Plaque Rupture Research Articles

Comparison of plaque characteristics among different age groups in patients with acute coronary syndromes with or without diabetes

Abstract Background It has been reported that young patients with diabetes mellitus (DM) had a higher mortality rate after myocardial infarction. However, plaque characteristics among different age groups in patients with acute coronary syndromes (ACS) with or without DM are unknown. Purpose The aim of this study was to investigate the plaque characteristics among different age groups in ACS patients with or without DM in a large population. Methods Patients who presented with ACS and underwent preintervention OCT imaging were included. The culprit plaque was categorized as plaque rupture (PR), plaque erosion (PE) or calcified plaque (CP), and stratified by 5 age groups. Features of plaque vulnerability were also analyzed. Results Among 1394 patients, 482 (34.6%) had DM. DM patients had a higher prevalence of lipid-rich plaque (71.2% vs. 64.8%, p=0.016), macrophage (72.0% vs. 62.6%, p<0.001), and cholesterol crystal (27.6% vs. 19.7%, p<0.001) than non-DM patients. Non-DM patients showed a significant ascending trend with age in PR (p=0.004), lipid-rich plaque (p=0.018), whereas DM patients had a high prevalence of these vulnerable features at early age, which plateaued across the different age groups. Both DM and non-DM groups showed a significant decreasing trend in PE with age (non-DM patients, p<0.001; DM patients, p=0.020). Conclusions DM patients had a high prevalence of lipid-rich plaque and a high incidence of plaque rupture at early age. This pattern persisted across the different age groups.

C-reactive protein levels and coronary in-stent restenosis: A systematic review and meta-analysis

Abstract Background C-reactive protein (CRP) is an inflammatory biomarker and has been implicated in the pathogenesis of atherosclerotic lesion formation, plaque rupture, and coronary thrombosis. Its relationship to adverse angiographic outcomes after coronary stenting however remains uncertain. Purpose We aimed to test the association of baseline CRP levels with the incidence of coronary in-stent restenosis (ISR) using a systematic review and meta-analysis. Methods Relevant published studies were identified following a US National Institutes of Health (PubMed), EMBASE, MEDLINE, Scopus and Web of Knowledge databases search, until 31st October 2022. Selected studies had to be/have (i) original research with an angiographically determined ISR and an angiographically or clinically determined no-ISR group, and (ii) CRP levels measured before index stenting for both groups. Mean difference in CRP levels with its 95%CI between ISR and no-ISR was ascertained for each included study. Pooled standard mean difference (SMD) and its 95%CI was derived after pooling study level results using random effects employing a Z test. Begg’s funnel plots and Egger’s test were used for publication bias assessment. Results Amongst total of 1,009 unique results, 497 full-text articles were assessed for eligibility, 461 were excluded for a variety of reasons, which left 36 articles with 37 different studies (Nst= 37), with a total sample of 10,577 (2,122 ISR cases / 8,455 controls), to be included for quantitative synthesis. Complete study flow is depicted in Figure 1. ISR group had higher pooled CRP levels (Nst= 37, SMD= 0.50, 95% CI= 0.33, 0.67 mg/L, p< 0.00001) as compared to no-ISR group. Sensitivity analysis found no instance of significant alteration from the original results. No evidence of publication bias was detected either visually by the Begg’s funnel plots or the Egger’s test (p= 0.07). Analysis was repeated after subgroup stratification of the included studies according to study design, stent type, assay type, ancestry, presentation diagnosis, and data type. Important findings identified by the subgroup analysis were the significant differences in CRP levels between ISR and no-ISR, amongst Middle Easterners (Nst= 10, SMD 0.63, 95%CI 0.33, 0.93 mg/L, p< 0.0001) and Asians (Nst= 18, SMD 0.71, 95%CI 0.46, 0.96 mg/L, p= 0.00001), however not amongst Europeans (Nst= 9, SMD -0.11, 95%CI -0.43, 0.21 mg/L, p= 0.50). Results obtained for other subgroups however remained consistent and showed significant positive associations. (Figure 2.) Conclusions The present systematic review and meta-analysis indicates a positive association of higher baseline CRP values with the incidence of angiographically confirmed ISR. In subgroup analysis there was no evidence of association amongst Europeans, in contrast to significant associations seen amongst rest of the ancestries. These results warrant further validation in dedicated large cohorts, ideally in a prospective setting.Figure 1.Figure 2.

Non-flow limiting non-culprit plaque characteristics in patients presenting with STEMI versus NSTEMI

Abstract Background Non-ST-elevation myocardial infarction (NSTEMI) and ST-elevation myocardial infarction (STEMI) are often considered distinct clinical entities. Although differences in culprit plaque characteristics have been described extensively, less is known about differences in non-culprit (NC) plaque characteristics. Purpose To compare plaque characteristics of fractional flow reserve (FFR)-negative NC lesions as assessed by optical coherence tomography (OCT) in STEMI and NSTEMI patients. Methods PECTUS-obs is a prospective, observational study in which 438 patients presenting with STEMI or NSTEMI underwent OCT of any intermediate FFR-negative NC lesion (defined as a FFR >0.80) after treatment of the infarct related artery. Quantitative and qualitative OCT analyses were performed by an independent core laboratory. A high risk plaque (HRP) was defined as the presence of ≥2 of the following prespecified criteria: 1) a lipid arc ≥90°, 2) a minimal fibrous cap thickness <65 µm, or 3) either cap rupture or thrombus presence. In the present sub-analysis, lesion-level plaque characteristics were compared between patients presenting with STEMI versus NSTEMI while accounting for within-patient clustering and correcting for prespecified clinical variables (age, history of myocardial infarction, diabetes, and estimated glomerular filtration rate (eGFR)). Results Among 420 patients with at least one analyzable OCT, 217 (51.7%) presented with STEMI and 203 (48.3%) with NSTEMI. Patients with STEMI were younger (mean age 62±10 vs 65±11 years, p=0.004) and less frequently had diabetes (11.1% vs 18.2%, p=0.037) and hypercholesterolemia (31.8% vs 41.6%, p=0.038). Baseline mean eGFR (84±19 vs 75±19 ml/min, p<0.001) and low density lipoprotein-cholesterol levels (3.2±1.2 vs 2.9±1.2, p=0.010) were higher in STEMI patients with fewer of these patients using lipid lowering therapy (18.9% vs 33.0%, p<0.001) before enrollment. A total of 494 NC lesions were analyzed, which were equally distributed in number and location between groups. The mean fractional flow reserve was 0.89±0.05 and was comparable between groups (p=0.26). Patients with STEMI had a smaller minimal lumen area (2.56±1.48 vs 2.84±1.58 mm2, p=0.031) and minimal lumen diameter (1.47±0.44 vs 1.55±0.45 mm, p=0.026) with a subsequent larger percentage area stenosis (64±15 vs 61±17%, p=0.022). Lipid plaques were more common in STEMI patients (81.7% vs 70.7%, p=0.006) and the maximal lipid arc more frequently was ≥90º (79.0% vs 69.0%, p=0.018). There was no difference in the presence of plaque ruptures (8.3% vs 11.2%, p=0.31) or HRP (32.9% vs 29.3%, p=0.40), whereas macrophage accumulation was more prevalent in STEMI patients (27.8% vs 18.2%, p=0.040). Conclusions FFR-negative NC lesions in patients with STEMI have smaller luminal dimensions, and more frequently harbor lipid plaques and macrophage accumulation. No difference was observed in the prevalence of HRP or plaque rupture.

Predictive value of d-dimer for plaque rupture, thrombus and worse clinical outcomes in acute coronary syndrome from TACTICS registry

Abstract Background Acute coronary syndrome (ACS) mainly occurs by the rupture of lipid plaques with platelet aggregation. D-dimer (DD) is a primary degradation product and circulating marker of fibrinolysis. The use of DD helps to diagnose thrombosis. The serum DD level may indicate a thrombus within coronary artery in patients with ACS. Purpose The present study determined the association of serum DD level on admission with a thrombus within culprit lesion and ACS mechanism assessed by optical coherence tomography (OCT), and clinical outcomes. Methods and Results Tokyo/ Kanagawa/ Chiba/ Shizuoka/ Ibaraki active OCT applications for ACS (TACTICS) registry includes 695 consecutive ACS patients who underwent emergent PCI with OCT guidance. Of those, the information of serum DD level was available in 653 cases. Those patients were divided into two groups according to serum DD level on admission: high DD group(≧0.73 μg/ml, n= 328) and low DD group(＜0.73 μg/ml, n= 325). Comparison of type of plaque morphology and thrombus are shown in Figure. ACS patients with high DD level had poor long-term outcomes. Conclusion High serum DD level was associated with red-thrombus, plaque rupture, and worse prognosis in ACS. The simple test of DD may give us useful information in clinical practice for ACS.

Sex differences in patients with MINOCA: baseline characteristics and prognosis

Abstract Background The difference between men and women regarding the diagnosis and treatment of cardiovascular diseases has been an object of study during the last few years, with an underrepresentation of female patients in old studies. The epidemiology, diagnosis, and treatment of patients with myocardial infarction with non-obstructive coronary arteries (MINOCA) has not yet been wholly elucidated up to this day. The aim of this study is to compare the characteristics and prognosis of MINOCA patients based on sex. Methods We analyzed all consecutive patients with MINOCA diagnosed at a University Hospital between 2016 and 2022. MINOCA diagnostic criteria compelled at the ESC Clinical Guidelines and the AHA Scientific Statement have been followed. Results Our sample comprises 107 patients with MINOCA, 61 male (57%) and 46 female (43%), but once the age of 80 years old was reached, MINOCA was more prevalent in women. We found the female population to have a higher prevalence of stress (usually chronic stress) and transient ischaemic attacks. On the contrary, men usually have more night shifts, psychiatric disorders, and a higher prevalence of smoking. We found no significant differences in cardiovascular risk factors (hypertension, dyslipidemia, or DM), clinical presentation, or other symptoms at admission. (Table 1). High-sensitivity troponin peak concentration was higher in women. As for the main MINOCA physiological mechanisms, we found a significantly higher prevalence of vasospasm in men and coronary artery dissection in women. There were no significant differences regarding coronary embolism, type II acute myocardial infarction (AMI), plaque rupture, or unknown mechanisms. Regarding prognosis, with a median follow-up of 45 [20-65] months, no significant differences were found between both groups for the development of in-hospital complications or mortality, nor cardiovascular readmissions, reinfarction or death from any cause (Table 2). Conclusion Unlike the previous popular perception of this disease, there are more MINOCA male patients than females in our sample, and psychiatric disorders are more prevalent in men. In octogenary people, MINOCA was more prevalent in women. At admission, symptoms and electrocardiographic parameters were very similar between both groups, while cardiac biomarkers reached higher levels in women, unrelated to coronary artery extension or the severity of left ventricular dysfunction.

Myocardial infarction with non obstructive coronary arteries (MINOCA): clinical profile and prognosis

Abstract Background MINOCA is a clinical condition that has grown interest in the last few years. The aim of this study is to compare the clinical profile, treatment and prognosis of MINOCA patients and those with myocardial infarction (MI) with obstructive coronary artery disease (MICAD). Methods We analyzed all consecutive patients with MI who underwent coronary angiography admitted in our Hospital. The database and all the patient's angiographies were revised by a group of experts in order to adequate MINOCA definition to 2020 ESC Guidelines definition and American Heart Association consensus statement. Results We included 915 patients, of whom 108 (12%) were MINOCA, with a median follow-up of 45 [21-65] months (see table 1). The underlying mechanism in MINOCA was coronary spasm (15%), plaque rupture (9.3%), coronary embolism (4.7%), coronary dissection (5.6%), type II infarction (17.8%) or unknown (43.8%). A total of 58.3% had angiographically smooth coronary arteries and 38.9% had plaques <50%. MINOCA patients in our study were younger and mostly female, with higher prevalence of connective tissue diseases, migraine or patient-reported stress and less smoking, diabetes and chronic kidney disease compared to patients with obstructive coronary artery disease. Symptoms at admission did not differ between both groups, although MINOCA had EKG with fewer alterations, most had a diagnosis of non-ST-elevation MI (NSTEMI) and significantly lower myocardial injury biomarkers’ levels (Troponine T hs peak 176 [37.25-430] vs 860 [187.50- 2640.50] ng/L, p<0.001 and CK 179 [86.75-342.75] vs 435 [159.50-1090] U/L, p<0.001). They had fewer cardiovascular complications during hospitalization such as inotropic requirements (0% vs 8%, P=0.003), cardiogenic shock (0% vs 6.4%, P=0.007) or left ventricular dysfunction (11.1% vs 29.6%, P<0.001). There were no significant differences in MACE (25.3% vs 34.7%, p=0,086): death (10.7% vs 15.5%, p=0.25), readmission (19% vs 28.7%, p=0.06), AMI (8.3 % vs 7.3%, p=0.74) and stroke (2.4% vs 3.4%, p=0.61) in both groups at follow-up. Conclusions 1) MINOCA is frequent (12% of MI), 2) the clinical profile of MINOCA patients is different than MICAD (lower cardiovascular risk factors burden, younger and more females), 3) the severity of myocardial infarction is lower (more diagnosis of NSTEMI, lower myocardial injury biomarkers’ levels, fewer complications during hospitalization and less left ventricular dysfunction), 4) we found no differences in prognosis in both groups.Table 1

A novel deep learning model for a coronary computed tomography angiography diagnosis of plaque erosion

Abstract Background Plaque erosion is the underlying pathology in up to 50% of patients with non-ST-segment elevation acute coronary syndromes (ACS). Previous studies suggest that patients with erosion might be treated conservatively without stenting. Currently, a diagnosis of plaque erosion requires invasive intracoronary imaging. Purpose We sought to develop a deep learning (DL) model that enables an accurate diagnosis of plaque erosion using coronary computed tomography angiography (CTA). Methods A total of 532 coronary CTA scans (143 coronary CTA scans with plaque rupture, 113 with plaque erosion, and 276 with reference segment) from 395 patients were included to develop a model: 426 coronary CTA scans from 316 patients for training and internal validation, and 106 separate scans from 79 patients for test set validation. Among ACS patients, the diagnosis of plaque rupture or erosion identified by OCT was used as the ground truth, and the corresponding site on the CTA image matched with OCT image was determined to be the culprit lesion. A novel DL, Momentum Distillation Composite Transformer Attention (MD-CTA) model, was developed that can effectively process the whole CTA scans to diagnose plaque erosion. Results The novel DL model showed diagnostic performance in the five-fold cross-validation with an area under the receiver-operating characteristic curve (AUC) of 0.901 (0.873-0.930), a sensitivity of 81.2 (72.8-88.0), and a specificity of 86.6 (82.4-90.2), all of which were significantly higher than those of convolutional neural network (CNN) model with an AUC of 0.621 (0.567-0.675), the sensitivity of 59.8 (50.1-69.0), and specificity of 60.2 (54.5-65.7) in training validation. Similarly, in the test set validation, the AUC, sensitivity, and specificity of the MD-CTA model were 0.899 (0.841-0.957), 87.1 (70.2-96.4), and 85.3 (75.3-92.4), respectively, higher than those of 0.724 (0.622-0.826), 71.0 (52.0-85.8), and 68.0 (56.2-78.3) of the CNN model. At the slice level, the MD-CTA model was also superior in the five-fold cross-validation and the test set validation compared to the CCN model. This model significantly outperformed experienced cardiologists, especially for sensitivity. Conclusions The newly developed DL model enables an accurate CTA diagnosis of plaque erosion, which might enable the cardiologist to provide tailored therapy without invasive procedures. This algorithm might lead to a major shift in managing millions of patients with plaque erosion each year.Table 1Figure 1

Poor prognosis after successful primary PCI in STEMI patients with calcified nodule

Abstract Background The prognostic impact of the underlying causes of ST-elevation myocardial infarction (STEMI) diagnosed by optical coherence tomography (OCT) has not been systematically examined in real-world settings. Methods We executed a post-hoc analysis of the TACTICS/TACTICS background registry, an investigator-initiated, multicenter, observational study conducted at 22 Japanese hospitals, involving 1046 STEMI patients (symptom onset within 24 hours) who underwent primary PCI included 441 patients with OCT-guidance. Underlying causes of STEMI (plaque rupture [PR], plaque erosion [PE] and calcified nodule [CN]) were identified in 338 patients using established OCT definition at independent core-laboratory. Major adverse cardiac events (MACE: cardiovascular death, MI, heart failure, or ischemia-driven revascularization) at 1 year were adjudicated by an independent clinical event committee. Results Of 1046 patients with STEMI, 441 (42.2%) underwent OCT-guided primary PCI deemed for analysis. TIMI 3 flow grade was obtained in 95.0% of patients on final angiogram, and optimal post-PCI OCT findings (minimum lumen area ≥4.5 mm2 or ≥70% of the mean reference lumen area) was achieved in 77.9%. The prevalence of PR, PE, and CN was 68.3%, 24.2%, and 3.7%, respectively. One-year MACE occurred most frequently in patients with CN (31.2%), then PR (14.0%) and PE (2.8%) (log-rank P<0.0001). On multivariate Cox regression analysis, the underlying ACS cause was associated with 1-year MACE (CN [HR 9.98, 95%CI 1.99–50.1, p=0.005]; PR [HR 4.84, 95%CI 1.49–15.7, p=0.009]; PE as reference). Conclusion OCT-guided primary PCI for STEMI patients seemed feasible for optimizing PCI and stratifying risk for future MACE.Figure

Association between cholesterol crystals and 6-month prognosis in patients with acute coronary syndrome: an optical coherence tomography study

Abstract Background Optical coherence tomography (OCT) guided percutaneous coronary intervention (PCI) has been demonstrated to improve short and long-term outcomes compared with standard angiography-guided PCI. However, little is known about the impact of cholesterol crystals on the prognosis of patients with acute coronary syndrome (ACS) in the setting of receiving OCT-guided PCI. Purpose This study aims to investigate the association between cholesterol crystals and 6-month outcomes in ACS patients who underwent OCT-guided PCI. Methods Patients with ACS who underwent OCT-guided PCI in a high-volume PCI center between July 2020 and June 2022 were retrospectively enrolled and were further divided into two groups according to the presence or absence of cholesterol crystals. OCT imaging characteristics including plaque morphology before the PCI procedure in target lesions were assessed. The primary outcome was a composite of all-cause death, ischemia-driven revascularization, or readmission for heart failure in a 6-month follow-up period. The association between cholesterol crystals and 6-month outcomes was evaluated using Kaplan-Meier curves. Independent predictors for cholesterol crystals and 6-month outcomes were evaluated by the logistic regression and Cox proportional hazards regression analyses, respectively. Results 403 patients were enrolled in this study. The mean age was 61 years old and 79.4% were men. Cholesterol crystals were presented in 224 (55.6%) target lesions in patients with ACS. Baseline characteristics were not statistically different between the two groups in age, sex, smoke, previous hyperlipidemia, and other clinical features, except for diabetes, multivessel disease, and ACS classification (p <0.05). In the multivariable logistic regression analysis, cholesterol crystals were associated with diabetes, plaque rupture, lipid length, calcification, macrophage infiltration, and thin-capped fibroatheroma (all p <0.05). Patients with cholesterol crystals had higher risks of poor 6-month composite outcomes when compared to those without cholesterol crystals (13.4% vs. 6.7%, HR 2.09, 95%CI 1.07-4.09, p = 0.031), even after confounders adjustment for age, sex, diabetes, multivessel disease and ACS classification using inverse probability of treatment weighting (p = 0.027). Subgroup analysis showed significant interactions between cholesterol crystals and 6-month outcomes with respect to the male (HR 2.82, 95%CI 1.22-6.51, p = 0.015), target lesions in LAD (HR 4.47, 95%CI 1.29-15.44, p = 0.018), and incomplete revascularization (HR 3.08, 95%CI 1.04-8.98, p = 0.042). The Cox regression analysis identified cholesterol crystal as an independent predictor for 6-month composite outcomes (HR 2.12, 95%CI 1.08-4.19, p = 0.030). Conclusions The presence of cholesterol crystals was associated with a poor 6-month prognosis in patients with ACS, even in the setting of receiving OCT-guided PCI.

Consensus on the diagnosis and management of patients with type 2 myocardial infarction: an international Delphi study

Abstract Background Type 2 myocardial infarction occurs due to a reduction in myocardial oxygen supply or an increase in demand without evidence of atherosclerotic plaque rupture. It is common representing around 20% of myocardial infarctions (1-4). Outcomes are poor with up to one third alive at five years, with cardiovascular outcomes comparable to type 1 myocardial infarction (1,5,6). Despite this, there are no evidence-based guidelines to guide assessment and management for clinicians. Purpose To gain consensus on the assessment and management of type 2 myocardial infarction from an international group of experts. Methods A systematic review of type 2 myocardial infarction was undertaken to identify the corresponding or senior author of all original research studies. We identified 73 experts from multiple clinical specialties. A three-round international eDelphi study was circulated, with round one consisting of open questioning to generate statements for deductive analysis. Consensus was defined a priori as >70% agreement on a 5-point Likert scale. Statements for which no consensus could be obtained were adapted and recirculated in round three (Figure 1). Results Of the 68 experts contacted there was a 56% (38/68), 54% (37/68) and 72% (49/68) response rate in round one, two and three, respectively. Consensus was achieved on 64% (43/67) of statements. Consensus varied across the following domains i) definition and diagnosis 42% (5/12), ii) risk stratification 75% (3/4), iii) assessment of coronary artery disease and cardiac function 50% (9/18), iv) specialty management 60% (6/10), v) treatment and secondary prevention 100% (9/9) and vi) communication and rehabilitation 79% (11/15). The panel agreed that all patients should undergo echocardiography (mean [SD] 2.08 [1.23]) and CT coronary imaging or a functional test should be performed on those with intermediate probability of future cardiovascular events (mean [SD] 1.81 [0.52]). Over 90% of the panel agreed that both patient and clinician understanding of type 2 myocardial infarction was poor and that further randomised controlled trials are need to direct care. Conclusion There remains uncertainty regarding the current definition of type 2 myocardial infarction and overall patient and clinician understanding was thought to be poor. However, it is generally accepted that the mainstay of management should be on the identification of coronary artery disease and left ventricular impairment with optimisation of therapies with proven benefit. Management should involve an individualised assessment and the multidisciplinary team.

New insights on the mechanisms of myocardial injury in hypertensive patients with COVID-19

Abstract Introduction Cardiac comorbidities, particularly hypertension, are highly prevalent in patients hospitalized with COVID-19 and are related directly to the risk of clinical disease progression. Cardiac injury is the most frequently reported cardiac abnormality in these patients. Diverse forms and mechanisms of myocardial injury, including acute myocardial ischemia due to plaque rupture, oxygen supply/demand imbalance, non-ischemic injuries such as myocarditis, direct virus-mediated injury, and immune system dysregulation, have been described in patients with COVID-19. Purpose The mechanism of the association among hypertension, COVID-19 and cardiac injury and the reasons for worse clinical progression in these patients have not been elucidated clearly. Considering that myocardial injury due to direct SARS-CoV-2 infection is rare and that the immune system is often dysregulated in patients with COVID-19, and also that cytokine storm and lymphopenia are important immune markers of progression to severe disease, the present study aimed to investigate the immune profile of hypertensive patients with COVID-19 and myocardial injury to obtain a better understanding of the immune dysregulation and to provide new insights on the mechanism of myocardial injury in hypertensive patients with this disease. Methods All patients were selected prospectively from a multicenter registry of adults hospitalized with confirmed COVID-19. Cases had hypertension and myocardial injury, defined by troponin levels above the 99th percentile upper reference limit, and controls were hypertensive patients with no myocardial injury. Biomarkers and immune cell subsets were quantified and compared between the two groups. A multiple logistic regression model was used to analyze the associations of clinical and immune variables with myocardial injury. Results The sample comprised 193 patients divided into two groups: 47 cases and 146 controls. Relative to controls, cases had lower total lymphocyte count, percentage of T lymphocytes, CD8+CD38+ mean fluorescence intensity (MFI), and percentage of CD8+ human leukocyte antigen DR isotope (HLA-DR)+ CD38–cells and higher percentage of natural killer lymphocytes, natural killer group 2A (NKG2A)+ MFI, percentage of CD8+CD38+cells, CD8+HLA-DR+MFI, CD8+NKG2A+MFI, and percentage of CD8+HLA-DR–CD38+cells. On multivariate regression, the CD8+HLA-DR+MFI, CD8+CD38+MFI, and total lymphocyte count were associated significantly with myocardial injury. Conclusion Our findings suggest that lymphopenia, CD8+CD38+MFI, and CD8+HLA-DR+MFI are immune biomarkers of myocardial injury in hypertensive patients with COVID-19. The immune signature described here may aid in understanding the mechanisms underlying myocardial injury in these patients. The study data might open a new window for improvement in the treatment of hypertensive patients with COVID-19 and myocardial injury.

Clinical profile and incidence of 36-month cardiovascular events in patients with MINOCA: a regional registry of 126 patients in a tertiary cardiology hospital

Abstract Introduction Atherosclerotic plaque rupture is the main etiology of acute myocardial infarction (AMI). In 5% to 6% of AMIs, however, no obstructive lesions greater than 50% are observed, which are then classified as MINOCA (Myocardial Infarction with Non-obstructive Coronary Arteries).The paradigm of MINOCA as a benign condition has been revisited in recent years, as reduced survival rates and a higher risk of subsequent AMIs have been observed when compared to control groups. Purpose To describe the clinical profile and the risk of cardiovascular outcomes in patients diagnosed with MINOCA in a tertiary cardiology hospital between March 2000 and June 2022. Methods In this single-center cohort, all patients meeting the diagnostic criteria for MINOCA with (1) AMI, as follows: (a) no coronary stenosis ≥ 50% in any potential infarct-related artery; and (b) no other clinically overt specific cause for the acute presentation were evaluated with a median follow-up of 30(9.5-67.3) months. Information was obtained by medical chart. Sample characteristics were described in frequencies and median values(p25%-p75%). The incidence of a new cardiovascular event within 36 months after the MINOCA was estimated using the Kaplan-Meier method and the log-rank test applied to compare groups, accompanied by confidence intervals at 95% and an alpha of 5%(R 3.6.1 for MacOS). Results Of the 126 patients, 57.1% were women about 50 years of age (42.0-57.8). 20.6% had diabetes, 47.6% dyslipidemia, 60.3% hypertension and 20% a previous AMI. The predominant clinical presentation was NSTEMI (55.6%) (Table 1), and 7 patients had an episode of aborted sudden death during hospitalization. 38.1% of patients did not have an identified etiology. The most prevalent pathophysiological mechanism was plaque disruption (16.7%), followed by coronary thromboembolism (13.5%) and spontaneous coronary dissection (SCAD) (13.5%). Among the less frequent causes, we had vasospasm (7.1%) and myocardial bridge (2.4%). Only 3.2% underwent optical coherence tomography (OCT) or intravascular ultrasound (IVUS). No provocative testing was performed. 44.4% underwent cardiac magnetic resonance (CMR), within a median time to perform of 180.0 (60.0-707.5) days after the event. Regarding the discharged medical therapy, 79.4% had a beta-blocker and ACEI/ARB prescribed, 14.3% started anticoagulation and only 34.1% received DAPT. The incidence of a composite outcome (CV death, new AMI, stroke and cardiovascular hospitalization) at 36 months was 15% (CI95% 8.9%-24.6%)(Figure 2). The incidence of new MI was 6.3%(N=8), of stroke 2.4% (N=3), and of cardiovascular hospitalization 17.5%(N=22), with only one death. Conclusion The risk of the primary outcome in 36 months is worthy of note. Notably, most of the incidence was attributable to CV hospitalization. An important number of patients were discharged without a known etiology for their clinical presentation, and, consequentially, lacked individualized treatment.Figure 1.Outcomes

Association of physical activity with the risk of major adverse cardiac and cerebrovascular events and mortality in patients with concomitant atrial fibrillation and coronary artery disease

Abstract Background Although regular physical activity benefits cardiovascular health, there is a concern that intense exercise is linked to the promotion of atrial fibrillation (AF) and coronary plaque rupture. However, the impact of physical activity on the outcomes of patients with concomitant AF and coronary artery disease (CAD) remains unclear. Purpose This study aimed to evaluate the association with clinical outcomes according to the level of physical activity in patients with concomitant AF and CAD. Methods We assessed 551 patients with AF and CAD (mean age, 67.1±9.8 years) who completed a self-reported questionnaire for physical activity from 2015 to 2020 in a single tertiary-care hospital. Physical activity levels were converted into metabolic equivalent of task (MET) per week and categorized to correspond with multiple public health recommendations. We examined the association between physical activity, all-cause mortality, and major adverse cardiac and cerebrovascular events (MACCE). Results The risks of all-cause mortality (P for linear trend=0.017) and MACCE (P for linear trend=0.05) were appeared inverse trend with a greater level of physical activity. Compared with inactive patients, patients who met the recommended target range of physical activity (500–1,000 MET-min/week: unadjusted hazard ratio [HR]=0.58, 95% confidence interval [CI]=0.36–0.99) and highly active patients who exceeded the minimum recommended level (≥1,000 MET-min/week: unadjusted HR=0.47, 95% CI=0.25–0.88) had a lower risk of all-cause mortality in the unadjusted model; however, these associations did not remain significant after adjusting for the model. There was no evidence of increased risk of all-cause mortality and MACCE at levels of physical activity above the recommended target range, even with vigorous intensity physical activity exceeding the recommended target range. Conclusions There appears to be an inverse trend between physical activity levels and all-cause mortality and MACCE in patients with concomitant AF and CAD. No excess risk of mortality or MACCE was found at exercise levels above the recommended target range. Further large-scale studies are warranted to create an improved evidence base concerning the effects of physical activity in patients with AF and CAD.

Design of knowledge-based mechanistic model of atherosclerotic cardiovascular disease for in silico trials

Abstract In silico trials applying a computational model (CM) of atherosclerotic cardiovascular disease (ASCVD) to virtual patients receiving alternative treatments provide an attractive option to complement randomised clinical trials (RCTs) by adding comparative effectiveness data and facilitating the demonstration of drug benefit. In silico modelling allows comparison between treatments with each virtual patient being his own control, and is not limited by the number of patients, comparative arms or trial duration. This study aims at building a knowledge-based mechanistic model of ASCVD. Once validated, the model will be used to run in silico clinical trials to compare the benefit of inclisiran, an siRNA targeting PCSK9 mRNA, vs other lipid-lowering therapies (LLT) on cardiovascular (CV) events in patients with ASCVD. An extensive literature review was performed to identify pathophysiological mechanisms involved in ASCVD and therapeutic mechanisms of action (MOAs). Every piece of knowledge extracted from the literature is awarded a strength of evidence grading to allow tracking of uncertainty in the model. A panel of multidisciplinary experts reviewed knowledge models and subsequent modelling hypotheses to validate their relevance. Knowledge was translated into mathematical equations. Each functional relationship between entities is represented by a biochemical/biophysical reaction with its reaction rate. A system of ordinary differential equations provides dynamics of modelled biological entities. A strategy of model calibration/validation was defined with the expert panel, by selecting relevant RCT and registry data, that the model should be able to reproduce. A virtual population was generated to account for inter-patient variability. A mechanistic CM of ASCVD (including 72 biological entities, 750 parameters) was built from knowledge, describing lipoproteins metabolism and cholesterol homeostasis, dynamics of atherosclerotic plaque growth with lipoproteins infiltration in the intima and evolution of lipidic, necrotic and fibrotic tissues as well as plaque rupture leading to myocardial infarction, ischemic stroke, lower extremity arterial disease or CV death. It also includes the impact of several risk factors (age, sex medical history, diabetes, hypertension, smoking, systemic inflammation, chronic kidney disease) and available LLT (atorvastatin, rosuvastatin, ezetimibe, evolocumab and inclisiran). After calibration, the model and virtual population reproduce pharmacokinetics of LLT, lipoproteins decrease under combinations of LLT and associated reduction in clinical events. ASCVD is ideally suited for in silico modelling: extensive literature is available regarding the pathophysiology, therapeutic MOAs are known and easily integrated in the model, clinically relevant outcomes are adequate model outputs, RCT and registry data exist to calibrate/validate the model. The next step is validation of the model before using it to run in silico trials.Plaque growth and rupture modelMulti-scale in silico model

Influence of wall shear and structural stress on plaque progression of different phenotype in human coronary arteries

Abstract Introduction Atherosclerotic plaque progression is affected by local wall shear stress (WSS), .i.e. the frictional force of the blood at the vessel wall [1,2]. However, the blood pressure also induces stress inside the vessel wall (wall stress, WMS) and is mainly studied for plaque rupture [3]. Little is known on the impact of WMS on plaque progression. Purpose In order to have a comprehensive understanding of the involvement of the biomechanical factors (WSS and WMS) in atherosclerotic artery disease, we studied the individual and combined effects of WMS and WSS in plaque free as well as in atherosclerotic coronary segments. Methods Forty non-stented, non-culprit human coronary arteries (IMPACT study) were imaged with near-infrared spectroscopy intravascular ultrasound (NIRS-IVUS) and optical coherence tomography (OCT) at the baseline and after 12 months [3]. The 2D and 3D lumen, vessel wall and lipid-rich necrotic core (LRNC) geometries were reconstructed based on the co-registration of NIRS-IVUS and OCT. WSS was computed with Computational Fluid Dynamics [3]. The WMS on the peri-luminal region was calculated via ABAQUS with hyperelastic material models [4] using intraluminal pressure of 120mmHg. The vessels were divided into 1.5mm/45° sectors. In each sector wall growth was quantified as plaque burden (plaque area/total vessel area*100%) change over time. Plaque was defined as wall thickness > 0.5 mm. The sectors were categorized as "plaque with lipid rich necrotic core (LRNC)", "plaque w/o lipid rich necrotic core (LRNC)", or "plaque free wall". The individual and combined effect of WSS and WMS on plaque progression was evaluated using Linear Mixed Model in SPSS and all stress metrics were divided into artery-based tertiles. Results Vessel sectors exposed to low WSS at baseline demonstrated a higher plaque burden increase over the follow up period compared to the vessel sectors exposed to mid or high WSS (Fig.1), which was significantly different for all the 3 categories (Plaque free wall, Plaque without LRNC, Plaque with LRNC). Vessel sectors exposed to increasing WMS demonstrated increasing plaque progression (Fig.1) Sectors that were simultaneously exposed to low WSS and high WMS revealed the highest change in plaque size and in particular in plaque sectors that were lipid rich (Fig.2). Conclusion Our findings suggest that the local atherosclerotic disease progression in coronary arteries is not only associated with the well-known WSS, but also with WMS. Moreover, our results show that there is an complex interplay between WSS, WMS and plaque composition, such that lipid rich plaques exposed to low WSS and high WMS demonstrated the highest plaque progression.Figure 1Figure 2

Risk predicting for acute coronary syndrome with conventional and unstable plaque radiomics features from serial coronary computed tomography angiography

Abstract Background Plaques with high-risk features are responsible for most acute cardiac events. However, there are still some lesions with high-risk plaque (HRP) morphology, which will not lead to cardiac events over time. It is crucial to precisely identify features of unstable plaque and to carry out individualized treatment, eventually aiming to reduce the likelihood of plaque rupture and lower the incidence of acute coronary events. Besides, the development of quantitative radiomics in recent years may further help with the diagnostic and predictive performance of coronary CTA. Purpose To establish machine learning models by combining traditional coronary CTA features of high-risk plaque and radiomics features of unstable plaque, so as to improve the efficiency of models and to predict acute cardiac events precisely. Methods A total of 133 elderly patients (407 lesions) were retrospectively enrolled in this cohort study who underwent serial CCTA with the interval ≥ 2 years between scans. The patients were divided into two groups according to the occurrence of acute coronary events within 1 year after coronary CTA scanning . We recorded anatomical characteristics, high-risk plaque characteristics, and acute coronary events of the elderly patients. Based on the coronary CTA image cohort, we applied 3D Slicer software to segment target lesions, delineate regions of interest, and extract radiomics features. After that, we used LASSO regression to reduce the dimensionality of the radiomics features, and finally screened out unstable radiomics features. Combining the HRP features with the selected radiomics features, we established a prediction model of acute cardiac events with machine learning method. The area under the receiver operating characteristic (ROC) curve (AUC) was analyzed to compare the classification ability of conventional and radiomics models in the validation set. Results 133 elderly patients were included, with an average age of 65.8 ± 5.3 years. A novel model has been established by combining HRP features and 4 selected unstable radiomics features (2 wavelet features, 1 shape feature and 1 GrayLevel feature) with SVM machine learning method. Compared with conventional HRP model, the novel model displayed a significantly improved predictive performance in the validation set (AUC 0.784 vs. 0.624, P < 0.001). Conclusions We have established a novel model by combining the traditional HRP features of coronary CTA and radiomics features of unstable plaque, assisting in better prediction of acute coronary events in elderly . Compared with traditional HRP feature model, the prediction efficiency of novel model was significantly improved.

Reduction of perivascular inflammation following long-term statin treatment - a coronary CT follow-up study using Fat Attenuation Index

Abstract Background Perivascular fat attenuation index (FAI) assessed by coronary computed tomography (CCTA) has been demonstrated to represent a reliable marker of coronary inflammation. Several studies have explored the potential anti-inflammatory effects of statins in reducing the risk of plaque rupture and subsequent cardiovascular events. However, the effect of statin therapy on FAI has not been clearly demonstrated so far. Purpose Our objective was to investigate the changes in perivascular FAI at the level of coronary lesions, as measured by coronary computed tomography (CCTA), following long-term high-dose statin therapy. Methods This study includes 23 patients who presented with typical chest pain, had a low to intermediate likelihood of coronary artery disease, and underwent a CCTA examination which revealed the existence of at least one coronary atheromatous plaque. Statin therapy was initiated in all patients according to guidelines. The CCTA was repeated after a time interval ranging from 1.5 to 3 years. Lesion-specific perivascular FAI, together with different plaque characteristics, were measured at both baseline and follow-up using a new AI-powered medical device called CaRi-Heart®. Results The mean age of the participants was 61.72 ± 8.86 at the time of the first scan, and 65.21% (n = 15) of them were male. At baseline, the CT density of the adipose tissue (ranging from -190 to -30 HU), was not significantly different between the two groups. A significant decrease in serum lipids following statin therapy was recorded during follow-up: from 193.4 ± 47.09 to 145.2 ± 34.7, p = 0.04 for total cholesterol, and from 101.77 ± 25.20 to 86.41 ± 21.09, p = 0.02 for LDL cholesterol. The FAI-score consistently decreased from baseline to follow-up, especially in the left anterior descending artery: from 15.87 ± 9.32 vs. 12.40 ± 7.55, p = 0.04, while there was no significant decrease in coronary inflammation at the level of left circumflex artery (13.98 ± 6.16 vs. 13.10 ± 6.59, p = ns), or right coronary artery (20.53 ± 13.74 vs. 19.96 ± 16.24, p = ns). Similarly, the FAI-Score Centile values were lower during the second scan, specifically for LAD (0.51 ± 0.28 vs. 0.69 ± 0.29, p = 0.04), while there were no significant differences of FAI score centile in the LCX (0.72 ± 0.28 vs. 0.74 ± 0.26, p = ns) and RCA (0.71 ± 0.32 vs. 0.78 ± 0.21, p = ns). Conclusion CaRi-Heart® mapping technology revealed a significant decrease of coronary inflammation, as expressed by the FAI-score, as a result of high-dose statin treatment especially at the level of the LAD. This indicates a potential role of local factors related to coronary circulation in the complex process of plaque inflammation. The perivascular FAI-score and FAI-score centile may serve as promising imaging biomarkers for monitoring the anti-inflammatory response to statin treatments.Color-coded FAI MappingPVAT-FAI Score of Coronary Inflammation

Cholesterol crystals as the main trigger of interleukin-6 production through innate inflammation in human spontaneously ruptured aortic plaques

Abstract Aim Cholesterol crystals (CCs) may provoke innate inflammation in experimental and animal model, however, whether CCs are bystanders or play central role for plaque rupture is unknown. This study aimed to clarify whether CCs was the main trigger of innate inflammation in human spontaneously ruptured aortic plaques (SRAPs). Methods This study included 260 SRAPs collected during non-obstructive general angioscopy (NOGA) from 126 patients with having or suspected CAD. Interleukin (IL)-6 levels in SRAPs were measured. IL-6 level at the Valsalva sinus, and femoral or brachial arteries were measured. IL-6 ratios, IL-6 level in SRAPs and arteries divided by IL-6 level at the Valsalva sinus at the beginning of aorta, were calculated. The number of CCs were counted in sampled blood. The correlation between the count of CCs and IL-6 levels in SRAPs and that between the counts of CCs and IL-6 ratios in SRAPs were analyzed. Results IL-6 ratios of the brachial and femoral arteries were 1.06 (95% CI, 0.99–1.20) and 1.11 (95% CI, 1.04–1.20), respectively. IL-6 ratio in SRAPs was 1.10 [1.00, 1.26]. (median [IQR]). CCs were detected in 94 of 260 SRAPs (36%). The count of CCs was 11,590 (95% CI: 2,386–30,113] per 10 mL in CCs positive samples. There was a moderate correlation between the counts of CCs and IL-6 ratios in SRAPs (r=0.496, r<0.0001)(Fig. 1), whereas there was no correlation between the count of CCs and IL-6 levels in SRAPs.(Fig. 2) Conclusions By the in-situ study, CC might be the main trigger of IL-6 through innate inflammation in human SRAPs.Fig 1Fig 2

Abstract 16828: Plaque Rupture is Not Associated With Worse Clinical Outcomes in Contemporary Patients With Acute Coronary Syndrome

Introduction: The worse clinical outcomes in patients with plaque rupture (PR) than those with other pathogenesis of acute coronary syndrome (ACS) including plaque erosion and calcified plaque-related ACS have been reported. Hypothesis: The incidence of recurrent adverse events in patients with PR is not higher than other ACS patients in the contemporary clinical setting of secondary prevention using high-intensity statin. Methods: A total of 329 consecutive patients with ACS who underwent optical coherence tomography imaging of culprit lesions were included. Patients were classified into either the PR group (n = 133) or the non-PR group (n = 196). The incidence of major adverse cardiovascular events (MACE) at 1-year was compared between the two groups. MACE included cardiac death, non-fatal myocardial infarction, target vessel revascularization (TVR), and non-TVR. Results: The prevalence of ST-elevation myocardial infarction (STEMI) as the initial clinical presentation was significantly higher in the PR group than in the non-PR group (58.6 vs. 42.3 %, p = 0.005). The prescription rate of high-intensity statin and/or ezetimibe at discharge was comparable in the two groups (84.2 vs. 84.7 %, p = 1.000). The incidence of MACE at 1-year was significantly lower in the PR group than in the non-PR group (log-rank p = 0.009) (Panel A). In the non-PR group, the levels of body mass index (26.5 ± 2.9 vs. 24.0 ± 3.9 kg/m 2 , p = 0.004) and hemoglobin A1c (7.2 ± 2.5 vs. 6.4 ± 1.2 %, p = 0.021) were significantly higher in patients with MACE than in those without (Panel B). Conclusions: The incidence of MACE at 1-year in patients with PR was significantly lower than in those without PR in contemporary patients with ACS despite of the higher prevalence of baseline STEMI presentation. Further tailored optimization of secondary prevention against obesity and diabetes may be still required in ACS patients without PR.

Abstract 14313: A Proteomic Atlas of Human Coronary Artery Reveals the Pathological Progression of Atherosclerosis

Introduction: The key molecular mechanisms associated with human atherosclerotic plaque progression, atherosclerotic lesion initiation and plaque destabilization are not fully understood. Hypothesis: Different stages of atherosclerosis (AS) progression have distinct pathological processes. Some key proteins induce AS progression. Methods: We employed 20 coronary artery samples among 4 explanted hearts from coronary heart disease patients. Each heart contains stages of unaffected control (NC), pathological intimal thickening (PIT), fibroatheroma (FA), transition to thin-cap fibroatheroma (TCFA) and ruptured plaque (RP), which were validated by hematoxylin and eosin (H&E) staining. We performed quantitative proteomics in each of the samples based on tandem-mass-tags and liquid chromatography-tandem mass spectrometry. Furthermore, we measured proteins in human coronary artery tissue via immunofluorescence. Results: Proteomics revealed that extracellular matrix (ECM) organization was the most significantly enriched pathway in PIT. FA exhibited an enrichment of immunologic processes, such as neutrophil degranulation, myeloid leukocyte activation and innate immune response. Molecular profiles of TCFA and RP are similar, with complement and coagulation cascades pathway as a hallmark of these stages. Clustering analysis of DEPs displayed 4 clusters, notably cluster 2 had a precipitous elevation from FA to TCFA. Within this cluster, we identified a high-rank molecule: macrophage-capping protein (CAPG). Immunohistochemistry and immunofluorescence revealed that CAPG is highly elevated in plaque compared to NC and is specifically expressed in the plaque. Conclusions: ECM organization was continuously dysregulated in AS progression. Immune response might initiate the atherosclerotic plaque. Complement and coagulation cascades pathway was a hallmark of TCFA and RP. CAPG might be a therapeutic target for AS progression.