Neutralizing injurious stimuli, proinflammatory mediator catabolism, and polymorphonuclear leukocyte (PMN) clearance are determinants of inflammatory resolution. To this, we recently added innate-type lymphocyte repopulation as being central for restoring postinflammation tissue homeostasis with a role in controlling innate immune–mediated responses to secondary infection. However, although macrophages dominate resolution, their phenotype and role in restoring tissue physiology once inflammation abates are unknown. Therefore, we isolated macrophages from the resolving phase of acute inflammation and found that compared with classically activated proinflammatory M1 cells, resolution-phase macrophages (rMs) possess weaker bactericidal properties and express an alternatively activated phenotype but with elevated markers of M1 cells including inducible cyclooxygenase (COX 2) and nitric oxide synthase (iNOS). This phenotype is controlled by cAMP, which, when inhibited, transforms rM to M1 cells. Conversely, elevating cAMP in M1 cells transforms them to rMs, with implications for cAMP in the resolution of systemic inflammation. It transpires that although rMs are dispensable for clearing PMNs during self-limiting inflammation, they are essential for signaling postresolution lymphocyte repopulation via COX 2 lipids. Thus, rM macrophages are neither classically nor alternatively activated but a hybrid of both, with a role in mediating postresolution innate-lymphocyte repopulation and restoring tissue homeostasis.

BackgroundPreclinical data suggest that an acute inflammatory response following myocardial infarction (MI) accelerates systemic atherosclerosis. Using combined positron emission and computed tomography, we investigated whether this phenomenon occurs in humans.Methods and ResultsOverall, 40 patients with MI and 40 with stable angina underwent thoracic 18F-fluorodeoxyglucose combined positron emission and computed tomography scan. Radiotracer uptake was measured in aortic atheroma and nonvascular tissue (paraspinal muscle). In 1003 patients enrolled in the Global Registry of Acute Coronary Events, we assessed whether infarct size predicted early (≤30 days) and late (>30 days) recurrent coronary events. Compared with patients with stable angina, patients with MI had higher aortic 18F-fluorodeoxyglucose uptake (tissue-to-background ratio 2.15±0.30 versus 1.84±0.18, P<0.0001) and plasma C-reactive protein concentrations (6.50 [2.00 to 12.75] versus 2.00 [0.50 to 4.00] mg/dL, P=0.0005) despite having similar aortic (P=0.12) and less coronary (P=0.006) atherosclerotic burden and similar paraspinal muscular 18F-fluorodeoxyglucose uptake (P=0.52). Patients with ST-segment elevation MI had larger infarcts (peak plasma troponin 32 300 [10 200 to >50 000] versus 3800 [1000 to 9200] ng/L, P<0.0001) and greater aortic 18F-fluorodeoxyglucose uptake (2.24±0.32 versus 2.02±0.21, P=0.03) than those with non–ST-segment elevation MI. Peak plasma troponin concentrations correlated with aortic 18F-fluorodeoxyglucose uptake (r=0.43, P=0.01) and, on multivariate analysis, independently predicted early (tertile 3 versus tertile 1: relative risk 4.40 [95% CI 1.90 to 10.19], P=0.001), but not late, recurrent MI.ConclusionsThe presence and extent of MI is associated with increased aortic atherosclerotic inflammation and early recurrent MI. This finding supports the hypothesis that acute MI exacerbates systemic atherosclerotic inflammation and remote plaque destabilization: MI begets MI.Clinical Trial RegistrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT01749254.

Abstract-Renin-angiotensin systems may mediate cardiovascular disease pathogenesis through a balance of actions of angiotensin II on (potentially proatherogenic) constitutive type 1 (AT 1 R) and (potentially antiatherogenic) inducible type 2 (AT 2 R) receptors. We explored such potential roles in a prospective candidate gene association study. Cardiovascular end points (fatal, nonfatal, and silent myocardial infarction and coronary artery bypass surgery/angioplasty) were documented among 2579 healthy UK men (mean age, 56.1Ϯ3.5 years; median follow-up, 10.1 years) genotyped for the AT 1 R1166AϾC and the X chromosome located AT 2 R1675AϾG and 3123CϾA polymorphisms. Baseline characteristics, including blood pressure, were independent of genotype. The AT 1 R1166CC genotype was associated with relative cardiovascular risk (hazard ratio, 1.65 [1.05 to 2.59]; Pϭ0.03) independent of blood pressure. Systolic blood pressure was associated with risk (Pϭ0.0005), but this association was restricted to AT 2 R1675A allele carriers (PϽ0.00001), with G allele carriers protected from the risk associated with blood pressure (Pϭ0.18). Hypertensive carriers with the AT 2 R1675A/3123A haplotype were at most risk, with 37.5% having an event. This is the first study to demonstrate an association of AT 2 R genotype with coronary risk, an effect that was confined to hypertensive subjects and supports the concept that the inducible AT 2 R is protective. Conversely, the AT 1 R1166CC genotype was associated with cardiovascular risk irrespective of blood pressure. These data are important to our understanding of the divergent role of angiotensin II acting at its receptor subtypes and coronary disease pathogenesis and for the development of future cardiovascular therapies. Coronary vascular ACE drives Ang II synthesis, whose action on local AT 1 and inducible AT 2 receptors (AT 2 R) 2,3 may contribute to coronary heart disease (CHD) pathogenesis: AT 1 R activation causes vascular smooth muscle cell hypertrophy, extracellular matrix production, and local inflammation, driving atherogenesis and plaque rupture, 4 whereas AT 2 R agonism inhibits vascular cell proliferation 5 and may be antiatherogenic. 6 The balance between AT 1 R and AT 2 R activation may therefore influence CHD risk. However, this remains difficult to explore, and supportive data are sparse. Studies involving selective AT 1 R antagonism are perhaps less informative than they might at first appear: although lowering CHD risk more than equihypotensive ␤-blockade, 7 this may be partly mediated through AT 2 R agonism-loss of negative feedback raising Ang II levels and hence binding to the vacant AT 2 R. 8Could there be a role for both the AT 1 R and AT 2 R in the development of CHD? Genetic studies may provide insight. A polymorphism of the AT 1 R gene exists at position 1166, where the C (rather than A) allele is associated with increased Ang II responsiveness. 9 Meanwhile, the A (rather than G) allele at position 1675 of the X-chromosomal AT 2 R gene is associated with a greater ...

Background: Oral factor XIa (FXIa) inhibitors may modulate coagulation to prevent thromboembolic events without significantly increasing bleeding. We explored the pharmacodynamics, safety, and efficacy of the oral FXIa inhibitor asundexian for secondary prevention after acute myocardial infarction (MI). Methods: We randomized 1601 patients with recent acute MI to oral asundexian 10, 20, or 50 mg or placebo once daily for 6–2 months in a double-blind, placebo-controlled, phase 2, dose-ranging trial. Patients were randomized within 5 days of their qualifying MI and received dual antiplatelet therapy with aspirin plus a P2Y12 inhibitor. The effect of asundexian on factor XIa inhibition was assessed at 4 weeks. The prespecified main safety outcome was Bleeding Academic Research Consortium type 2, 3, or 5 bleeding comparing all pooled asundexian doses with placebo. The prespecified efficacy outcome was a composite of cardiovascular death, MI, stroke, or stent thrombosis comparing pooled asundexian 20 and 50 mg doses with placebo. Results: The median age was 68 years, 23% were women, 51% had ST-elevation MI, 80% were treated with aspirin plus ticagrelor or prasugrel, and 99% underwent percutaneous coronary intervention before randomization. Asundexian caused dose-related inhibition of FXIa activity with 50 mg resulting in >90% inhibition. Over a median follow-up of 368 days, the main safety outcome occurred in 30 (7.6%), 32 (8.1%), 42 (10.5%), and 36 (9.0%) patients receiving asundexian 10, 20, 50 mg, and placebo (pooled asundexian vs. placebo: HR 0.98, 90% CI 0.71–1.35). The efficacy outcome occurred in 27 (6.8%), 24 (6.0%), 22 (5.5%), and 22 (5.5%) patients assigned asundexian 10, 20, 50 mg, and placebo (pooled asundexian 20 and 50 mg vs. placebo: HR 1.05, 90% CI 0.69–1.61). Conclusions: : In patients with recent acute MI, 3 doses of asundexian, when added to aspirin plus a P2Y12 inhibitor, resulted in dose-dependent, near-complete inhibition of FXIa activity without a significant increase in bleeding and a low rate of ischemic events. These data support the investigation of asundexian at a dose of 50 mg daily in an adequately powered clinical trial of patients following acute MI.

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South Asian patients were more likely to require re-admission to treat clinical restenosis of the index lesion. There was no significant long-term difference in all-cause mortality between SA and WE patients.

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