Sodium-glucose cotransporter 2 inhibitors, inflammation, and heart failure: a two-sample Mendelian randomization study.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are increasingly recognized for their role in reducing the risk and improving the prognosis of heart failure (HF). However, the precise mechanisms involved remain to be fully delineated. Evidence points to their potential anti-inflammatory pathway in mitigating the risk of HF. METHODS: A two-sample, two-step Mendelian Randomization (MR) approach was employed to assess the correlation between SGLT-2 inhibition and HF, along with the mediating effects of inflammatory biomarkers in this relationship. MR is an analytical methodology that leverages single nucleotide polymorphisms as instrumental variables to infer potential causal inferences between exposures and outcomes within observational data frameworks. Genetic variants correlated with the expression of the SLC5A2 gene and glycated hemoglobin levels (HbA1c) were selected using datasets from the Genotype-Tissue Expression project and the eQTLGen consortium. The Genome-wide association study (GWAS) data for 92 inflammatory biomarkers were obtained from two datasets, which included 14,824 and 575,531 individuals of European ancestry, respectively. GWAS data for HF was derived from a meta-analysis that combined 26 cohorts, including 47,309 HF cases and 930,014 controls. Odds ratios (ORs) and 95% confidence interval (CI) for HF were calculated per 1 unit change of HbA1c. RESULTS: Genetically predicted SGLT-2 inhibition was associated with a reduced risk of HF (OR 0.42 [95% CI 0.30-0.59], P < 0.0001). Of the 92 inflammatory biomarkers studied, two inflammatory biomarkers (C-X-C motif chemokine ligand 10 [CXCL10] and leukemia inhibitory factor) were associated with both SGLT-2 inhibition and HF. Multivariable MR analysis revealed that CXCL10 was the primary inflammatory cytokine related to HF (MIP = 0.861, MACE = 0.224, FDR-adjusted P = 0.0844). The effect of SGLT-2 inhibition on HF was mediated by CXCL10 by 17.85% of the total effect (95% CI [3.03%-32.68%], P = 0.0183). CONCLUSIONS: This study provides genetic evidence supporting the anti-inflammatory effects of SGLT-2 inhibitors and their beneficial impact in reducing the risk of HF. CXCL10 emerged as a potential mediator, offering a novel intervention pathway for HF treatment.

Prognostic significance of serial N-terminal pro-B-type natriuretic peptide levels in patients with acute myocardial infarction: A prospective study.

OBJECTS: This study aimed to investigate the association between N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels at different sampling times and prognosis in patients with acute myocardial infarction (AMI) undergoing emergency percutaneous coronary intervention (PCI). METHODS AND RESULTS: Between March 2017 and January 2020, 1,105 patients with AMI who underwent emergency PCI were included. NT-proBNP levels were measured on days 0, 1, 2, 3, and 7. A composite of all-cause death, MI recurrence (reMI), and rehospitalization due to heart failure, known as major adverse cardiovascular events (MACE), was recorded. During the 36.8-month follow-up, 175 patients (15.8%) experienced MACEs. When patients were grouped based on quartiles of NT-proBNP levels on days 0 and 7, the results demonstrated that patients in quartile 4 showed a substantially increased MACE risk compared to those in quartile 1 (hazard ratio [HR] 2.27, 95% confidence interval [CI]:1.27-4.08, P = .006; HR 2.20, 95%CI:1.23-3.94, P = .008). There were U-shaped relationships between the HR for MACE and NT-proBNP levels on days 2, 3, and 7, as well as peak NT-proBNP (P for nonlinearity = .007, .006, .004, and .009, respectively). A similar relationship was observed in the HR for reMI and NT-proBNP levels on days 2 and 3. For MACE at 3 years, serial NT-proBNP levels improved the predictive accuracy of the Global Registry of Acute Coronary Events (GRACE) risk score (concordance index [C-index]: 0.711; continuous net reclassification improvement [NRI]: 0.192, 95% CI: 0.022-0.445; integrated discrimination improvement [IDI]: 0.034, 95% CI: 0.016-0.064). For all-cause death at 3 years, the combination of NT-proBNP and GRACE score showed excellent performance, with C-index, continuous NRI, and IDI values of 0.801, 0.373 (95%CI: 0.072-0.853), and 0.051 (95%CI: 0.025-0.091), respectively. CONCLUSIONS: Early and sequential measurement of NT-proBNP levels could assist in predicting MACE risk. Moreover, the relationship between MACE risk and NT-proBNP levels was U-shaped. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov NCT: 03593928.

Prognostic impacts of diabetes status and lipoprotein(a) levels in patients with ST-segment elevation myocardial infarction: a prospective cohort study.

OBJECTS: This study aimed to investigate the impact of lipoprotein(a) [Lp(a)] levels on the prognosis of Chinese patients with ST-segment elevation myocardial infarction (STEMI), and to explore if the impact may differ in the diabetes mellitus (DM) and nonDM groups. METHODS: Between March 2017 and January 2020, 1543 patients with STEMI who underwent emergency percutaneous coronary intervention (PCI) were prospectively recruited. The primary outcome was a composite of all-cause death, MI recurrence (reMI), and stroke, known as major adverse cardiovascular events (MACE). Analyses involving the Kaplan-Meier curve, Cox regression, and restricted cubic spline (RCS) were conducted. RESULTS: During the 1446-day follow-up period, 275 patients (17.8%) experienced MACEs, including 141 with DM (20.8%) and 134 (15.5%) without DM. As for the DM group, patients with Lp(a) ≥ 50 mg/dL showed an apparently higher MACE risk compared to those with Lp(a) < 10 mg/dL (adjusted hazard ratio [HR]: 1.85, 95% confidence interval [CI]:1.10-3.11, P = 0.021). The RCS curve indicates that the HR for MACE appeared to increase linearly with Lp(a) levels exceeding 16.9 mg/dL. However, no similar associations were obtained in the nonDM group, with an adjusted HR value of 0.57 (Lp(a) ≥ 50 mg/dL vs. < 10 mg/dL: 95% CI 0.32-1.05, P = 0.071). Besides, compared to patients without DM and Lp(a) ≥ 30 mg/dL, the MACE risk of patients in the other three groups (nonDM with Lp(a) < 30 mg/dL, DM with Lp(a) < 30 mg/dL, and DM with Lp(a) ≥ 30 mg/dL) increased to 1.67-fold (95% CI 1.11-2.50, P = 0.013), 1.53-fold (95% CI 1.02-2.31, P = 0.041), and 2.08-fold (95% CI 1.33-3.26, P = 0.001), respectively. CONCLUSIONS: In this contemporary STEMI population, high Lp(a) levels were linked to an increased MACE risk, and very high Lp(a) levels (≥ 50 mg/dL) significantly indicated poor outcomes in patients with DM, while not for those without DM. TRIAL REGISTRATION: clinicaltrials.gov NCT: 03593928.

Associations of Culprit Vessel Size and Plaque Characteristics in Patients with ST-Segment Elevation Myocardial Infarction.

Background: Small vessel disease (SVD) widely exists in patients with acute coronary syndrome. However, the plaque characteristic of SVD has not been investigated. Methods: Optical coherence tomography (OCT) of culprit lesion was examined in 576 patients with ST-segment elevation myocardial infarction (STEMI) and finally 404 patients with qualified images were analysed of plaque phenotypes and microstructure. The cohort was divided into three groups according to vessel diameters of culprit lesion which were measured by OCT. Major adverse cardiac events (MACEs) were recorded of each patient and compared among patients with different vessel diameters and plaque phenotypes. Results: Gender, age and body mass index (BMI) were significantly different among patients with different diameters of culprit vessels (98.4% vs. 85.7% vs.71.4%, p < 0.001; 40.0 ± 7.0 vs. 54.9 ± 6.6 vs. 68.9 ± 5.8, p < 0.001; 28.4 ± 4.0 vs. 25.8 ± 2.9 vs. 25.2 ± 3.0, p < 0.001, respectively). Moreover, patients with diameters of culprit lesion > 3 mm presented with more incidence of plaque rupture and macrophage (57.7% vs. 42.1% vs. 46.2%, p = 0.015, 55.1% vs. 41.0% vs. 36.9%, p = 0.010). Total MACE did not differ among groups of different vessel diameters and plaque phenotypes. Conclusions: Vessel size of culprit lesion is significantly associated with plaque phenotype in patients with STEMI. However, patients with different diameters and plaque phenotypes showed no significant difference of clinical outcomes. Clinical Trial Registration: NCT03593928.

Prognostic impacts of Lipoxin A4 in patients with acute myocardial infarction: A prospective cohort study.

Lipoxin A4 (LXA4) is one of the specialized pro-resolving lipid mediators proved to suppress the progression of atherosclerosis in vivo, but its clinical impacts in atherosclerotic patients is unclear. In this study, we assessed the prognostic impacts of LXA4 in patients with acute myocardial infarction (AMI). A total of 1569 consecutive AMI patients were prospectively recruited from March 2017 to January 2020. Plasma samples of AMI patients were collected, and LXA4 levels were determined using enzyme-linked immunosorbent assay. The primary outcome was major adverse cardiovascular event (MACE), a composite of all-cause death, recurrent MI, ischemic stroke, or ischemia-driven revascularization. Cox regression was used to assess associations between LXA4 and clinical outcomes. Overall, the median level of LXA4 was 5.637 (3.047-9.014) ng/mL for AMI patients. During a median follow-up of 786 (726-1108) days, high LXA4 (≥ 5.637 ng/mL) was associated with lower risk of MACE (hazard ratio [HR]: 0.73, 95% confidence interval [CI]: 0.60-0.89, P = 0.002), which was sustained in propensity score matching (HR: 0.73, 95% CI: 0.60-0.90, P = 0.004) and inverse probability weighting analysis (HR: 0.74, 95% CI: 0.61-0.90, P = 0.002). Combined with pro-inflammatory biomarker, patients with high levels of LXA4 (≥ 5.637 ng/mL) but low levels of high-sensitivity C-reactive protein (< 5.7 mg/L) acquired the lowest risk of MACE (HR: 0.68, 95% CI: 0.51-0.92, P = 0.012). In sum, high levels of LXA4 were associated with lower risk of recurrent ischemic events for AMI patients, which could serve as new therapeutic target to tackle cardiovascular inflammation.

Effect of early use of ivabradine on left ventricular remodeling after primary percutaneous coronary intervention in patients with acute ST-segment elevation myocardial infarction: A pilot test.

OBJECTIVE: To investigate the effect of early use of ivabradine on left ventricular remodeling after primary percutaneous coronary intervention (PCI) in patients with acute ST-segment elevation myocardial infarction (STEMI). METHODS: A total of 66 STEMI patients with sinus rhythm and the resting heart rate ≥80 bpm after successful emergency PCI were included. The patients in the test group were treated with ivabradine combined with metoprolol at 12 hr after PCI, while the control group was given only metoprolol orally. Their resting heart rate was controlled to <70 bpm at discharge and followed for 180 days. Heart rate and blood pressure were measured regularly. Echocardiogram was performed. N-terminal pro-B-type natriuretic peptide (NT-proBNP), high sensitivity troponin T, high sensitivity troponin I, and high sensitivity C-reactive protein were measured. The major adverse cardiovascular events during hospitalization and follow-up period were recorded. RESULTS: Compared with the control group, the heart rate of the test group decreased significantly (p < .05). Compared with the control group, the left ventricular end-diastolic volume and left ventricular end-systolic volume were significantly decreased while left ventricular ejection fraction was significantly increased in the test group at 90 days after operation. NT-proBNP of the test group was significantly lower than that of the control group at 7 days after operation (p < .05). CONCLUSION: For STEMI patients, early use of ivabradine combined with standard therapy such as ß-blocker after successful reperfusion can achieve effective heart rate control, with great safety and tolerance. But the effect of ivabradine on left ventricular remodeling is uncertain.

Relation between serum calcium levels and mortality in patients with coronary artery disease.

OBJECTIVES: Calcium has a critical role in a spectrum of biological processes related to cardiovascular disease. This study aimed to evaluate associations of baseline serum calcium levels with both short-term and long-term outcomes in CAD patients. MATERIALS AND METHODS: 3109 consecutive patients with angiography confirmed CAD, admitted to West China hospital of Sichuan University between July 2008 and September 2012 were enrolled and were categorized into quartiles according to admission serum calcium to determine the association of serum calcium level with in-hospital and long-term mortality by multivariable Logistic and Cox regression analysis respectively. RESULTS: The admission serum calcium was normally distributed with a mean level of 2.20±0.15 mmol/L. A total of 259 deaths, including 58 in-hospital deaths, occurred during a mean follow-up of 20 months. Patients in the upper quartiles of serum calcium, as compared to the lowest quartile of serum calcium, were presented with lower in-hospital mortality [HR was 0.391 (95% CI: 0.188-0.812), 0.231(95% CI: 0.072-0.501) and 0.223 (95% CI: 0.093-0.534) for three upper quartiles versus lowest quartile respectively] and long-term mortality [HR was 0.614 (95% CI: 0.434-0.869), 0.476(95% CI: 0.294-0.698) and 0.553 (95% CI: 0.349-0.777) respectively]. Similar association between serum calcium and long-term mortality as showed in total cohort were also obtained when restricting analyses to subgroups: stable CAD patients, ACS patients and discharged patients. CONCLUSIONS: As a widely available clinical index, serum calcium was an independent predictor of both in-hospital and long-term mortality among CAD patients. Further studies are warranted to determine mechanisms and whether patients with hypocalcaemia could benefit from calcium supplement.

Lipid Content Distribution and its Clinical Implication in Patients with Acute Myocardial Infarction-Plaque Erosion: Results from the Prospective OCTAMI Study.

AIMS: Plaque erosion (PE) is one of the main plaque phenotypes of acute coronary syndrome (ACS). However, the underlying plaque component and distribution have not been systematically analysed. This study aims to investigate the distribution of lipid and calcium content in culprit lesions assessed by optical coherence tomography (OCT) in patients with PE and explore its relationship with prognosis in a cohort of ST segment elevation myocardial infarction (STEMI) patients. METHODS: A prospective cohort of 576 patients with STEMI was enrolled in our study. After exclusion, 152 PE patients with clear underlying plaque components were ultimately analysed. The culprit lesion was divided into the border zone, external erosion zone and erosion site in the longitudinal view. Each pullback of the culprit lesions was assessed by 3 independent investigators frame-by-frame, and the quantity and distribution of lipid and calcium components were recorded. RESULTS: Of the 152 PE patients, lipid and calcium contents were more likely to exist in the external erosion zone than in the other regions. In particular, a high level of lipid content proximal to the erosion site was significantly associated with plaque vulnerability and a higher incidence of MACEs. CONCLUSION: This study revealed that high level of lipid content in the proximal external erosion zone was related to high-risk plaque characteristics and poor prognosis, which provided a novel method for risk stratification and precise management in patients with plaque erosion.

A Combined Measure of the Triglyceride Glucose Index and Trimethylamine N-Oxide in Risk Stratification of ST-Segment Elevation Myocardial Infarction Patients with High-Risk Plaque Features Defined by Optical Coherence Tomography: A Substudy of the OCTAMI Registry Study.

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.

Effect of Triglyceride-Glucose Indices and Circulating PCSK9-Associated Cardiovascular Risk in STEMI Patients with Primary Percutaneous Coronary Artery Disease: A Prospective Cohort Study.

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.

Associations Between Resolvin D1 and Culprit Plaque Morphologies: An Optical Coherence Tomography Study in Patients with ST-Segment Elevation Myocardial Infarction.

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.

Prognostic Value of Admission Peak NT-proBNP Combined with Culprit Plaque Types for Predicting Cardiovascular Risk in ST-Segment Elevated Myocardial Infarction: An Optical Coherence Tomography Study.

OBJECTIVE: Different culprit plaque phenotypes including plaque rupture (PR) and non-plaque rupture (NPR), and N-Terminal prohormone of brain natriuretic peptide (NT-proBNP) have been reported to influence clinical outcomes in patients with acute coronary syndrome (ACS). We aimed to investigate the prognostic implication of the peak and baseline values at admission for NT-proBNP for major adverse cardiovascular events (MACE) in ST-Segment Elevated Myocardial Infarction (STEMI) patients with different plaque phenotype. METHODS: A total of 428 patients with STEMI undergoing optical coherence tomography (OCT) were enrolled and divided into four groups: PR/Tertile1-2 NT-proBNP (n = 132), PR/Tertile3 NT-proBNP (n = 65), NPR/Tertile1-2 NT-proBNP (n = 154), NPR/Tertlie3 NT-proBNP (n = 77). Baseline and Peak values of NT-proBNP were obtained in the admission period. The MACEs were defined as the composite of all-cause death, recurrence of myocardial infarction and stroke. RESULTS: High levels for peak NT-proBNP were significantly associated with a higher incidence of MACE and death (Log rank p = 0.037 and 0.0012, respectively). In the subgroup with NPR, a high level for peak NT-proBNP was significantly associated with higher incidence of death (Log rank p = 0.0022) but this association was not significant in the subgroup of PR (Log rank p = 0.24). Though plaque types were not associated with adverse event, the combination of NPR and a higher peak value for NT-proBNP indicated higher incidence of death compared with other groups (Log rank p = 0.0017). The area under the receiver operating characteristic curve for predicting death to evaluate the diagnostic value of the peak value for NT-proBNP and plaque types combined with traditional risk factors was 0.843 (95% CI: 0.805-0.876), which is superior to solely traditional risk factors: NRI (26.8% [95% CI: 0.4-53.1%], p = 0.046) and IDI (5.1% [95% CI: 1.0-9.2%], p = 0.016). CONCLUSION: STEMI patients with NPR and a high level for peak NT-proBNP showed higher incidence of death. The peak value of NT-proBNP in combination with plaque types can be used in risk stratification and prediction of death in patients with STEMI.

Association between the Changes in Trimethylamine N-Oxide-Related Metabolites and Prognosis of Patients with Acute Myocardial Infarction: A Prospective Study.

This study aimed to investigate the association between changes in levels of trimethylamine N-oxide (TMAO) and its precursors and the prognosis of patients with acute myocardial infarction (AMI). Patients diagnosed with AMI were prospectively enrolled at Fuwai Hospital between March 2017 and January 2020. TMAO, betaine, choline, and L-carnitine were measured in 1203 patients at their initial admission and 509 patients at their follow-up of one month. Major adverse cardiovascular events (MACE), a composite of all-cause death, recurrence of MI, rehospitalization caused by HF, ischemic stroke, and any revascularization, were followed up. A decision tree by TMAO levels implicated that compared to those with low levels at admission, patients with high TMAO levels at both time points showed an increased risk of MACE (adjusted hazard ratio (HR) 1.59, 95% confidence interval (CI): 1.03-2.46; p = 0.034), while patients with high TMAO levels at admission and low levels at follow-up exhibited a similar MACE risk (adjusted HR 1.20, 95% CI: 0.69-2.06; p = 0.520). Patients with high choline levels at admission and follow-up showed an elevated MACE risk compared to those with low levels at both time points (HR 1.55, 95% CI: 1.03-2.34; p = 0.034). Repeated assessment of TMAO and choline levels helps to identify the dynamic risk of cardiovascular events.

Association between trimethylamine N-oxide and prognosis of patients with acute myocardial infarction and heart failure.

AIMS: This study aimed to investigate the association between trimethylamine N-oxide (TMAO) and the prognosis and association between high-sensitivity C-reactive protein (hsCRP) and TMAO-associated cardiovascular risk in patients with acute myocardial infarction (AMI) complicated by heart failure (HF). METHODS AND RESULTS: A total of 985 patients presenting with AMI and HF were consecutively enrolled at the Fuwai Hospital between March 2017 and January 2020. Patients were stratified into groups according to tertiles of TMAO levels and the median hsCRP levels. The primary endpoint was major adverse cardiac events (MACE), including all-cause death, recurrence of myocardial infarction, and rehospitalization due to HF. During a median follow-up of 716 days, 138 (14.0%) patients experienced MACE. Cox regression analyses showed that the adjusted hazard ratio (HR) for MACE was higher in patients in tertile 3 [TMAO > 9.52 µmol/L, HR: 1.85, 95% confidence interval (CI): 1.18-2.89; P = 0.007] than in tertile 1 (TMAO < 4.74 µmol/L), whereas no significant differences were detected between the patients in tertiles 1 and 2 (TMAO = 4.74-9.52 µmol/L, HR: 0.96, 95% CI: 0.59-1.58; P = 0.874). Restricted cubic spline regression depicted an S-shaped association between TMAO and MACE (P for nonlinearity = 0.012). In the setting of hsCRP above the median level (6.68 mg/L), per unit increase of TMAO was associated with a 20% increase of MACE risk (HR: 1.20, 95% CI: 1.05-1.37, P = 0.009); increasing tertiles of TMAO were significantly associated with a higher risk of MACE (adjusted P = 0.007 for interaction; P < 0.001 for trend across tertiles). The Kaplan-Meier analysis indicated that patients in tertile 3 had a significantly lower event-free survival (P = 0.001) when the hsCRP level was above the median level. No similar association between TMAO and MACE was observed when the hsCRP level was below the median level. CONCLUSIONS: High plasma TMAO levels were independently correlated with poor prognosis in patients with AMI complicated by HF, especially in those with higher hsCRP levels. There was an S-shaped relationship between TMAO and HR for MACE.

Prognostic Impacts of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Acute Coronary Syndrome Patients Without Heart Failure.

Background: Despite the recommendations from mainstream guidelines, the use of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) for acute coronary syndrome (ACS) patients without heart failure (HF) is controversial, as its evidence is lacking in the era of reperfusion and intensive secondary preventions. This study aimed to investigate the impacts of ACEI/ARB on outcomes of ACS patients without HF treated by percutaneous coronary intervention (PCI). Methods: A total of 2,397 non-HF ACS patients treated by PCI were retrospectively recruited. Prognostic impacts of ACEI/ARB were assessed by unadjusted analysis, followed by propensity score matching (PSM) and propensity score matching weight (PSMW) analysis to control the between-group differences. The primary outcome was a composite of all-cause death and recurrent myocardial infarction (MI). Results: Among the included patients, 1,805 (75.3%) were prescribed with ACEI/ARB at discharge. The median follow-up time was 727 (433-2016) days, with 129 (5.4%) primary endpoint events, consisting of 55 (2.3%) cases of all-cause death and 74 (3.1%) cases of recurrent MI. The use of ACEI/ARB was not associated with significant risk reduction of primary endpoint events in unadjusted analysis (hazard ratio [HR]: 0.95, 95% confidence interval [CI]: 0.64-1.39, p = 0.779), PSM analysis (HR: 0.94, 95% CI: 0.60-1.47, p = 0.784), and PSMW analysis (HR: 0.91, 95% CI: 0.55-1.49, p = 0.704). Similar results were observed for secondary outcomes of all-cause death, cardiac death, and recurrent MI. Conclusion: For ACS patients without HF, the use of ACEI/ARB was not associated with lower risk of death or recurrent MI after PCI.

High-Risk Culprit Plaque Predicts Cardiovascular Outcomes Independently of Plaque Rupture in ST-Segment Elevation Myocardial Infarction: Insight From Optical Coherence Tomography.

The present study explored the predictive value of culprit high-risk plaque (HRP) detected by optical coherence tomography (OCT) for predicting major adverse cardiovascular events (MACEs) in patients with ST-segment elevation myocardial infarction (STEMI). HRP was defined as the simultaneous presence of four criteria: minimum lumen area <3.5 mm2, fibrous cap thickness <75 µm, lipid plaque with lipid arc extension >180°, and presence of macrophages. Patients (n = 274) were divided into non-HRP group (n = 206) and HRP group (n = 68). MACEs were defined as a composite of all-cause death, myocardial infarction, stroke, and revascularization. During a mean follow-up of 2.2 years, 47 (17.5%) MACEs were observed: 28 (13.6%) in the non-HRP group and 19 (27.9%) in the HRP group (log-rank P = .005). Patients with HRP were 2.05 times more likely to suffer from a MACE than those without HRP (hazards ratio: 2.05, 95% confidence interval: 1.04-4.02, P = .038); MACE risk was comparable between plaque rupture and plaque erosion. In conclusion, HRP was present in 24.8% of STEMI patients and associated with higher cardiovascular risk independent of plaque rupture, suggesting that HRP detected by OCT may help identify patients at high risk of future cardiac events.

The relationship between Hemoglobin A1c and the maximal plaque stress of culprit ruptured plaques in patients with ST-segment elevated myocardial infarction.

BACKGROUND: Plaque rupture occurs when the structural stress inside plaques exceeds the capacity of the overlying fibrous cap. Plaque structural stress has been acknowledged as an index to evaluate the risk of plaque rupture. However, impacting factors associated with the level of plaque structural stress in ST-segment elevated myocardial infarction patients with ruptured plaques remain unknown. METHODS: Based on optical coherence tomography, we analyzed the plaque characteristics and calculated the maximal plaque stress of the culprit lesions in 162 patients with plaque rupture by performing finite element analysis. All enrolled patients were divided into two groups according to the level of maximal plaque stress. Cardiovascular risk factors, laboratory findings and clinical outcomes were compared between the two groups. RESULTS: Hemoglobin A1c (HbA1c) was significantly higher in the high stress group than in the low stress group (7.0% ± 1.8 vs. 6.3% ± 1.2, p = 0.003). The maximal plaque stress of patients with diabetes was significantly higher than that of patients without diabetes (538.7 kPa [346.2-810.6] vs. 425.9 kPa [306.2-571.4], p = 0.006). Moreover, the level of maximal plaque stress was significantly associated with HbA1c (Pearson's correlation coefficient: r = 0.289, P < 0.001). OCT findings showed that the fibrous cap thickness and maximal lipid arc were significantly associated with maximal plaque stress (r = -0.163, p = 0.038; r = 0.194, p = 0.013, respectively). CONCLUSION: OCT-based finite-element analysis showed that HbA1c was independently associated with the level of maximal plaque stress in STEMI patients with plaque rupture, thus indicating the importance of glucose control in patients with coronary atherosclerotic disease.

The value of combining CYP2C19*2 polymorphism with classic risk factors in prediction of clinical prognosis in acute coronary syndrome patients.

OBJECTIVES: To assess the impact of different CYP2C19*2 polymorphisms on clinical outcomes and the effects of CYP2C19*2 polymorphism on predicting clinical outcomes in association with classic risk factors in patients with acute coronary syndromes (ACS). METHODS: Between July 2008 and September 2009, 497 consecutive patients with ACS who were admitted to the West China Hospital of Sichuan University were enrolled and underwent CYP2C19*2 determination. The clinical outcomes were the composite of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke. RESULTS: Baseline characteristics were balanced between noncarrier, heterozygous and homozygous groups of the CYP2C19*2 variant. The clinical endpoint occurred more frequently in the homozygous group (HR 4.86, CI 1.62-14.56, p = 0.005). After multivariable analysis, the CYP2C19*2 genetic variant was an independent predictor of cardiovascular events (HR 5.96, CI 1.77-20.03, p = 0.0039) as well as GRACE score and Killip class. The combination of CYP2C19*2 with GRACE score and Killip class increases the potential to predict adverse outcomes. CONCLUSIONS: Homozygosity (A/A) for CYP2C19*2 mutant is an independent determinant of prognosis in patients with ACS. The combination of CYP2C19*2 polymorphism with classic risk factors may be a useful tool to predict the risk of cardiovascular events.

EPC-Derived Exosomal miR-1246 and miR-1290 Regulate Phenotypic Changes of Fibroblasts to Endothelial Cells to Exert Protective Effects on Myocardial Infarction by Targeting ELF5 and SP1.

Myocardial infarction (MI) remains a leading cause of morbidity and mortality worldwide. Endothelial progenitor cell (EPC)-derived exosomes have been found to be effective in alleviating MI, while the detailed mechanisms remain unclear. The present study aimed to determine the protective effects of EPC-derived exosomal miR-1246 and miR-1290 on MI-induced injury and to explore the underlying molecular mechanisms. The exosomes were extracted from EPCs; gene expression levels were determined by quantitative real-time PCR, and protein expression levels were determined by western blot and immunofluorescence staining, respectively. The angiogenesis and proliferation of human cardiac fibroblasts (HCFs) were determined by tube formation assay and immunofluorescence staining of PKH67, respectively. Luciferase reporter, CHIP, and EMSA assays determined the interaction between miR-1246/1290 and the targeted genes (EFL5 and SP1). The protective effects of miR-1246/1290 on MI were evaluated in a rat model of MI. EPC-derived exosomes significantly upregulated miR-1246 and miR-1290 expression and promoted phenotypic changes of fibroblasts to endothelial cells, angiogenesis, and proliferation in HCFs. Exosomes from EPCs with miR-1246 or miR-1290 mimics transfection promoted phenotypic changes of fibroblasts to endothelial cells and angiogenesis in HCFs, while exosomes from EPCs with miR-1246 or miR-1290 knockdown showed opposite effects in HCFs. Mechanistically, miR-1246 and miR-1290 from EPC-derived exosomes induced upregulation of ELF5 and SP1, respectively, by targeting the promoter regions of corresponding genes. Overexpression of both ELF5 and SP1 enhanced phenotypic changes of fibroblasts to endothelial cells and angiogenesis in HCFs pretreated with exosomes from EPCs with miR-1246 or miR-1290 mimics transfection, while knockdown of both EFL5 and SP1 exerted the opposite effects in HCFs. Both ELF5 and SP1 can bind to the promoter of CD31, leading to the upregulation of CD31 in HCFs. Furthermore, in vivo animal studies showed that exosomes from EPCs with miR-1246 or miR-1290 overexpression attenuated the MI-induced cardiac injury in the rats and caused an increase in ELF5, SP1, and CD31 expression, respectively, but suppressed α-SMA expression in the cardiac tissues. In conclusion, our study revealed that miR-1246 and miR-1290 in EPC-derived exosomes enhanced in vitro and in vivo angiogenesis in MI, and these improvements may be associated with amelioration of cardiac injury and cardiac fibrosis after MI.

Serum calcium levels correlates with coronary artery disease outcomes.

BACKGROUND: Effect of serum calcium levels on prognosis of patients with coronary artery disease (CAD) is not well evaluated. We aimed to assess the associations of baseline serum calcium levels with both short-term and long-term outcomes in CAD patients. METHODS: This study included 3,109 consecutive patients with angiographically confirmed CAD. Patients were categorized into quartiles according to admission serum calcium. Multivariable regression analysis was used to determine the association of serum calcium with mortality. RESULTS: Compared to patients in the lowest quartile of serum calcium, patients in upper quartiles were presented with lower all-cause mortality (Hazard ratios [HRs] were -0.636 [95% CI: -0.424 to -0.954], -0.545 [95% CI: -0.351 to -0.846] and -0.641 [95% CI: -0.450 to -0.913] for three upper quartiles versus lowest quartile respectively), cardiovascular mortality (HRs 0.594 [0.368-0.961], 0.261 [0.124-0.551] and 0.407 [0.229-0.725]), and in-hospital mortality (Odd ratios [ORs] 0.391 [0.188-0.812], 0.231 [0.072-0.501] and 0.223 [0.093-0.534]). Consistent associations between serum calcium and long-term mortality were also obtained in subgroup analysis of ACS patients, stable CAD patients and discharged patients. CONCLUSIONS: Serum calcium is inversely associated with CAD and can independently predict both in-hospital and long-term mortality among CAD patients.