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 ($ 3 times the laboratory upper normal limit), or in CPK ($ 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 ($ 3 times the laboratory upper normal limit), or in CPK ($ 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. Rosuvastatin9s LDLC lowering potency often facilitates reaching LDLC goals by use of low doses, 5 or 10 mg/day.

In 10 normolipidemic patients with 1 or more myocardial infarctions (MI) < age 45, 8 of whom had MI < age 35 years, we speculated that hereditary thrombophilias promoted arterial thrombosis. Thrombophilias studied by PCR included 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, S, and antithrombin III, homocysteine, and factors VIII and XI. Hypofibrinolysis studies included the 4G4G plasminogen activator inhibitor 1 mutation, plasminogen activator inhibitor activity (PAI-Fx), and Lp(a). Cases were compared to healthy normal controls (239 for PCR, 75 for serologic measures). At study entry, without diet-pharmacotherapy, 10 normolipidemic patients with one or more MI < 45 were selected by LDL cholesterol (LDLC) < 130 mg/dL, HDL cholesterol (HDLC) > 35 in men and > 40 mg/dL in women, and triglycerides (TG) < 200 mg/dL. In these 10 normolipidemic patients (7 men, 3 women, 9 white, 1 black, 1 smoker, 2 diabetic), mean ± SD age was 46 ± 13, BMI 26.0 ± 2.8, LDLC 90 ± 31, HDLC 49 ± 10, and TG 93 ± 35 mg/dL. Factor V Leiden heterozygosity was present in 2 of 10 (20%) cases vs 8 of 239 (3%) controls (p = .055). High factor VIII (> 150%) was present in 4 of 7 (57%) cases vs 0/36 controls (p = .0003). Of 14 hyperlipidemic patients having an arterial event < age 45 (6 MI, 1 coronary artery bypass graft, 1 angioplasty, 2 ischemic stroke, 4 TIA), 8 men, 6 women, 12 white, 2 other, 6 smokers, 3 diabetic, 1 smoker and diabetic, mean ± SD age was 40 ± 8, BMI 31.3 ± 6.5, LDLC 105 ± 42, HDLC 38 ± 9, and TG 243 ± 203 mg/dL. Four of these 14 cases (29%) had high factor VIII (> 150%) vs 0/36 controls (p = .004), 2 of 11 (18%) had high factor XI (> 150%) vs 0/61 controls (p = .022), and 5 of 13 (38%) had hypofibrinolytic high PAI-Fx (> 21.1 U/mL) vs 4/61 (7%) controls (p = .007). In both normo- and hyperlipidemic patients sustaining an arterial thrombotic event before age 45, and especially before age 35, we speculate that heritable thrombophilias (factors VIII, XI, factor V Leiden) or hypofibrinolysis (PAI-Fx) may contribute to endothelial damage or altered hemostatic equilibrium and thus promote arterial thrombotic events. In patients with thrombophilia and/or hypofibrinolysis-mediated arterial thrombotic events before age 45, we speculate that thromboprophylaxis might have value in secondary prevention of subsequent arterial thrombotic events.

In 81 women referred for diagnosis-therapy of atherothrombotic and endocrine disorders, and found to be heterozygous (n = 49) or homozygous (n = 3) for the G1691A Factor V Leiden mutation (FV), or heterozygous (n = 29) for the G20210A prothrombin gene mutation (PTG), and having ≥ 1 pregnancy, our specific aim was to assess relationships of familial thrombophilia to previous pregnancy outcomes. The 52 women with FV (1 black, 43 white, 8 other, 47 ± 13 years old) had 164 pregnancies with 114 live births (70%) and 50 miscarriages (30%). The 29 women with PTG (1 black, 28 white, 51 ± 15 years old) had 64 pregnancies with 50 live births (83%) and 10 miscarriages (17%). In 130 normal control women referred for diagnosis-therapy of atherosclerotic and endocrine disorders, having wild-type normal FV and PTG, there were 125 pregnancies with 110 live births and 13 miscarriages (10.4%). The miscarriage rate in women with FV (30%) was 3 times higher (p<.0001) than in the 130 normal controls (10.4%). The miscarriage rate in women with PTG (17%) was not significantly (p = .24) higher than in the 130 normal controls (10.4%). Of the 52 women with FV, 38 had concurrent measurement of the hypofibrinolytic 4G4G plasminogen activator inhibitor-1 (PAI-1) mutation. In 15 (of 38) women with 4G4G homozygosity and the FV mutation, there were 22 miscarriages (44%) in 50 pregnancies; in the 23 (of 38) women with 4G5G/5G5G genotypes and the FV mutation, there were 27 miscarriages (39%) in 70 pregnancies, p = 0.6. Of the 52 women with FV, 43 had measurement of the thrombophilic C677T methylenetetrahydrofolate reductase (MTHFR) mutation. In 8 women with MTHFR homozygosity and the FV mutation, the miscarriage rate was 33% (7 of 21 pregnancies); in 35 MTHFR heterozygous/wild-type normal genotypic women and the FV mutation, the miscarriage rate was 35% (42 of 120 pregnancies), p = 0.9.Heterozygosity for the Factor FV mutation is a major risk factor for miscarriage, reversible by low molecular weight heparin thromboprophylaxis throughout pregnancy.

We hypothesized that the thrombophilic G1691A Factor V Leiden gene mutation was a common, significant, treatable cause of sporadic miscarriage. We used PCR techniques to characterize thrombophilic (G1691A V Leiden [FV], G20210A prothrombin, C677T/A1298C MTHFR) and hypofibrinolytic (plasminogen activator inhibitor activity [PAI-1] 4G4G) gene mutations. We carried out serologic measures of thrombophilia (homocysteine, ACLA IgG and IgM, lupus anticoagulant, Factor VIII, Factor XI, protein C, total and free protein S, antithrombin III) and hypofibrinolysis (plasminogen activator inhibitor activity [PAI-Fx]), Lp[a]). We compared thrombophilia-hypofibrinolysis in 89 women (83 white, 4 black, 2 other) with ≥ 1 pregnancy and 1 miscarriage (139 live births, 89 miscarriages) and in 363 women (338 white, 21 black, 4 other) with ≥ 1 pregnancy and 0 miscarriages (901 live births). Of the 363 women in the 0 miscarriage group, 8 (2.2%) had FV heterozygosity vs 11 heterozygous and 2 homozygous FV women in the sporadic miscarriage group (14.6%), p 150%) was more common in cases (11/33, 33%) than controls (3/28, 11%), p = .04.There were no other group differences (p>0.05) in measures of thrombophilia and hypofibrinolysis. After unexplained sporadic miscarriage, we suggest that measurements be done of the FV mutation, PAI-Fx, and Factor VIII. Recognition of FV heterozygosity-homozygosity or high Factor VIII after sporadic miscarriage allows prospective thromboprophylaxis with enoxaparin (60-80 mg/day) to optimize live birth outcomes in subsequent pregnancies. High PAI-Fx can often be lowered with Glucophage (2.5 g/day) to further optimize live birth outcomes.

In a 26-year-old white male with Buerger9s disease we hypothesized that gene polymorphisms which confer susceptibility to arterial spasm (stromelysin-1 5A/6A, eNOS T-786C) and C677T-A1298C MTHFR compound heterozygosity with decreased bioavailability of nitric oxide (NO) interacted with cigarette-cannabis smoking, as gene-environment interactive etiologies for the peripheral artery spasm, thrombosis, and arterial occlusion of Buerger9s disease. In a 26-year-old male who had heavily smoked cigarettes-cannabis, Buerger9s disease with rapid progression of bilateral lower limb gangrenous ischemia and intractable ischemic pain on rest despite smoking cessation threatened high above-knee amputations. There was complete arterial occlusion at the level of the left popliteal trifurcation. After documentation of thrombophilic C677T-A1298C compound MTHFR heterozygosity, folic acid 5 mg, vitamin B6 100 mg, and vitamin B12 2000 μg/day were started to optimize homocysteine metabolism and to reduce asymmetric dimethylarginine (ADMA) levels, an endogenous inhibitor of NO synthase. L-Arginine (15 g/day) was given as an approach to increase vasodilatory NO production via endothelial NO synthase (eNOS). Within 8 weeks on therapy, gangrenous ulcers on the right foot and leg healed, pain subsided, and peripheral arterial pulses normalized. Previously existing gangrene of the left great toe and second toe became complicated with cellulitis, necessitating below knee amputation. Healing was subsequently uneventful with bilateral normal peripheral arterial pulses. PCR analyses revealed heterozygosity for stromelysin-1 5A/6A and eNOS T-786C polymorphisms, previously shown to confer susceptibility to coronary artery spasm and myocardial infarction in synergy with cigarette smoking. In cigarette-cannabis smokers, we speculate that the development and severity of Buerger9s disease are related to a gene-environment interaction in subjects heterozygous for the stromelysin-1 5A/6A and eNOS T-786C polymorphisms, as well as C677T-A1298C MTHFR compound heterozygosity, which altogether reduce endogenous NO-mediated vasodilatation. In such cases, Buerger9s disease can successfully be treated by increasing NO production by giving oral L-arginine (15 g/day) while also optimizing homocysteine metabolism by provision of folic acid (5 mg), vitamin B6 (100 mg), and vitamin B12 (2000 μg)/day.

In 791 women with polycystic ovary syndrome (PCOS), we assessed the success of metformin-diet (MET-D) in reducing weight, triglycerides (TG), LDL cholesterol (LDLC), and blood pressure (SBP, DBP), while elevating HDL cholesterol (HDLC). At pre-treatment (pre-Rx) entry in the 791 women, median weight was 95 kg, with 15% overweight (BMI>25<30), 46% obese (BMI 30-40), and 29% severely obese (BMI ≥ 40). Median pre-Rx TG was 108 mg/dL (30% ≥ 150 mg/dL), LDLC 116 mg/dL (32% ≥ 130 mg/dL), HDLC 46 mg/dL (62%<50 mg/dL), SBP 124 mm Hg (37% ≥ 130 mm Hg), and DBP was 80 mm Hg (30% ≥ 85 mm Hg). Women with BMI<25 or ≥ 25 kg/m2 were given a 2000 or 1500 calorie/day, high protein (26% of calories), low carbohydrate (44%) diet. Metformin was targeted to 2500 mg/day. On MET-D, change in weight was positively associated with change in TG (r = .23, p<.0001), LDLC (r = .11, p = .004), SBP (r = .21, p<.0001), and DBP (r = .17, p = .0003), and was inversely associated with change in HDLC (r = -.10, p = .007). In 102 women (age 30 ± 9 years) on MET-D for 12-18 months (median 14.5), median weight reduction was 5 kg (5%), p <.0001, and median LDLC reduction 6 mg/dL (4%), p = .04. Weight reduction was<5% in 50% of these 102 women, 5-10% in 25%, 10-15% in 13%, and ≥ 15% in 13%. In 65 women (age 31 ± 9 years) on MET-D for 18-24 months (median 21 months), median weight reduction was 6 kg (6%), p<.0001, TG fell 17 mg/dL (19%), p = .045, and HDLC rose 2 mg/dL (6%), p = .002. Weight reduction was<5% in 46% of these 65 women, 5-10% in 26%, 10-15% in 14%, and ≥ 15% in 14%. In 210 women (age 31 ± 9 years) on MET-D for>24 months (median 40), median weight reduction was 5 kg (5%), p<.0001, HDLC rose 4 mg/dL (8%), p<.0001, and LDLC fell 9 mg/dL (7%), p = .0004. Weight reduction was<5% in 48% of these 210 women, 5-10% in 23%, 10-15% in 15%, and ≥ 15% in 15%. In these 210 women, of 108 with HDLC<50 mg/dL pre-Rx, 38 (35%) had HDLC on MET-D>50 mg/dL (p = .002), and of 64 with LDLC ≥ 130 mg/dL pre-Rx, 41 (64%) had LDLC on MET-D<130 mg/dL, p <.0001. In PCOS, where 75% of women are obese or severely obese, and where obesity is often accompanied by high TG, LDLC, and low HDLC, MET-D is very effective in reducing weight, TG, LDLC, and raising HDLC.

We hypothesized that the thrombophilic G1691A factor V Leiden gene mutation was a common significant cause of sporadic first trimester miscarriage. We compared thrombophilia and hypofibrinolysis in 92 women (85 white, 5 black, 2 other) with 1 or more pregnancies and 1 miscarriage (143 live births, 92 miscarriages) (cases) and in 380 female controls (355 white, 21 black, 4 other) with 1 or more pregnancies and 0 miscarriages (964 live births). We used polymerase chain reaction techniques to characterize thrombophilic gene mutations (G1691A V Leiden [FV], G20210A prothrombin, C677T/A1298C MTHFR) and hypofibrinolytic gene mutations (plasminogen activator inhibitor [PAI-1] activity 4G4G). We carried out serologic measures of thrombophilia (homocysteine, anticardiolipin antibodies [ACLA] immunoglobulin G and immunoglobulin M, lupus anticoagulant, factor VIII, factor XI, protein C, total and free protein S, antithrombin III) and hypofibrinolysis (plasminogen activator inhibitor activity [PAI-Fx], lipoprotein[a]). Of the 380 controls, 6 (1.6%) had FV heterozygosity vs 12 heterozygous and 2 homozygous FV cases (15.2% [14/92]; P < .0001). Plasminogen activator inhibitor activity was high (> or =21.1 U/mL) in 21 (33%) of 63 cases vs 27 (18%) of 152 controls (P = .013). Factor VIII was high (>150%) in 15 (31%) of 48 cases vs 19 (18%) of 103 controls (P = .079). By logistic regression, with age and factor VIII (categorical [< or =150%, >150%]) as explanatory variables and group (cases, controls) as the dependent variable, after adjusting for age, high factor VIII was a significant predictor for miscarriage (odds ratio, 3.28; 95% confidence interval, 1.34-8.04; P = .01). There were no other group differences (P > .05) in measures of thrombophilia and hypofibrinolysis. After unexplained sporadic first trimester miscarriage, we suggest that measurements be done of the FV mutation, PAI-Fx, and factor VIII, etiologies for sporadic miscarriage.