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Buerger’s disease (BD) etiologies are poorly understood. Beyond smoking cessation, medical-surgical treatments have limited success. We hypothesized that mutations associated with arterial vasospasm (stromelysin-1 5A/6A, eNOS T-786C) and C677T-A1298C methylene tetrahydrofolate reductase (MTHFR) interacted with cigarette-cannabis smoking, reducing vasodilatory nitric oxide (NO), promoting arterial spasm-thrombosis. Of 21 smoking BD patients (14 men [2 siblings], 7 women; 20 white, 1 African-American), compared to 21 age-gender-race matched healthy controls, 5A/6A stromelysin- 1 homozygosity was present in 7 of 21 (33%) BD cases versus 5 of 21 (24%) controls (risk ratio 1.4; 95% confidence interval [CI] 0.5-3.7), and eNOS T-786C homozygosity was present in 3 of 21 (14%) BD cases versus 1 of 21 (5%) controls (risk ratio 3.0; 95% CI 0.3-26.6). C677T MTHFR homozygosity or compound C677T-A1298C heterozygosity was present in 7 of 21 cases (33%) versus 11 of 21 controls (52%) (risk ratio 0.6; 95% CI 0.3-1.3). In 18 patients who stopped and 3 who continued smoking, all stromelysin-1 5A/6A and/or eNOS heterozygotes-homozygotes, superficial phlebitis, lower limb gangrenous ulcers, and intractable ischemic rest pain with arterial occlusion progressed despite conventional medical therapy, threatening amputation. In 15 patients, to increase vasodilatory NO via endothelial NO synthase, l-arginine (15 g/day) was given, along with folic acid (5 mg), vitamin B6 (100 mg), and B12 (2000 mg/day) to optimize homocysteine metabolism and reduce asymmetric dimethylarginine, a NO synthase inhibitor. Unexpectedly quickly and strikingly, within 8 weeks to 8 months receiving l-arginine-folic acid, 11 of 15 treated patients improved with uniform pain reduction, ulcer healing, and in 5, full recovery of previously absent peripheral pulses. In smokers homo/heterozygous for stromelysin-1 5A/6A and eNOS T-786C mutations, we speculate that the development and severity of BD are related to a gene-environment vasospastic interaction with reduced NO-mediated vasodilatation. Increasing NO production by l-arginine while optimizing homocysteine metabolism by folic acid-B6-B12 may have therapeutic benefit. Further blinded, placebo-controlled studies are needed to determine whether our observations can be generalized to larger BD cohorts.

We assessed whether hypofibrinolytic plasminogen activator inhibitor (PAI-Fx) was independently associated with first-trimester miscarriage in 430 women with polycystic ovary syndrome (PCOS) who had previous pregnancies. We hypothesized that Glucophage optimizes live births in women with PCOS by lowering PAI-Fx before conception and further lowering PAI-Fx in the first trimester of pregnancy. We also assessed whether PAI-Fx levels were independently related to PAI-1 genotype and to modifiable risk factors, BMI, insulin, and triglyceride (TG). By stepwise logistic regression with the dependent variable being previous pregnancy outcomes at 3 levels (live birth pregnancies only [n = 208], both one or more 1 live births and $ one or more first-trimester miscarriages [n = 111] or first-trimester miscarriages only [n = 71]), and explanatory variables PAI-1 genotype, PAI-Fx, insulin, HOMA IR, BMI, and TG, PAI-Fx was positively associated with first-trimester miscarriage, p = .004. For each 5 IU/mL increment in PAI-Fx, the risk being in an adverse first-trimester miscarriage category increased, odds ratio 1.12, 95% CI 1.04 to 1.20. Prospectively, from pretreatment to the last preconception visit on Glucophage, in 30 women who subsequently had live births, PAI-Fx fell 44% but rose 19% in 23 women with first-trimester miscarriage, p = .03. In the 30 women with live birth pregnancies, median PAI-Fx fell continuously from pretreatment through the first trimester (from 16.8 to 6.7 IU/mL), while PAI-Fx was either unchanged or rose in women with first-trimester miscarriage. Of the 921 PCOS women who had 4G5G data, 718 (78%) had 4G4G-4G5G genotypes vs 87/126 (69%) normal female controls (x2 = 4.95, p = .026). The 4G-allele frequency was 53% in PCOS women vs 46% in controls (x2 = 4.3, p = .04). By stepwise regression, positive independent determinants of PAI-Fx included BMI (partial R2 = 10.6%, p

Buerger9s disease (BD) etiologies are poorly understood. Beyond smoking cessation, medical-surgical treatments have limited success. We hypothesized that mutations associated with arterial vasospasm (stromelysin-1 5A/6A, eNOS T-786C) and C677T-A1298C methylenetetrahydrofolate reductase (MTHFR) interacted with cigarette-cannabis smoking, reducing vasodilatory nitric oxide (NO), promoting arterial spasm-thrombosis. Of 19 smoking BD patients (13 men [2 siblings], ± women, 18 Caucasian, 1 African American), compared to 200 healthy Caucasian controls, BD patients were more likely to have 6A6A stromelysin-1 homozygosity (7/19 [37%] vs 46/200 [23%]) and to have eNOS T-786C homozygosity (3/19 [16%] vs 22/200 [11%]), but these patient-control differences were not significant, p = .4, 0.5. C677T MTHFR homozygosity or compound C677T-A1298C heterozygosity did not differ in patients vs controls (6/19 [32%] vs 70/200 [35%]), p = .8. In 9 patients who stopped and 1 who continued smoking, all stromelysin-1 5A/6A and/or eNOS heterozygotes-homozygotes, lower limb gangrenous ulcers, and intractable ischemic rest pain with arterial occlusion progressed despite conventional medical therapy, threatening amputation. In these 10 patients, to increase vasodilatory NO via endothelial NO synthase, L-arginine (15 g/day) was given, along with folic acid 5 mg, vitamin B6 (100 mg), and B12 (2,000 μg/day) to optimize homocysteine metabolism and reduce asymmetric dimethylarginine, a NO synthase inhibitor. Unexpectedly quickly and strikingly, within 8 weeks to 8 months on L-arginine-folic acid, all 10 treated patients improved with uniform pain reduction, ulcer healing, and in 5, full recovery of previously absent peripheral pulses. In smokers homo-heterozygous for stromelysin-1 5A/6A, eNOS T-786C, and C677T-A1298C MTHFR mutations, we speculate that the development and severity of BD are related to a gene-environment vasospastic interaction with reduced NO-mediated vasodilatation. Increasing NO production by L-arginine while optimizing homocysteine metabolism by folic acid-B6-B12 may have therapeutic benefit. Further blinded, placebo-controlled studies are needed to determine whether our observations can be generalized to larger BD cohorts.