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.

Identification of a potent and specific retinoic acid-inducible gene 1 pathway activator as a Hepatitis B Virus antiviral through a novel cell-based reporter assay.

Chronic Hepatitis B Virus (HBV) infection remains a global burden. To identify small molecule RIG-I agonists as antivirals against HBV, we developed an HBV-pgRNA-based interferon-ß (IFN-ß) luciferase reporter assay with high level of assay sensitivity, specificity and robustness. Through HTS screening, lead compound (JJ#1) was identified to activate RIG-I signaling pathway by inducing TBK1 phosphorylation. Knockdown experiments demonstrated that JJ#1-induced retinoic acid-inducible gene 1 (RIG-I) signaling pathway activation was MAVS-dependent. Furthermore, JJ#1 exhibited HBV antiviral potency in HBV-infected cell models by reducing HBV DNA and antigens (HBsAg and HBeAg).

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.

Atherosclerotic Autoantigen ALDH4A1 as a Novel Immunological Indicator for Plaque Erosion in Patients with ST Segment Elevated Myocardial Infarction.

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.

RAP80 phase separation at DNA double-strand break promotes BRCA1 recruitment.

RAP80 has been characterized as a component of the BRCA1-A complex and is responsible for the recruitment of BRCA1 to DNA double-strand breaks (DSBs). However, we and others found that the recruitment of RAP80 and BRCA1 were not absolutely temporally synchronized, indicating that other mechanisms, apart from physical interaction, might be implicated. Recently, liquid-liquid phase separation (LLPS) has been characterized as a novel mechanism for the organization of key signaling molecules to drive their particular cellular functions. Here, we characterized that RAP80 LLPS at DSB was required for RAP80-mediated BRCA1 recruitment. Both cellular and in vitro experiments showed that RAP80 phase separated at DSB, which was ascribed to a highly disordered region (IDR) at its N-terminal. Meanwhile, the Lys63-linked poly-ubiquitin chains that quickly formed after DSBs occur, strongly enhanced RAP80 phase separation and were responsible for the induction of RAP80 condensation at the DSB site. Most importantly, abolishing the condensation of RAP80 significantly suppressed the formation of BRCA1 foci, encovering a pivotal role of RAP80 condensates in BRCA1 recruitment and radiosensitivity. Together, our study disclosed a new mechanism underlying RAP80-mediated BRCA1 recruitment, which provided new insight into the role of phase separation in DSB repair.

Mechanistic insights into the improving effects of germination on physicochemical properties and antioxidant activity of protein isolate derived from black and white sesame.

Germination is a natural green technology to improve the nutritional and techno-functional quality of plant-based proteins. In this study, the mechanism of improving the functional and antioxidant properties of black and white sesame protein isolates (SPI) through germination process was investigated. Results showed that the surface hydrophobicity and sulfhydryl content increased significantly after germination, which were supported by multispectral analysis suggesting the exposed and unfolded conformational transition of germinated SPI. Moreover, the increased particle size was observed by microscopy analysis and reducing electrophoresis, which indicated that depolymerized protein molecules were rearranged to form protein aggregates during germination. The structural modification induced by germination contributed to the superior solubility (increased to 3.15-fold and 2.36-fold at pH 8 for black and white SPI, respectively), foaming capacity (increased to 3.99-fold and 1.69-fold, respectively), emulsifying ability (increased to 2.84-fold and 2.71-fold, respectively), and diverse chemical antioxidant activities (increased up to 5.60-fold) of SPI in both varieties. This was the first comprehensive study to investigate germination as a promising technology for obtaining high-quality SPI.

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.

Anonymous Comparison of Various Angiography-Derived Fractional Flow Reserve Software With Pressure-Derived Physiological Assessment.

BACKGROUND: Software to compute angiography-derived fractional flow reserve (angio-FFR) have been validated against pressure wire-derived fractional flow reserve (PW-FFR) with an area under the receiver-operating characteristic curve (AUC) of 0.93 to 0.97. OBJECTIVES: The aim of this study was to investigate diagnostic accuracies of 5 angio-FFR software/methods by an independent core lab in a prospective cohort of 390 vessels with carefully documented sites of PW-FFR and pressure wire-derived instantaneous wave-free ratio. METHODS: One "matcher investigator" colocalized on angiography the sites of pressure wire measurement with angio-FFR measurements and provided the same 2 optimal angiographic views and frame selection to independent analysts who were blinded to invasive physiological results and results from other software. The results were anonymized and randomly presented. The AUC of each angio-FFR was compared with 2-dimensional quantitative coronary angiography (QCA) percent diameter stenosis (%DS) using a 2-tailed paired comparison of AUC. RESULTS: All 5 software/methods yielded a high proportion of analyzable vessels (A: 100%, B: 100%, C: 92.1%, D: 99.5%, and E: 92.1%). The AUCs for predicting fractional flow reserve ≤0.8 for software A, B, C, D, E, and 2-dimensional QCA %DS were 0.75, 0.74, 0.74, 0.73, 0.73, and 0.65, respectively. The AUC for each angio-FFR was significantly greater than that for 2-dimensional QCA %DS. CONCLUSIONS: This head-to-head comparison by an independent core lab demonstrated that the diagnostic accuracy of various angio-FFR software for predicting PW-FFR ≤0.80 was useful, with a higher discrimination compared with 2-dimensional QCA %DS; however, it did not reach the diagnostic accuracy previously reported in validation studies of various vendors. Therefore, the intrinsic clinical value of "angiography-derived fractional flow reserve" requires confirmation in large clinical trials.

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.

Effects of medium-chain fatty acids (MCFAs) on in vitro rumen fermentation, methane production, and nutrient digestibility under low- and high-concentrate diets.

This experiment was conducted to investigate the effects of different dosages and types of medium-chain fatty acids (MCFAs) on rumen fermentation in vitro under low- and high-concentrate diets. For this purpose, two in vitro experiments (Exp.) were conducted. In Exp. 1, the concentrate-roughage ratio of the fermentation substrate [total mixed rations (TMR), dry matter (DM) basis] was 30:70 (low-concentrate diet), while in Exp. 2, it was 70:30 (high-concentrate diet). Three types of MCFAs with octanoic acid (C8 ), capric acid (C10 ), and lauric acid (C12 ) were added accounting for 1.5%, 6%, 9%, and 15% of the in vitro fermentation substrate weight (200 mg or 1 g, DM basis) based on control group, respectively. The results showed that the addition of MCFAs all could significantly reduce methane (CH4 ) production and the number of rumen protozoa, methanogens, and methanobrevibacter under the two diets with the dosages increased (p < 0.05). In addition, MCFAs had a certain degree of improvement on rumen fermentation and influenced in vitro digestibility under low- and high-concentrate diets, and their effects were related to the dosages and types of MCFAs. This study provided a theoretical basis for the selection of types and dosages of MCFAs in ruminants production.

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.

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.

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.

Prognostic Impacts of LL-37 in Relation to Lipid Profiles of Patients with Myocardial Infarction: A Prospective Cohort Study.

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) (<300 mg/L, HR: 0.96, 95% CI: 0.70−1.31, p = 0.781, pinteraction = 0.035) or PCSK9 (<47.4 ng/mL, HR: 1.02, 95% CI: 0.68−1.54, p = 0.905, pinteraction = 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.

Low-density lipoprotein cholesterol in oldest old with acute myocardial infarction: Is lower the better?

BACKGROUND: the relationship between low-density lipoprotein cholesterol (LDL-C) and adverse outcomes among the older people remains controversial. OBJECTIVE: to further clarify the association between admission LDL-C levels and cardiovascular mortality (CVM) among oldest old individuals (≥80 years) with acute myocardial infarction (AMI). DESIGN: a prospective cohort study. SETTING: two-centre. SUBJECTS: a consecutive sample of 1,224 oldest old individuals with AMI admitted to Beijing FuWai and Shenzhen FuWai hospitals. METHODS: all individuals were subdivided according to baseline LDL-C levels (<1.8, 1.8-2.6 and ≥ 2.6 mmol/l) and further stratified by high-sensitivity C-reactive protein (hsCRP) concentrations (<10 and ≥10 mg/l). The primary outcome was CVM. The time from admission to the occurrence of CVM or the last follow-up was analysed in Kaplan-Meier and Cox analyses. RESULTS: the median age of the overall population was 82 years. During an average of 24.5 months' follow-up, 299 cardiovascular deaths occurred. Kaplan-Meier analysis showed that LDL-C < 1.8 mmol/l group had the highest CVM among oldest old individuals with AMI. Multivariate Cox regression analysis further revealed that compared with those with LDL-C levels <1.8 mmol/l, subjects with LDL-C levels ≥2.6 mmol/l (hazard ratio: 0.67, 95% confidence interval: 0.46-0.98) had significantly lower risk of CVM, especially in those with high hsCRP levels. Moreover, when categorising according to LDL-C and hsCRP together, data showed that individuals with low LDL-C and high hsCRP levels had the highest CVM. CONCLUSIONS: LDL-C < 1.8 mmol/l was associated with a high CVM after AMI in oldest old individuals, especially when combined with high hsCRP levels, which may need to be confirmed by randomised controlled trials.

Angiography derived assessment of the coronary microcirculation: is it ready for prime time?

INTRODUCTION: Non-obstructive coronary arteries (NOCA) are present in 39.7% to 62.4% of patients who undergo elective angiography. Coronary microcirculation (<400 µm) is not visible on angiography therefore functional assessment, invasive or noninvasive plays a prior role to help provide a more personalized diagnosis of angina. AREA COVERED: In this review, we revisit the pathophysiology, clinical importance, and invasive assessment of the coronary microcirculation, and discuss angiography-derived indices of microvascular resistance. A comprehensive literature review over four decades is also undertaken. EXPERT OPINION: The coronary microvasculature plays an important role in flow autoregulation and metabolic regulation. Invasive assessment of microvascular resistance is a validated modality with independent prognostic value, nevertheless, its routine application is hampered by the requirement of intravascular instrumentation and hyperemic agents. The angiography-derived index of microvascular resistance has emerged as a promising surrogate in pilot studies, however, more data are needed to validate and compare the diagnostic and prognostic accuracy of different equations as well as to illustrate the relationship between angiography-derived parameters for epicardial coronary arteries and those for the microvasculature.

Development and Validation of a Prediction Rule for Major Adverse Cardiac and Cerebrovascular Events in High-Risk Myocardial Infarction Patients After Primary Percutaneous Coronary Intervention.

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.

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.