Patients with type 2 diabetes (T2DM) are at high risk for cardiovascular events, which usually arise from the rupture of a vulnerable coronary plaque. The minimal fibrous cap thickness (FCT) overlying a necrotic lipid core is an established predictor for plaque rupture. Recently, coronary calcification has emerged as a relevant feature of plaque vulnerability. However, the impact of T2DM on these morphological plaque parameters is largely unexplored. Therefore, this study aimed to compare differences of coronary plaque morphology in patients with and without T2DM with a particular focus on coronary calcification. In 91 patients (T2DM = 56, non-T2DM = 35) with 105 coronary de novo lesions (T2DM = 56, non-T2DM = 49) plaque morphology and calcification were analyzed using optical coherence tomography (OCT) prior to coronary intervention. Patients with T2DM had a lower minimal FCT (80.4 ± 27.0 µm vs. 106.8 ± 27.8 µm, p < 0.001) and a higher percent area stenosis (77.9 ± 8.1% vs. 71.7 ± 11.2%, p = 0.001) compared to non-diabetic subjects. However, patients with and without T2DM had a similar total number of calcifications (4.0 ± 2.6 vs. 4.2 ± 3.1, p = ns) and no significant difference was detected in the number of micro- (0.34 ± 0.79 vs. 0.31 ± 0.71), spotty (2.11 ± 1.77 vs. 2.37 ± 1.89) or macro-calcifications (1.55 ± 1.13 vs. 1.53 ± 0.71, all p = ns). The mean calcium arc (82.3 ± 44.8° vs. 73.7 ± 31.6), the mean thickness of calcification (0.54 ± 0.13 mm vs. 0.51 ± 0.15 mm), the mean calcified area (0.99 ± 0.72 mm2 vs. 0.78 ± 0.49 mm2), the mean depth of calcification (172 ± 192 μm vs. 160 ± 76 μm) and the cap thickness overlying the calcification (50 ± 71 μm vs. 62 ± 61 μm) did not differ between the diabetic and non-diabetic groups (all p = ns). T2DM has an impact on the minimal FCT of the coronary target lesion, but not on localization, size, shape or extent of calcification. Thus, the minimal FCT overlying the necrotic lipid core but not calcification is likely to contribute to the increased plaque vulnerability observed in patients with T2DM.

Plaque rupture occurs if stress within coronary lesions exceeds the protection exerted by the fibrous cap overlying the necrotic lipid core. However, very little is known about the biomechanical stress exerting this disrupting force. Employing optical coherence tomography (OCT), we generated plaque models and performed finite-element analysis to simulate stress distributions within the vessel wall in 10 ruptured and 10 non-ruptured lesions. In ruptured lesions, maximal stress within fibrous cap (peak cap stress [PCS]: 174 ± 67 vs. 52 ± 42 kPa, p<0.001) and vessel wall (maximal plaque stress [MPS]: 399 ± 233 vs. 90 ± 95 kPa, p=0.001) were significantly higher compared to non-ruptured plaques. Ruptures arose in the immediate proximity of maximal stress concentrations (angular distances: 21.8 ± 30.3° for PCS vs. 20.7 ± 23.7° for MPS); stress concentrations excellently predicted plaque rupture (area under the curve: 0.940 for PCS, 0.950 for MPS). This prediction of plaque rupture was superior to established vulnerability features such as fibrous cap thickness or macrophage infiltration. In conclusion, OCT-based finite-element analysis effectively assesses plaque biomechanics, which in turn predicts plaque rupture in patients. This highlights the importance of morpho-mechanic analysis assessing the disrupting effects of plaque stress.

The presence of plaque macrophages and microcalcifications are acknowledged features of plaque vulnerability. Experimental data suggest that microcalcifications promote inflammation and macrophages foster microcalcifications. However, co-localization of plaque macrophages and calcification (ColocCaMa) in coronary segments and its impact on plaque phenotype and lesion vulnerability is unexplored. Plaque morphology including ColocCaMa of calcified coronary target segments in patients with stable coronary artery disease (n = 116) was analyzed using optical coherence tomography (OCT) prior to coronary intervention. Therefore we considered macrophages co-localized with calcification if their distance in an OCT frame was <100μm and OCT-defined microcalcifications with a calcium arc <22.5°. ColocCaMa was present in 29/116(25.0%) coronary segments. Calcium burden was greater (calcium volume index:1731±1421°*mm vs. 963±984°*mm, p = 0.002) and calcifications were more superficial (minimal thickness of the fibrous cap overlying the calcification 35±37μm vs. 64±72μm, p = 0.005) in the presence of ColocCaMa. Segments with ColocCaMa demonstrated a higher incidence of newly suggested features of plaque vulnerability, with a 3.5-fold higher number of OCT-defined microcalcifications (0.7±1.0 vs. 0.2±0.6, p = 0.022) and a 6.7-fold higher incidence of plaque inflammation (macrophage volume index:148.7±248.3°*mm vs. 22.2±57.4°*mm, p<0.001). Clinically, intima–media thickness (IMT) in carotid arteries was increased in patients with ColocCaMa (1.02±0.30mm vs. 0.85±0.18, p = 0.021). In a multivariate model, IMT (OR1.76 for 100μm, 95%CI 1.16–2.65, p = 0.007), HDL-cholesterol (OR0.36 for 10mg/dl, 95%CI 0.16–0.84, p = 0.017), calcium volume index (OR1.07 for 100°*mm, 95%CI 1.00–1.14, p = 0.049), macrophage volume index (OR5.77 for 100°*mm, 95%CI 2.04–16.3, p = 0.001) and minimal luminal area (OR3.41, 95%CI 1.49–7.78, p = 0.004) were independent predictors of ColocCaMa. Plaque macrophages co-localize with calcifications in coronary target segments and this is associated with high-risk morphological features including microcalcifications and macrophage infiltration as well as with greater calcification burden. Our data may add to the understanding of the relationship between plaque macrophages, vascular calcification and their clinical impact.

Background: Coronary calcification is associated with high risk for cardiovascular events. However, its impact on plaque vulnerability is incompletely understood. In the present study we defined the intrinsic calcification angle (ICA) as the angle externally projected by a vascular calcification and analyzed its role as novel feature of coronary plaque vulnerability in patients with type 2 diabetes. Methods: Optical coherence tomography was used to determine ICA in 219 calcifications from 56 patients with stable coronary artery disease (CAD) and 143 calcifications from 36 patients with acute coronary syndrome (ACS). We then used finite elements analysis to gain mechanistic insight into the effects of ICA. Results: Minimal (139.8 ± 32.8° vs. 165.6 ± 21.6°, p < 0.001) and mean ICA (164.1 ± 14.3° vs. 176.0 ± 8.4°, p < 0.001) were lower in ACS vs. stable CAD patients. Mean ICA predicted ACS with very good diagnostic efficiency (AUC = 0.840, 95% CI 0.797–0.882, p < 0.001, optimal cut-off 175.9°); younger age (OR 0.95 per year, 95% CI 0.92–0.98, p = 0.002), male sex (OR 2.18, 95% CI 1.41–3.38, p < 0.001), lower HDL-cholesterol (OR 0.82 per 10 mg/dl, 95% CI 0.68–0.98, p = 0.029) and ACS (OR 14.71, 95% CI 8.47–25.64, p < 0.001) were determinants of ICA < 175.9°. A lower ICA predicted ACS (OR for 10°-variation 0.25, 95% CI 0.13–0.52, p < 0.001) independently from fibrous cap thickness, presence of macrophages or extension of lipid core. In finite elements analysis we confirmed that lower ICA causes increased stress on a lesion’s fibrous cap; this effect was potentiated in more superficial calcifications and adds to the destabilizing role of smaller calcifications. Conclusion: Our clinical and mechanistic data for the first time identify ICA as a novel feature of coronary plaque vulnerability.

Introduction: Myocardial infarction without obstructive coronary artery disease (MINOCA) is a heterogeneous clinical condition presenting with myocardial necrosis not due to an obstruction of a major coronary artery. Recently, a relevant role of coronary microvascular dysfunction (CMD) in the pathogenesis of MINOCA has been suggested; however, data on this are scarce. Particularly, it is unclear if CMD is equally present in all subtypes of MINOCA or differentially identifies one or more of these conditions. Therefore, the aim of this study was to assess CMD in all three coronary vessels of MINOCA patients, relating it with the clinical subtype. Methods: We retrospectively assessed coronary microvascular function in all three coronary territories by means of angiography-based index of microvascular resistance (aIMR) in 92 patients (64 with working diagnosis of MINOCA, 28 control patients). To further assess the association of CMD with MINOCA subtypes, MINOCA patients were subdivided according to clinical data in coronary cause (n = 13), takotsubo (n = 13), infiltrative or inflammatory cardiomyopathy (n = 9) or unclear (n = 29). Results: Patients with working diagnosis of MINOCA showed a significantly elevated average aIMR compared to control patients (30.5 ± 7.6 vs. 22.1 ± 5.9, p < 0.001) as a marker of a relevant CMD; these data were consistent in all vessels. Among MINOCA subtypes, no significant difference in average aIMR could be detected between patients with coronary cause (33.2 ± 6.6), takotsubo cardiomyopathy (29.2 ± 6.9), infiltrative or inflammatory cardiomyopathy (28.1 ± 6.8) or unclear cause (30.6 ± 8.5; p = 0.412). Interestingly, aIMR was significantly elevated in the coronary vessel supplying the diseased myocardium compared with other vessels (31.9 ± 11.4 vs. 27.8 ± 8.2, p = 0.049). Conclusion: Coronary microvascular dysfunction is a hallmark of all MINOCA subtypes. This study adds to the pathophysiological understanding of MINOCA and sheds light into the role of CMD in MINOCA.