not metabolized by the 3A4 isoenzyme of the cytochrome P450 enzyme system and is < 10% metabolized by the 2C9 isoenzyme, we speculate that its acceptability, efficacy, and safety in hypercholesterolemic patients unable to tolerate other statins are related to reduced interactions with other drugs known to inhibit CYP 450 enzymes. By contrast, atorvastatin, lovastatin, and simvastatin are metabolized through the 3A4 pathway and fluvastatin through 2C9, common pathways for many other drugs, facilitating drug-drug interactions, which may be expressed clinically as muscle symptoms, leading to discontinuance of the statin. Rosuvastatins LDLC lowering potency often facilitates reaching LDLC goals by use of low doses, 5 or 10 mg/day.

Thrombophilia–hypofibrinolysis and atherothrombotic cardiovascular disease ≤ age 45 years

In 35 postmenarchal adolescent females (17 ± 2 years, range 14-19) with polycystic ovary syndrome (PCOS), in a case-series prospective description, we assessed effectiveness of metformin-diet for 1 year for reduction of weight, insulin, HOMA insulin resistance (IR), cholesterol, triglycerides, and resumption of regular menses. By selection, all 35 girls met the 2003 consensus criteria for diagnosis of PCOS; all 35 had clinical hyperandrogenism, 37% were amenorrheic, and 60% oligomenorrheic. Pretreatment median weight was 82.7 kg, BMI 30.8 kg/m2, and 19 (54%) girls had BMI > the CDC age-gender-specific 95th percentile (overweight). Calories (26% protein, 44% carbohydrate) were targeted to 1,500-1,800/day if BMI was < 25 or to 1,200-1,500/day if BMI was

53 CARDIOVASCULAR EVENTS ≤ AGE 45: ATHEROTHROMBOSIS.

25, along with 2,550 mg metformin. After 1 year on metformin-diet, median weight fell from 82.7 to 79.1 kg (p = .009); the median of the percent change was -5%. In 6 girls (17%) weight loss was