Ye-Xuan Cao’s research while affiliated with Fu Wai Hospital and other places

Background: Although experimental studies have demonstrated the protective role of total bilirubin (TBil) in cardiovascular diseases, several previous clinical observations are controversial. More importantly, no data are currently available regarding the relation of TBil to major adverse cardiovascular events (MACE) in patients with previous myocardial infarction (MI). Objectives: This study sought to explore the association between TBil and long-term clinical outcomes in patients with previous MI. Methods: A total of 3,809 patients who are post-MI were consecutively enrolled in this prospective study. Cox regression models using HRs and CIs were applied to investigate associations between the TBil concentration category (group 1: bottom to median tertiles within the reference range; group 2: top tertile; group 3: above reference range) and main outcome (recurrent MACE) as well as secondary outcomes (hard endpoints and all-cause mortality). Results: During the 4-year follow-up period, 440 patients (11.6%) suffered from recurrent MACE. Kaplan-Meier survival analysis showed the lowest MACE incidence in group 2 (P < 0.001). When compared with the reference group (group 1) in multivariable analysis, a J-shaped association was apparent for MACE, with decreased risk in group 2 (HR: 0.76; 95% CI: 0.59-0.96) and elevated risk in group 3 (HR: 1.29; 95% CI: 1.03-1.61). Similar associations were identified regarding hard endpoints and all-cause mortality. Moreover, TBil demonstrated incremental discriminatory strength when added to the predictive model. Conclusions: In this prospective cohort study with long-term follow-up, higher TBil levels within the physiological range reduced the incidence of long-term cardiovascular events in patients who are post-MI.

Background Patients with previous myocardial infarction (MI) have a poor prognosis and stratification for recurrent major adverse cardiovascular events (MACE) among these patients is of considerable interest. N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity C-reactive protein (hs-CRP) are considered to be potential cardiovascular risk factors, but less is known about their prognostic importance in post-MI patients. This study aimed to evaluate the prognostic value of NT-proBNP and hs-CRP alone or together in patients who reported a prior MI. Methods In this prospective study, we consecutively enrolled 3,306 post-MI patients to assess the recurrent MACE. The predictive values of NT-proBNP and hs-CRP alone and together were assessed by multivariable Cox regression using hazard ratios (HR) and 95% confidence intervals (CI). Results During the 4-year follow-up period, 335 patients developed recurrent MACE. Multivariate Cox regression analysis showed a significant correlation between NT-proBNP levels and MACE (HR: 2.99, 95%CI: 2.06–4.36, p < 0.001), hard endpoints (HR: 5.44, 95%CI: 2.99–9.90, p < 0.001), cardiac mortality (HR: 5.92, 95%CI: 2.34–14.96, p < 0.001) and all-cause mortality (HR: 5.03, 95%CI: 2.51–10.09, p < 0.001). However, hs-CRP was not an independent predictor after adjusting for NT-proBNP. When patients were divided into six groups by using tertiles values of NT-proBNP and median values of hsCRP, patients with high NT-proBNP/hs-CRP values were 3.27 times more likely to experience MACE than patients with low NT-proBNP/hs-CRP values. The addition of NT-proBNP and hs-CRP to a prognostic model revealed a significant improvement in C-statistic, net reclassification, and integrated discrimination. Conclusions Increased NT-proBNP levels were associated with long-term worse outcomes and the combination of NT-proBNP and hs-CRP has an incremental value in the further risk stratification of post-MI patients.

Background The risk of liver fibrosis in non-alcoholic fatty liver disease (NAFLD) can be easily evaluated by noninvasive scoring systems, of which the NAFLD fibrosis score (NFS) is the most commonly used. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a new predictor of cardiovascular events, has been reported to be associated with cardiovascular outcomes and NAFLD. However, the relationship of NFS with PCSK9 and their prognostic abilities in cardiovascular risks are unknown. Methods A total of 2008 hospitalized subjects who had chest pain without lipid-lowering therapy were consecutively included. Baseline clinical data were collected, and the NFS was calculated. The circulating PCSK9 concentration was determined by enzyme immunoassay. The major adverse cardiovascular event (MACE) occurrences were recorded in the follow-up period. Associations of PCSK9 concentration with NFS were examined. All of the participants were categorized into three groups according to NFS levels and were further stratified by PCSK9 tertiles to evaluate the MACEs. Results 158 (7.87%) MACEs were observed during a mean of 3.2 years of follow-up. NFS levels were independently related to higher PCSK9 levels according to multivariable linear regression analysis. Furthermore, elevated PCSK9 and NFS concentrations were respectively associated with increased MACE incidence in multivariable Cox regression models. When combining NFS status with PCSK9 tertiles as a stratifying factor, patients with intermediate-high NFS and high PCSK9 levels had higher risks of events than those with low NFS and low PCSK9 levels. Conclusions This study revealed for the first time that NFS is positively related to PCSK9 and that the combination of NFS and PCSK9 greatly increased the risk of MACEs in patients with chest pain, providing a potential link between NFS and PCSK9 for predicting cardiovascular events.

Background It has been demonstrated that patients with type 2 diabetes mellitus (DM) is associated with increased cardiovascular risk. However, little is known regarding the long-term prognosis in diabetic patients who experience mild-to-intermediate coronary artery stenosis (CAS). This study was to assess the clinical outcomes of diabetic patients with different severity of CAS. Methods We consecutively enrolled 10,940 patients hospitalized due to angina-like chest pain and followed up for major adverse cardiovascular events (MACEs) covering cardiac death, myocardial infarction, ischemic stroke, unplanned coronary revascularization and angina-related hospitalization. According to coronary angiography, patients were divided into non-obstructive CAS (NOCAS, < 50% stenosis), intermediate CAS (ICAS, 50–69% stenosis), and severe CAS (SCAS, 70–100% stenosis) subgroups, and were further categorized into six groups as NOCAS with DM and non-DM, ICAS with DM and non-DM, and SCAS with DM and non-DM. Results During a median follow-up of 40 months, 1,017 (11.1%) MACEs occurred. In patients with ICAS or SCAS, the incidence of events was higher when patients coexisted with DM (p < 0.05, respectively). In subgroup analyses, patients with ICAS and DM, SCAS and non-DM, SCAS and DM had increased risk of events [adjusted hazard ratio (HR): 1.709, 95% confidence interval (CI) 1.106–2.641, p = 0.016; HR: 1.911, 95% CI 1.460–2.501, p < 0.001; HR: 2.053, 95% CI 1.514–2.782, p < 0.001] compared to ones with NOCAS and non-DM. Besides, the Kaplan–Meier curves indicated the highest risk of MACEs in patients with SCAS and DM than others (p < 0.001). Conclusions Diabetic patients with ICAS had the worse outcome, which was comparable to patients with SCAS alone.

Background and aimsA consensus of experts suggests that nonalcoholic fatty liver disease (NAFLD) does not appropriately reflect current knowledge and metabolic-associated fatty liver disease (MAFLD) is supposed to be a more suitable overarching concept. However, the association of MAFLD with cardiovascular outcomes in patients with coronary artery disease has not been examined yet. Thus, this study aimed to assess the impact of MAFLD on major adverse cardiac events (MACEs) in patients with chronic coronary syndrome (CCS).Methods This study included 3306 patients with CCS who were diagnosed with MAFLD. Controls without MAFLD were matched (1:1) to cases by age and gender. All participants were followed up for the occurrence of MACEs. Finally, the association between MAFLD and the risk of MACEs was assessed.ResultsDuring an average of 55.09 ± 19.92 months follow-up, 376 and 248 MACEs were observed in MAFLD and control groups, respectively. When compared with controls, Kaplan–Meier analysis showed that patients with MAFLD had significantly lower event-free survival rate and multivariate Cox regression analysis further revealed that MAFLD group had significantly increased MACEs risk (both p < 0.05). Stratification analysis suggested that patients with MAFLD overlapped with NAFLD or MAFLD-only had 1.33-fold and 2.32-fold higher risk of MACEs respectively compared with controls (both p < 0.05).Conclusion This study firstly showed that MAFLD was significantly associated with the risk of MACEs in patients with CCS. Moreover, this relationship remained unchanged irrespective of whether satisfying the NAFLD criteria, providing novel evidence for the good utility of MAFLD criteria in clinical practice.Graphic abstract

Background The deeper understanding of the complex hereditary basis of familial hypercholesterolemia (FH) has raised the rationale of genetic testing, which has been underutilized in clinical practice. Objectives The present study aimed to explore the variant spectrum of FH in an expanding manner and compare its diagnostic performance. Methods A total of 169 Chinese individuals (124 index cases and 45 relatives) with clinical definite/probable FH were consecutively enrolled. Next-generation sequencing was performed for genetic analysis of 9 genes associated with hypercholesterolemia (major genes: LDLR, APOB, and PCSK9; minor genes: LDLRAP1, LIPA, STAP1, APOE, ABCG5, and ABCG8) including the evaluations of small-scale variants and large-scale copy number variants (CNVs). Results Among the 169 clinical FH patients included, 98 (58.0%) were men. A total of 85 (68.5%) index cases carried FH-associated variants. The proportion of FH caused by small-scale variants in LDLR, APOB, and PCSK9 genes was 62.1% and then increased by 6.5% when other genes and CNVs were further included. Furthermore, the variants in LDLR, APOB, and PCSK9 genes occupied 75% of all FH-associated variants. Of note, there were 8 non-LDLR CNVs detected in the present study. Conclusions LDLR, APOB, and PCSK9 genes should be tested in the initial genetic screening, although variants in minor genes also could explain phenotypic FH, suggesting that an expanding genetic testing may be considered to further explain phenotypic FH.

Background and aims: The association of triglyceride-rich lipoprotein-cholesterol (TRL-C) with recurrent cardiovascular events (RCVEs) has not been studied. Moreover, whether inflammation can affect TRL-C-associated cardiovascular risk is unknown. This study sought to examine the association between TRL-C and RCVEs, and whether this relationship is modulated by systemic inflammation in statin-treated patients with coronary artery disease (CAD) and nearly normal triglyceride. Methods: In this study, 6723 CAD patients were consecutively enrolled, following a first CVE with triglyceride <2.3 mmol/L. Baseline lipid profile and high-sensitivity C-reactive protein (hsCRP) levels were determined. All patients were searched for RCVEs. The risk of RCVEs was assessed across quartiles (Q) of baseline TRL-C and further stratified by the median of hsCRP. Results: Over a mean follow-up of 58.91 ± 17.79 months, 538 RCVEs were recorded. After adjustment for potential confounders, Q4 of TRL-C was significantly associated with the risk of RCVEs, which remained unchanged after hsCRP stratification. When subjects were grouped according to both TRL-C and hsCRP levels, patients with Q4 of TRL-C and hsCRP had the highest increase of the risk of RCVEs compared with the reference group (TRL-C Q1-3 and hsCRP Q1-3; HR, 1.90; 95%CI: 1.27-2.87). Furthermore, adding TRL-C to the original predicting model led to a slight but significant improvement. Conclusions: The present analysis firstly showed that elevated TRL-C was associated with an increased RCVEs risk in statin-treated patients with CAD independent of systemic inflammation, suggesting that it might be a useful marker for risk stratification and a treatment target in this patient population.

Although emerging data suggest that circulating lipoprotein (a) [Lp (a)] could predict cardiovascular events (CVEs) in patients with cardiovascular disease, no study is currently available regarding the prognostic linkage of Lp (a) and hypertension in patients with coronary artery disease (CAD). This study sought to evaluate the association of Lp (a), hypertension and cardiovascular outcomes in patients with stable CAD. A total of 8668 patients with stable CAD were consecutively enrolled. Baseline Lp (a) concentrations were measured. All subjects were categorized according to Lp (a) levels of <10 (low), 10–30 (medium) and ≥30 mg/dL (high) and were further stratified by hypertension status. They were regularly followed-up for the occurrence of cardiovascular death, nonfatal myocardial infarction, and stroke. Over an average of 54.81 ± 18.60 months of follow-up, 584 (6.7%) CVEs occurred. Kaplan–Meier and multivariate Cox regression analyses showed that elevated Lp (a) levels had a significant association with CVEs in hypertensive patients, regardless of the control status of blood pressure, but not in normotensive subjects. Moreover, when analyzed by subgroups according to both Lp (a) category and hypertension status, the risk of CVEs was only significantly elevated in the high Lp (a) plus hypertension group compared with the reference group with low Lp (a) levels and normotension (hazard ratio: 1.80, 95% confidence interval: 1.11–2.91). Elevated Lp (a) was associated with an increased risk of CVEs in stable CAD patients with hypertension. Moreover, the coexistence of high Lp (a) concentrations and hypertension greatly worsened the clinical prognosis in patients with CAD, which may suggest a prognostic correlation between Lp (a) and hypertension.

Background The prognostic value of N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with coronary artery disease (CAD) with different glucose status has not been established. This study sought to evaluate the significance of NT-proBNP in predicting major adverse cardiovascular events (MACEs) in patients with chronic coronary syndrome (CCS) and normal left-ventricular systolic function (LVSF) according to different glucose status, especially in those with abnormal glucose metabolism. Methods A total of 8062 patients with CCS and normal LVSF were consecutively enrolled in this prospective study. Baseline plasma NT-proBNP levels were measured. The follow-up data of all patients were collected. Kaplan-Meier and Cox regression analyses were used to assess the risk of MACEs according to NT-proBNP tertiles stratified by glucose status. Results Over an average follow-up of 59.13 ± 18.23 months, 569 patients (7.1 %) suffered from MACEs, including cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Kaplan-Meier analysis showed that high NT-proBNP levels had a significant association with MACEs in subjects with prediabetes mellitus (pre-DM) or DM, but not in patients with normoglycemia. Multivariate Cox regression analysis revealed that NT-proBNP remained an independent predictor of MACEs in patients with pre-DM [hazard ratio (HR): 2.56, 95% confidence interval (CI): 1.34–4.91] or DM (HR: 2.34, 95% CI: 1.32–4.16). Moreover, adding NT-proBNP to the original Cox model including traditional risk factors significantly increased the C-statistic by 0.035 in pre-DM and DM, respectively. Conclusions The present study indicated that NT-proBNP could well predict worse outcomes in dysglycemic patients with CCS and normal LVSF, suggesting that NT-proBNP may help with risk stratification in this population.