Acute Coronary Syndrome

BackgroundDespite advances in therapeutic strategies a significant proportion of acute coronary syndrome (ACS) patients experience early coronary artery disease (CAD) progression, particularly those with diabetes.AimTo evaluate CAD progression in diabetic patients treated with glucagon-like peptide 1 receptor agonists (GLP-1Ra) over 1 year after an ACS.MethodsPatients presenting with non-ST-elevation ACS between 2019 and 2022 were enrolled in a prospective registry and underwent serial coronary computed tomography angiography (CCTA) at baseline (after revascularization, during the index hospitalization) and at 1-year follow-up. The primary endpoint was the absolute change (1 year - baseline) in non-culprit lesion plaque burden (ΔPB) on CCTA, with the absolute change in patient percent atheroma volume (ΔPAV) as a key secondary endpoint. A comprehensive lipidomic, metabolomic, and proteomic plasma assessment was also performed in all GLP-1Ra-treated patients and four randomly selected controls.ResultsOf 28 diabetic patients, 7 (25%) with 22 coronary plaques were treated with GLP-1Ra, and 21 (75%) with 65 plaques received other antidiabetic agents. In the 1-year observation frame, both ΔPB (-5.8 ± 12.8% vs. -1.1 ± 13.6%, p = 0.041) and ΔPAV (-6.1% [-7.3, -1.8] vs. -0.7% [-2.4, 9.8], p = 0.039) were significantly lower in GLP-1Ra-treated patients. Total atheroma volume also showed a numerically greater reduction in the GLP-1Ra cohort (0.7 mm³ [-2.5-8.7] vs. 25.0 mm³ [4.8-39.7]), primarily due to a decrease in plaque fibrofatty volume percentage (-2.9 ± 10.1% vs. 1.0 ± 6.8%, p = 0.042). Lipidomic, metabolomic, and proteomic analyses identified reductions in monoacylglycerols and triacylglycerols, increases in diacylglycerols and phosphatidylethanolamine, a shift from carbohydrate metabolism toward lipid metabolism and hormone regulation, and differential expression of proteins involved in complement activation, endothelial function, and cytoskeletal organization in GLP-1Ra-treated patients compared with controls.ConclusionsIn diabetic patients with ACS, GLP-1Ra therapy was associated with a significant regression in coronary plaque burden at 1 year, supported by favorable lipidomic, metabolomic, and proteomic changes. These findings suggest a potential role for GLP-1Ra in modifying atherosclerosis progression beyond glycemic control.

Regulatory T (Treg) cells are powerful endogenous modulators of the immune response and their levels are reduced in patients with acute coronary syndromes (ACSs). Low-dose interleukin-2 (IL-2) has been shown to increase Treg cell levels, potentially providing an immunomodulatory strategy in ACSs. The IVORY trial was a double-blind, placebo-controlled, phase 2 trial in which patients presenting with ACSs and high-sensitivity C-reactive protein levels >2 mg l-1 were randomized in a 1:1 ratio to receive subcutaneous low-dose IL-2 (1.5 × 106 IU) or placebo for 8 weeks. [18F]Fluorodeoxyglucose positron emission tomography-computed tomography of the ascending aorta and carotid arteries was performed before and after treatment. Here the primary outcome was the difference in arterial inflammation in the index vessel (the vessel with the highest average maximum target-to-background ratio pre-treatment) on follow-up imaging between the two groups (placebo = 29 (female-to-male ratio (F-to-M) = 6:23); low-dose IL-2 = 31 (F-to-M = 3:28)). At the end of treatment, arterial inflammation was -0.171 (-7.7%) lower in the low-dose IL-2 group compared to the placebo group (95% confidence interval -0.308 to -0.034, P = 0.015). In secondary efficacy analyses, the difference in arterial inflammation between the low-dose IL-2 and placebo groups was greater (-8.3%, P = 0.009) in more inflamed segments and low-dose IL-2 treatment increased Treg cell levels compared to placebo (P reg cell levels and reduces arterial inflammation. The clinical benefit of low-dose IL-2 requires validation in larger studies. ClinicalTrials.gov registration: NCT04241601 .

Background and aimsPatients with acute coronary syndromes (ACS) are at high ischaemic risk to which cholesterol, inflammation, and yet-to-be-identified pathways jointly contribute. The junctional protein associated with coronary artery disease (JCAD) drives incident cardiovascular events by acting on coagulation and fibrinolysis. This study aimed to assess whether JCAD serves as a novel marker of or target to address residual risk.MethodsIn the discovery cohort (SPUM-ACS; n = 4787), ACS patients at residual lipid risk [RLR; on-statin LDL cholesterol (LDL-c) ≥70 mg/dL or ≥1.8 mmol/L], residual inflammatory risk [RIR; on-statin high-sensitivity C-reactive protein (hs-CRP) ≥2.0 mg/L], or both (RILR; on-statin LDL-c ≥70 mg/dL and hs-CRP ≥2.0 mg/L) were identified and compared with propensity-score matched controls. Contributions of hs-CRP, LDL-c and JCAD to recurrent major adverse cardiovascular events (MACE) were analysed. In an independent cohort (RISK-PPCI study; n = 496), effects of JCAD on endogenous coagulation and fibrinolysis were gauged, and JCAD-MACE associations were externally validated.ResultsAt 1 year, patients at RLR, RIR, or RILR were at higher MACE risk as compared to controls [hazard ratio (HR), 1.55, 95% confidence interval (CI) 1.08-2.23; HR 1.80, 95% CI 1.24-2.61; and HR 1.75, 95% CI 1.12-2.75, respectively]. In those at RLR, MACE risk rose with increasing hs-CRP and JCAD, respectively, in uni- (HR per log2 increase, 1.17, 95% CI 1.06-1.30; HR 1.29, 95% CI 1.03-1.62) and multivariable-adjusted models [adjusted (a)HR 1.16, 95% CI 1.03-1.30; aHR 1.27, 95% CI 1.01-1.60]. In those at RIR, MACE risk increased 1.28-fold per log2 increase in JCAD (HR 1.28, 95% CI 1.03-1.59), which prevailed in multivariable-adjusted models (aHR 1.31, 95% CI 1.04-1.65). Similarly, in patients at RILR, MACE risk increased almost linearly with increasing JCAD (HR 1.45, 95% CI 1.09-1.92), independently of potential confounders (aHR 1.47, 95% CI 1.11-1.97). Plasma levels of JCAD correlated positively with proxies of impaired endogenous fibrinolysis, with the JCAD-MACE association being similarly observed in the external validation cohort.ConclusionsAcute coronary syndrome patients at RLR, RIR, or both are at high ischaemic risk. By modulating coagulation and endogenous fibrinolysis, JCAD represents a promising candidate to address the high residual risk that persists in ACS patients receiving guideline-recommended care.Clinicaltrials.gov identifiersNCT01000701, NCT02562690.