BACKGROUNDExperimental and clinical evidence supports the role of inflammation in atherosclerosis and its complications. Colchicine is an orally administered, potent antiinflammatory medication that is indicated for the treatment of gout and pericarditis. METHODSWe performed a randomized, double-blind trial involving patients recruited within 30 days after a myocardial infarction. The patients were randomly assigned to receive either low-dose colchicine (0.5 mg once daily) or placebo. The primary efficacy end point was a composite of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization. The components of the primary end point and safety were also assessed. RESULTSA total of 4745 patients were enrolled; 2366 patients were assigned to the colchicine group, and 2379 to the placebo group. Patients were followed for a median of 22.6 months. The primary end point occurred in 5.5% of the patients in the colchicine group, as compared with 7.1% of those in the placebo group (hazard ratio, 0.77; 95% confidence interval [CI], 0.61 to 0.96; P = 0.02). The hazard ratios were 0.84 (95% CI, 0.46 to 1.52) for death from cardiovascular causes, 0.83 (95% CI, 0.25 to 2.73) for resuscitated cardiac arrest, 0.91 (95% CI, 0.68 to 1.21) for myocardial infarction, 0.26 (95% CI, 0.10 to 0.70) for stroke, and 0.50 (95% CI, 0.31 to 0.81) for urgent hospitalization for angina leading to coronary revascularization. Diarrhea was reported in 9.7% of the patients in the colchicine group and in 8.9% of those in the placebo group (P = 0.35). Pneumonia was reported as a serious adverse event in 0.9% of the patients in the colchicine group and in 0.4% of those in the placebo group (P = 0.03). CONCLUSIONSAmong patients with a recent myocardial infarction, colchicine at a dose of 0.5 mg daily led to a significantly lower risk of ischemic cardiovascular events than placebo. (Funded by the Government of Quebec and others; COLCOT ClinicalTrials.gov number, NCT02551094.

Aims In the randomized, placebo-controlled Colchicine Cardiovascular Outcomes Trial (COLCOT) of 4745 patients enrolled within 30 days after myocardial infarction, low-dose colchicine (0.5 mg once daily) reduced the incidence of the primary composite endpoint of cardiovascular death, resuscitated cardiac arrest, myocardial infarction (MI), stroke, or urgent hospitalization for angina leading to coronary revascularization. To assess the in-trial period and lifetime cost-effectiveness of low-dose colchicine therapy compared to placebo in post-MI patients on standard-of-care therapy. Methods and Results A multistate Markov model was developed incorporating the primary efficacy and safety results from COLCOT, as well as healthcare costs and utilities from the Canadian healthcare system perspective. All components of the primary outcome, non-cardiovascular deaths, and pneumonia were included as health states in the model as both primary and recurrent events. In the main analysis, a deterministic approach was used to estimate the incremental cost-effectiveness ratio (ICER) for the trial period (24 months) and lifetime (20 years). Over the in-trial period, the addition of colchicine to post-MI standard-of-care treatment decreased the mean overall per patient costs by 47%, from $502 to $265 CAD, and increased the quality adjusted life years (QALYs) from 1.30 to 1.34. The lifetime per patient costs were further reduced (69%) and QALYs increased with colchicine therapy (from 8.82 to 11.68). As a result, both in-trial and lifetime ICERs indicated colchicine therapy was a dominant strategy. Conclusion Cost-effectiveness analyses indicate that the addition of colchicine to standard-of-care therapy after myocardial infarction is economically dominant and therefore generates cost savings.

The renin-angiotensin-aldosterone (RAA) system is markedly activated in pregnancy. We evaluated if mineralocorticoid receptors (MR), a major component of the RAA system, are involved in the reduced vascular reactivity associated with pregnancy. Canrenoate (MR antagonist; 20 mg·kg Ϫ1 ·day Ϫ1 ) was administered to nonpregnant (NP) rats for 7 days and to pregnant rats from day 15 to 22 of gestation. These were killed on day 17, 19, or 22 of gestation and, for NP rats, after 7 days treatment. Constrictor responses to phenylephrine (PhE) and KCl were measured in endothelium-denuded thoracic aortic rings under the influence of modulators of potassium (activators) and calcium (blocker) channels. Responses to the constrictors were blunted from days 17 to 22 of gestation. Although canrenoate increased responses to PhE and KCl, it did not reverse their blunted responses in gestation. NS-1619 and cromakalim (respectively, highconductance calcium-activated potassium channels and ATP-sensitive potassium channel activators) diminished responses to both PhE and KCl. Inhibition by NS-1619 on responses to both agonists was decreased under canrenoate treatment in NP, but the reduced influence of NS-1619 during gestation was reversed by the mineralocorticoid antagonist. Cromakalim reduced the response to PhE significantly in the pregnant groups; this effect was enhanced by canrenoate. Finally, nifedipine (calcium channel blocker) markedly reduced KCl responses but to a lesser extent at the end of pregnancy, an inhibiting effect that was increased with canrenoate treatment. These data demonstrate that treating rats with a MR antagonist increased vascular reactivity but that it differentially affected potassium and calcium channel activity in aortas of NP and pregnant animals. This suggests that aldosterone is one of the components involved in vascular adaptations to pregnancy. potassium canrenoate; renin angiotensin aldosterone system; voltagedependent calcium channels; ATP-sensitive potassium channels; highconductance calcium-activated potassium channels IN HUMANS, arterial blood pressure (BP) decreases early in pregnancy, reaching a nadir during the second trimester (10, 26), whereas in rats it is stable until day 17 of gestation to decline gradually until term (day 23) (4, 37). This BP reduction is consequent to reduced vascular peripheral resistance associated with decreased influence of vasoconstrictor stimuli (3, 9, 10, 34, 37). These changes occur despite increases in blood volume and cardiac output and activation of the renin-angiotensin-aldosterone (RAA) system (2, 10, 39). In humans, by the sixth week of gestation, plasma renin activity (PRA) and aldosterone levels are already elevated and rise until term (10).In pregnant rats, PRA is increased early in gestation while aldosterone levels raise from midpregnancy until term (7, 18). In conditions other than pregnancy, such increases of the RAA system are associated with hypertension. This renders paradoxical the role of heightened RAA system in pregnancy (36).We have report...

Uterine blood supply is a critical issue for fetal well-being, since it carries all the nutrients, including O2, required for fetal growth and gets rid of several fetal waste products. During pregnancy, uterine blood flow increases by almost 20 times and this is permitted by marked remodeling of the vessel wall. In the rat, uterine arterial remodeling takes place in the last 7-8 days of gestation (over 22) and is reversible in the postpartum period upon a similar time frame. It was also described as both hypertrophy and hyperplasia of all the constituents of the vascular wall. Several hypotheses have been proposed to explain such a phenomenon, including the driving role not only of sexual steroid hormones, progesterone and estrogens, but also of trophic factors of fetal origin. We have shown that alterations of the renin-angiotensin-aldosterone system, by manipulating sodium intake in the rats, reduced the pregnancy-induced remodeling of uterine arteries. These maneuvres resulted in the birth of pups that had characteristics of intrauterine growth restriction or in the development in the mother of "experimental" gestational hypertension, depending on, respectively, restriction or increased of sodium intake.