Features of atherosclerosis in patients with angina and no obstructive coronary artery disease.

BACKGROUND: An association between atherosclerosis and coronary vasospasm has previously been suggested. However, to date, no conclusive data on the whole spectrum of these disorders have been published. AIMS: This study aimed to define specific morphological features of atherosclerosis in patients with angina and no obstructive coronary artery disease (ANOCA) due to coronary vasospasm. METHODS: From February 2019 to January 2020, we enrolled 75 patients referred to our laboratory for a coronary function test (CFT) due to ANOCA and suspected coronary vasomotor dysfunction. The CFT consisted of an acetylcholine test and a physiology assessment with hyperaemic indexes using adenosine. Patients were divided into two groups according to the presence or absence of coronary vasospasm triggered by acetylcholine (ACH+ and ACH-, respectively). In addition, optical coherence tomography (OCT) was performed to assess the lipid index (LI), a surrogate for lipid area, and the prevalence of markers of plaque vulnerability. RESULTS: ACH+ patients had a higher LI than ACH- patients (LI: 819.85 [460.95-2489.03] vs 269.95 [243.50-878.05], respectively, p=0.03), and a higher prevalence of vulnerable plaques (66% vs 38%, p=0.04). Moreover, ACH+ patients showed a higher prevalence of neovascularisation compared to ACH- subjects (37% vs 6%, p=0.02) and a trend towards a higher prevalence of all individual markers, in particular thin-cap fibroatheroma (20% vs 0%, p=0.06). No differences were detected between patterns of coronary vasospasm. CONCLUSIONS: The presence of coronary vasospasm, regardless of its phenotype, is associated with higher lipid burden, plaque vulnerability and neovascularisation.

MAb therapy against the IFN-α/ß receptor subunit 1 stimulates arteriogenesis in a murine hindlimb ischaemia model without enhancing atherosclerotic burden.

AIMS: IFN-beta (IFNß) signalling is increased in patients with insufficient coronary collateral growth (i.e. arteriogenesis) and IFNß hampers arteriogenesis in mice. A downside of most pro-arteriogenic agents investigated in the past has been their pro-atherosclerotic properties, rendering them unsuitable for therapeutic application. Interestingly, type I IFNs have also been identified as pro-atherosclerotic cytokines and IFNß treatment increases plaque formation and accumulation of macrophages. We therefore hypothesized that mAb therapy to inhibit IFNß signalling would stimulate arteriogenesis and simultaneously attenuate-rather than aggravate-atherosclerosis. METHODS AND RESULTS: In a murine hindlimb ischaemia model, atherosclerotic low-density lipoprotein receptor knockout (LDLR(-/-)) mice were treated during a 4-week period with blocking MAbs specific for mouse IFN-α/ß receptor subunit 1 (IFNAR1) or murine IgG isotype as a control. The arteriogenic response was quantified using laser Doppler perfusion imaging (LDPI) as well as immunohistochemistry. Effects on atherosclerosis were determined by quantification of plaque area and analysis of plaque composition. Downstream targets of IFNß were assessed by real-time PCR (RT-PCR) in the aortic arch. Hindlimb perfusion restoration after femoral artery ligation was improved in mice treated with anti-IFNAR1 compared with controls as assessed by LDPI. This was accompanied by a decrease in CXCL10 expression in the IFNAR1 MAb-treated group. Anti-IFNAR1 treatment reduced plaque apoptosis without affecting total plaque area or other general plaque composition parameters. Results were confirmed in a short-term model and in apolipoprotein E knockout (APOE)(-/-) mice. CONCLUSION: Monoclonal anti-IFNAR1 therapy during a 4-week treatment period stimulates collateral artery growth in mice and did not enhance atherosclerotic burden. This is the first reported successful strategy using MAbs to stimulate arteriogenesis.