Background-In healthy humans, continuous treatment with nitroglycerin (GTN) causes nitric oxide synthase dysfunction, probably through the reduced bioavailability of tetrahydrobiopterin. Recent studies proposed that folic acid is involved in the regeneration of tetrahydrobiopterin in different disease states. Therefore, we investigated whether folic acid administration would prevent this phenomenon. We also sought to determine if folic acid supplementation could prevent the development of tolerance to GTN. Methods and Results-On the first visit, 18 healthy male volunteers (aged 19 to 32 years) were randomized to receive either oral folic acid (10 mg once a day) or placebo for 1 week in a double-blind designed study. All subjects also received continuous transdermal GTN (0.6 mg/h). On the second visit, forearm blood flow was measured with venous occlusion strain gauge plethysmography in response to incremental infusions of acetylcholine (7.5, 15, and 30 g/min), N-monomethyl-L-arginine (1, 2, and 4 mol/min), and GTN (11 and 22 nmol/min). Folic acid prevented GTN-induced endothelial dysfunction, as assessed by responses to intraarterial acetylcholine and N-monomethyl-L-arginine (PϽ0.01). Moreover, in the subjects treated with folic acid plus transdermal GTN, responses to intraarterial GTN were significantly greater than those observed after transdermal GTN plus placebo (PϽ0.05). Conclusion-Our data demonstrate that supplemental folic acid prevents both nitric oxide synthase dysfunction induced by continuous GTN and nitrate tolerance in the arterial circulation of healthy volunteers. We hypothesize that the reduced bioavailability of tetrahydrobiopterin is involved in the pathogenesis of both phenomena. Our results confirm the view that oxidative stress contributes to nitrate tolerance.

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Background As a result of the COVID-19 pandemic first wave, reductions in STEMI invasive care ranging from 23% to 76% have been reported from various countries. Whether it had any impact on coronary angiography (CA) volume or on mechanical support device use for ST-elevation myocardial infarction (STEMI) and post-STEMI mechanical complications in Canada is unknown. Methods We administered a Canada-wide survey to all Cardiac Catheterization Laboratory Directors seeking the volume of CA for STEMI performed during 01/03/2020-31/05/2020 (pandemic period) and from two control periods (01/03/2019-31/05/2019 and 01/03/2018-31/05/2018). The number of left ventricular support devices used, as well as the number of ventricular septal defects or papillary muscle rupture cases diagnosed, were also recorded. We also assessed if the number of COVID-19 cases recorded in each province was associated with STEMI CA volume. Results Forty-one out of 42 Canadian catheterization laboratories (98%) provided data. There was a modest but statistically significant 16% reduction (Incidence Rate Ratio or IRR 0.84; 95%CI 0.80-0.87) in CA for STEMI during the first wave of the pandemic compared to control periods. IRR was not associated with provincial COVID-19 caseload. We observed a 26% reduction (IRR 0.74; 95%CI 0.61-0.89) in the use of intra-aortic balloon pump in STEMI. Use of Impella® and mechanical complications from STEMI were exceedingly rare. Conclusion We observed a modest 16% decrease in CA for STEMI during the pandemic first wave in Canada, lower than reported in other countries. Provincial COVID-19 caseload did not influence this reduction.

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