Runzhen Chen

Abnormalities in glucose and lipid metabolism are prevalent among individuals suffering from myocardial infarction, with insulin resistance playing an integral role in these pathological processes. This study aims to follow up on incident ischemic stroke events to evaluate whether any alterations in risk estimation merit a reassessment of therapeutic strategies. Herein, we present findings derived from a prospective cohort engaged in this ongoing investigation. In our analysis, three novel lipid biomarkers—namely proprotein convertase subtilisin/kexin type 9, fatty acid-binding protein 4, and Resolvin D1—emanating from diverse pathophysiological pathways were meticulously evaluated alongside six conventional lipid parameters within a population cohort comprising 1580 individuals, both diabetic and non-diabetic. 1) Furthermore, among DM patients, group 1 (0–1 lipid parameters increased) and group 2 (2–4 lipid parameters increased) had significantly better ischemic stroke-free survival than other groups (p=0.025) when TyG index ≥median. 2) Adding novel lipid associated parameters and TyG index to the conventional lipid risk factors model in the cohort validated it by improved net reclassification index (p<0.05) and integrated discrimination improvement and led to significant reclassification of individuals into risk categories. The incorporation of a biomarker score that encompasses innovative lipid-associated biomarkers alongside the TyG index into a traditional risk assessment framework significantly enhanced the evaluation of ischemic stroke events within myocardial infarction populations afflicted by diabetes mellitus.

The association between matrix Gla protein (MGP) and vascular calcification has been investigated in recent years; however, studies focusing on MGP with plaque calcification are lacking. In the present study, we aimed to explore the association of circulating and regional levels, as well as polymorphism of MGP with plaque calcification detected by optical coherence tomography (OCT) and adverse clinical outcome in patients with ST-segment elevation myocardial infarction (STEMI). A prospective cohort of 1,648 consecutive patients with STEMI were established. Circulating level of dephosphorylated-uncarboxylated MGP (dp-ucMGP) was determined using enzyme-linked immunosorbent assay. The primary outcome was major adverse cardiovascular event (MACE), composite of all-cause death, recurrent myocardial infarction, and ischemic stroke. Plaque calcification of 326 patients in the cohort was analyzed via OCT and MGP single nucleotide polymorphism (SNP) was detected in 1,313 patients. A total of 54 patients with aspirated coronary material undertook immunohistochemical (IHC) staining for quantifying regional MGP expression surrounding culprit lesions. During a median follow-up of 4 years, patients with high dp-ucMGP (≥1128 ng/mL) were associated with higher risk of death (hazard ratio [HR]: 1.41, 95% confidence interval [CI]: 1.02–1.97, p = 0.040), which was sustained in propensity score matching (HR: 1.488, 95% CI: 1.049–2.109, p = 0.026). In OCT observation, patients with annular calcification had higher level of dp-ucMGP than those without calcification (1,273 ng/mL [972.2–2168] vs. 1,079 ng/mL [729.2–1888], p = 0.0136). On IHC examination, patients with culprit plaque calcifications had significantly higher regional MGP expression than those without in their aspirated coronary material (AOD: 0.225 ± 0.021 vs. 0.183 ± 0.021, p < 0.0001). However, MGP variants showed no correlation with plaque calcification or the prognosis of patients in the cohort. High levels of circulating dp-ucMGP were significantly associated with increased mortality and annular plaque calcification in patients with STEMI. Moreover, higher expression of regional MGP in aspirated coronary material showed more indicative value for patients with culprit lesion calcification. However, MGP variants including rs4236, rs1800801, and rs1800802 in the current study were not significantly correlated with plaque calcification or poorer prognosis.

Background: The protein known as Fatty Acid-Binding Protein 4 (FABP4), predominantly found in adipocytes, macrophages, and endothelial cells, has emerged as a pivotal biomarker linking inflammation and metabolism in the context of cardiovascular diseases. Aim: The present investigation sought to elucidate the influence of FABP4 on the prognostic ramifications for patients experiencing ischemic vascular events, which encompass ischemic cerebrovascular occurrences, myocardial infarctions, and cardiovascular mortality. Methods: A total of 1102 consecutive patients diagnosed with acute myocardial infarction (AMI) and aged over 55 years were prospectively enrolled from March 2017 to January 2020. Initially, participants were stratified into three groups according to the tertile levels of FABP4, followed by further categorization based on various lipid profiles and specific inflammatory markers. Results: On follow-up (median 751 days, maximum 1506 days), a total of 158 ischemic events were recorded. 1) In multivariable models meticulously adjusted for age, gender, traditional coronary heart disease factors, Killip classification, and discharge medications, the association of elevated levels of FABP4 (Tertile 3 HR 1.618 [1.061 to 2.468], p=0.026), augmented concentrations of PTX3 (Tertile 3 HR 1.811 [1.211 to 2.710], p=0.004), or LL-37 (Tertile 3 HR 0.651 [0.433 to 0.981], p=0.040) with ischemic risk was markedly intensified. 2) Multivariate HRs associated with 1 standard deviation (SD) (mg/dL) increase in the FABP4 parameters were as follows in different subgroups. 1-SD difference in FABP4 was associated with a 23%, 23%, 21 and 29% increase in ischemic events over after fully adjusted the confounding risk factors among male, patients with hyperlipidemia, hypertension and diabetes respectively. 3) The Kaplan-Meier curve demonstrated significant differences between the tertiles of FABP4 index levels among all enrolled participants (p=0.0180). Conclusion: This study reinforces the utility of FABP4 for enhancing risk stratification specifically among older patients diagnosed with ST-elevation myocardial infarction.

Background and Aim: An elevated triglyceride-glucose (TyG) level is associated with increased risk of mortality in patients with CAD. Trimethylamine N-oxide (TMAO) has mechanistic links to atherosclerotic coronary artery disease (CAD) pathogenesis and is correlated with adverse outcomes. However, the incremental prognostic value of TMAO and TyG in the cohort of optical coherence tomography (OCT)-defined high-risk ST-segment elevation myocardial infarction (STEMI) patients is unknown. Methods: We studied 274 consecutive aged ≥ 18 years patients with evidence of STEMI and detected on pre-intervention OCT imaging of culprit lesions between March 2017 and March 2019. Outcomes: There were 22 (22.68%), 27 (27.84%), 26 (26.80%), and 22 (22.68%) patients in groups A-D, respectively. The baseline characteristics according to the level of TMAO and TyG showed that patients with higher level in both indicators were more likely to have higher triglycerides (p < 0.001), fasting glucose (p < 0.001) and higher incidence of diabetes (p = 0.008). The group with TMAO > median and TyG ≤ median was associated with higher rates of MACEs significantly (p = 0.009) in fully adjusted analyses. During a median follow-up of 2.027 years, 20 (20.6%) patients experienced MACEs. To evaluate the diagnostic value of the TyG index combined with TMAO, the area under the receiver operating characteristic curve for predicting MACEs after full adjustment was 0.815 (95% confidence interval, 0.723– 0.887; sensitivity, 85.00%; specificity, 72.73%; cut-off level, 0.577). Among the group of patients with TMAO > median and TyG ≤ median, there was a significantly higher incidence of MACEs (p= 0.033). A similar tendency was found in the cohort with hyperlipidemia (p= 0.016) and diabetes mellitus (p= 0.036). Conclusion: This study demonstrated the usefulness of combined measures of the TyG index and TMAO in enhancing risk stratification in STEMI patients with OCT-defined high-risk plaque characteristics. Trial Registration: This study was registered at ClinicalTrials.gov as NCT03593928.

Objective Aldehyde dehydrogenase 4A1 (ALDH4A1) was recently reported to be a novel autoantigen of atherosclerosis. However, its role in different phenotypes of acute coronary syndrome remains unclear. Herein, we planned to explore the circulating and regional expression of ALDH4A1 in patients with plaque rupture (PR) and plaque erosion (PE) determined by optical coherence tomography (OCT). Methods and Results After applying the inclusion and exclusion criteria, a prospective series of 312 patients with ST segment elevated myocardial infarction (STEMI), including 161 patients with PR and 151 patients with PE determined by OCT, were enrolled for plasma ALDH4A1 testing. In addition, ALDH4A1 was quantified using immunofluorescence in aspirated coronary thrombus samples obtained from 31 patients with PR and 25 patients with PE. In addition, we established an atherosclerosis mouse model and analyzed the distribution of ALDH4A1 expression in different mouse organs. Furthermore, we compared the level of ALDH4A1 in the spleen and carotid artery between Apoe^−/− and C57 mice. The results showed that the plasma level of ALDH4A1 was significantly higher in STEMI patients with PE than in those with PR (4.6 ng/mL [2.2–8.7] vs. 3.5 ng/mL [1.6–5.6] p = 0.005). The expression of ALDH4A1 in aspirated coronary thrombi was also significantly higher in patients with PE than in those with PR (mean gray value: 32.0 [23.6–40.6] vs. 16.8 [14.0–24.5], p < 0.001). In animal models, the expression of ALDH4A1 is much higher in the spleen than in other organs, and the level of ALDH4A1 is significantly elevated in the spleen and carotid artery of Apoe^−/− mice compared with C57 mice. Conclusion The high levels of ALDH4A1 in the plasma and aspirated coronary thrombi independently correlated with PE in patients with STEMI. These results suggested that ALDH4A1 is involved in the mechanism of PE and serves as a promising biomarker and treatment target for patients with PE. Received: 17 January 2023 Accepted: 26 October 2023 Article published online: 18 December 2023 © 2023. Thieme. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Background: As a specialized pro-resolving lipid mediator, resolvin D1 (RvD1) inhibits atherosclerosis progression in vivo by reducing regional oxidative stress and chronic inflammation. However, it is unclear how RvD1 is involved in human coronary artery disease. This study aims to investigate the association between plasma levels of RvD1 and culprit-plaque characteristics in patients with ST-segment elevation myocardial infarction (STEMI). Methods: A total of 240 STEMI patients undergoing optical coherence tomography (OCT) examination were analyzed. RvD1 levels were measured in patient plasma samples using an enzyme-linked immunosorbent assay. Logistic regression was performed to assess the association between RvD1 levels and various culprit plaque morphologies, and the receiver operating curve was used to search for an optimal cutoff threshold to predict certain pathological features. Results: The median RvD1 level was 129.7 (56.6– 297.8) pg/mL. According to multivariable logistic regression, high RvD1 was associated with plaque rupture (≥ 111.5 pg/mL, odds ratio [OR]: 2.09, 95% confidence interval [CI]: 1.20– 3.66, P = 0.010), healed plaques (≥ 246.4 pg/mL, OR: 2.17, 95% CI: 1.11– 4.24, P = 0.023), and calcification (≥ 293.38 pg/mL, OR: 2.10, 95% CI: 1.21– 3.66, P = 0.008) at culprit lesions. Conclusion: Increased levels of RvD1 were associated with higher instability of coronary atherosclerotic plaques in STEMI patients.

Background and Aims: This study aimed to determine whether convertase subtilisin/kexin type 9 (PCSK9)-associated cardiovascular risk is modulated by triglyceride-glucose (TyG) in ST-segment elevation myocardial infarction (STEMI) patients with primary percutaneous coronary disease (PCI). Methods: A total of 1541 patients with STEMI (aged ≥ 18 years) undergoing primary PCI were consecutively enrolled between March 2017 and March 2019. Outcomes: When stratifying the overall population according to TyG indices less than or greater than the median (TyG median = 9.07) as well as according to quartiles of PCSK9 levels, higher TyG index levels were significantly associated with all-cause mortality only when TyG levels were 9.07 or higher (ie, relative to quartile 1 [Q1], the adjusted HR for all-cause mortality was 3.20 [95% CI, 0.54– 18.80] for Q2, p = 0.199; 7.89 [95% CI, 1.56– 40.89] for Q3, p = 0.013; and 5.61 [95% CI, 1.04– 30.30] for Q4, p = 0.045. During a median follow-up period of 1.96 years, the HR for all-cause mortality was higher in the subset of patients with TyG ≥median and PCSK9 ≥median (p for trend = 0.023) among those with type 2 diabetes mellitus (T2DM). However, there were no statistically significant differences among the subgroups. Among T2DM patients with a TyG index greater than the median, the Kaplan-Meier curve showed that patients with the highest PCSK9 levels had an increased risk of all-cause mortality (log-rank p = 0.017) and cardiac-cause mortality (log-rank p = 0.037) compared with lower PCSK9 quartile levels. Conclusion: Elevated PCSK9 levels are related to all-cause mortality and cardiac-related mortality when TyG levels are greater than the median, but not when levels are less than the median. This suggests a potential benefit of lowering circulating PCSK9 levels in STEMI patients with insulin resistance.

Background. In vivo studies show that LL-37 inhibits the progression of atherosclerosis and predicts a lower risk of recurrent ischemia in patients with acute myocardial infarction (AMI), which could be mediated by the modulation of lipid metabolism. The current study aimed to investigate the effects of various lipid contents on the prognostic impacts of LL-37 in patients with AMI. Methods. A total of 1567 consecutive AMI patients were prospectively recruited from March 2017 to January 2020. Patients were firstly stratified into two groups by the median level of LL-37 and then stratified by levels of various lipid contents and proprotein convertase subtilisin/kexin type 9 (PCSK9). Cox regression with multiple adjustments was performed to analyze associations between LL-37, lipid profiles, PCSK9, and various outcomes. The primary outcome was major adverse cardiovascular event (MACE), a composite of all-cause death, recurrent MI, and ischemic stroke. Results. During a median follow-up of 786 (726–1107) days, a total of 252 MACEs occurred. A high level of LL-37 was associated with lower risk of MACE in patients with elevated lipoprotein(a) (≥300 mg/L, hazard ratio (HR): 0.49, 95% confidence interval (CI): 0.29–0.86, p = 0.012) or PCSK9 levels above the median (≥47.4 ng/mL, HR: 0.57, 95% CI: 0.39–0.82, p < 0.001), which was not observed for those without elevated lp(a) (p = 0.781, p_interaction = 0.035) or PCSK9 (p = 0.905, p_interaction = 0.032). Conclusions. For patients with AMI, a high level of LL-37 was associated with lower ischemic risk among patients with elevated lp(a) and PCSK9.

Background and Aims: We aimed to develop a clinical prediction tool to improve the prognosis of major adverse cardiac and cerebrovascular events (MACCE) among high-risk myocardial infarction (MI) patients undergoing primary percutaneous coronary intervention (PCI). Methods: The present study was a prospective and observational study. A total of 4151 consecutive MI patients who underwent primary PCI at Fuwai Hospital in Beijing, China (January 2010 and June 2017) were enrolled. Forty-eight patients without follow-up data were excluded from the study. The pre-specified criteria (Supplementary Information 1) were chosen to enroll MI patients at high risk for MACCE complications after PCI. Results: The full model included seven variables, with a risk score of 160 points. Derivation and validation cohort models predicting MACCE had C-statistics of 0.695 and 0.673. The area under the curve (AUC) of the survival receiver operating characteristic curve (ROC) for predicting MACCE was 0.991 and 0.883 in the derivation and validation cohorts, respectively. Conclusion: The predicted model was internally validated and calibrated in large cohorts of patients with high-risk MI receiving primary PCI to predict MACCE and showed modest accuracy in the derivation and validation cohorts.