Fibrinogen is associated with glucose metabolism and cardiovascular outcomes in patients with coronary artery disease.

BACKGROUND: The present cohort study aims to examine the relationship between fibrinogen (Fib) levels and glucose metabolism [fasting blood glucose (FBG) and hemoglobin A1c (HbA1c)] and investigate the impact of high Fib on cardiovascular outcomes in patients with stable CAD and pre-diabetes mellitus (pre-DM) or diabetes mellitus (DM). METHODS: This study included 5237 patients from March 2011 to December 2015. Patients were distributed into three groups according to Fib levels (low Fib, median Fib, high Fib) and further categorized by glucose metabolism status [normal glucose regulation (NGR), Pre-DM, DM]. All patients were followed up for the occurrences of major adverse cardiovascular events (MACEs), including cardiovascular mortality, nonfatal MI, stroke, and unplanned coronary revascularization. RESULTS: Linear regression analyses showed that FBG and HbA1c levels were positively associated with Fib in overall CAD participants, either with or without DM (all P < 0.001). During an average of 18,820 patient-years of follow-up, 476 MACEs occurred. High Fib was independently associated with MACEs after adjusting for confounding factors [Hazard Ratio (HR): 1.57, 95% confidence interval (CI) 1.26-1.97, P < 0.001]. Furthermore, DM but not pre-DM was a significant predictor of MACEs (P < 0.001 and P > 0.05, respectively). When patients were stratified by both glucose metabolism status and Fib levels, high Fib was associated with a higher risk of MACEs in pre-DM (HR 1.66, 95% CI 1.02-2.71, P < 0.05). Medium and high Fib levels were associated with an even higher risk of MACEs in DM (HR 1.86, 95% CI 1.14-3.05 and HR 2.28, 95% CI 1.42-3.66, all P < 0.05). After adding the combination of Fib and glucose status to the Cox model, the C-statistic was increased by 0.015 (0.001-0.026). CONCLUSIONS: The present study suggested that Fib levels were associated with FBG and HbA1c in stable CAD patients. Moreover, elevated Fib was independently associated with MACEs in CAD patients, especially among those with pre-DM and DM, suggesting that Fib may provide incremental value in the cardiovascular risk stratification of pre-DM and DM patients.

A modified algorithm with lipoprotein(a) added for diagnosis of familial hypercholesterolemia.

BACKGROUND: Previous studies have observed that high level of lipoprotein (a) [Lp(a)] was common in the phenotypic familial hypercholesterolemia (FH) and may explain part of the clinical diagnosis of FH. HYPOTHESIS: We aim to develop a modified model including Lp(a) and compare its diagnostic performance with Dutch Lipid Clinic Network (DLCN) criteria. METHODS: Data of 10 449 individuals were utilized for the model establishment (7806 for derivation and 2643 for validation) from January 2011 to March 2018. The novel score model was modified on the basis of DLCN. Furthermore, 718 patients were screened for LDLR, APOB, and PCSK9 gene mutations. RESULTS: The novel modified model consisted of untreated low-density lipoprotein cholesterol (LDL-C) level, Lp(a), personal premature coronary heart disease (CHD), tendon xanthomas and family history of CHD and/or hypercholesterolemia. It has shown high discrimination (area under curve [AUC] 0.991, 95% confidence interval [CI[ 0.988-0.994, P < .001) for distinguishing clinical FH from non-FH diagnosed using DLCN. Furthermore, a concordance analysis was performed to compare the modified model with DLCN and it showed a good agreement with DLCN (κ = 0.765). External validation of the novel model also showed good accordance (κ = 0.700). Further genetic analysis showed that the agreements between the new model and mutation improved a little compared to that between DLCN and mutation. CONCLUSIONS: The novel modified model, including Lp(a), could provide new insights into FH diagnosis in Chinese population with more concerns on the patients with high level of Lp(a).

A Novel Modified System of Simplified Chinese Criteria for Familial Hypercholesterolemia (SCCFH).

BACKGROUND AND OBJECTIVE: The most significant clinical implication of familial hypercholesterolemia (FH) is early-onset coronary artery disease (CAD), highlighting the importance of a definitive diagnosis being available. Unfortunately, the existing algorithms are complex and it is often difficult to obtain information on the patient's family history. Hence, we aimed to establish a novel system of Simplified Chinese Criteria for FH (SCCFH). METHODS: We recruited 12,921 participants undergoing routine blood collection from November 2011 to June 2018. Clinical characteristics, laboratory examination, and genetic testing were obtained. FH was diagnosed based on the Simon Broome (SB) criteria, Dutch Lipid Clinic Network (DLCN) criteria, and SCCFH. The sensitivity, specificity, and agreement of SCCFH to these existing criteria were investigated. RESULTS: Of 12,921 participants reviewed, the prevalence of definite FH was 223 (1.73%), 202 (1.56%), and 205 (1.59%) based on the DLCN, SB, and SCCFH approaches, respectively. Compared with the DLCN and SB criteria, the SCCFH showed high sensitivity (91.9% and 100%), high specificity (100% and 99.9%), and good agreement (κ = 0.958 and 0.993). Similar results were found in several relevant clinical subgroups. CONCLUSIONS: The SCCFH system is comparable to the existing criteria with high levels of sensitivity and specificity, and is easier to use clinically. Further larger prospective studies are needed to evaluate the feasibility and reliability of this system.

High-sensitivity C-reactive protein and hypertension: combined effects on coronary severity and cardiovascular outcomes.

High-sensitivity C-reactive protein (hsCRP), a marker of inflammation, can promote atherosclerosis and predict cardiovascular events. However, no data are currently available about the combined effects of hsCRP and hypertension on cardiovascular risk. This study sought to elucidate this matter. A total of 7325 consecutive patients with angina-like chest pain undergoing coronary angiography were evaluated, and 4291 patients with stable, newly diagnosed coronary artery disease (CAD) were enrolled. They were subdivided into three groups according to baseline hsCRP levels (<1, 1-3, and >3 mg/L) and further stratified by hypertension status. The severity of CAD was assessed by the Gensini score and number of diseased vessels. All participants were followed for the occurrence of cardiovascular events. The coronary severity and cardiovascular outcomes were compared among these groups. We observed 530 (12.35%) incident cardiovascular events over 14,210 person-years. Elevated hsCRP was associated with more severe coronary lesions (p < 0.05) and an elevated but nonsignificant increased risk of cardiovascular events (p > 0.05). When hypertension was included as a stratifying factor, both patients with high hsCRP and normal blood pressure and hypertensive patients with any level of hsCRP had more severe coronary lesions compared with the reference group with low hsCRP and normotension. However, compared with the reference group, the cardiovascular event risk was only significantly elevated in patients with high hsCRP and hypertension (p < 0.05). The combination of elevated hsCRP and hypertension greatly increased the cardiovascular risk in patients with stable, newly diagnosed CAD, supporting that hsCRP could be treated as a marker for stratification in high-risk patients.

Lipoprotein(a) and Cardiovascular Outcomes in Patients With Coronary Artery Disease and Prediabetes or Diabetes.

OBJECTIVE: The aim of the current study is to determine the impact of elevated lipoprotein(a) [Lp(a)] on cardiovascular events (CVEs) in stable coronary artery disease (CAD) patients with different glucose metabolism status. RESEARCH DESIGN AND METHODS: In this multicenter study, we consecutively enrolled 5,143 patients from March 2011 to February 2015. Patients were categorized according to status of glucose metabolism (diabetes mellitus [DM], pre-diabetes mellitus [pre-DM], and normal glucose regulation [NGR]) levels and further classified into 12 groups by Lp(a) levels. CVE end points included nonfatal acute myocardial infarction (MI), stroke, and cardiovascular mortality. All subjects were followed up for the occurrence of the CVEs. RESULTS: During a median of 6.1 years' follow-up, 435 (8.5%) CVEs occurred. No significant difference in occurrence of CVEs was observed between NGR and pre-DM groups (hazard ratio 1.131 [95% CI 0.822-1.556], P > 0.05). When status of glucose metabolism was incorporated in stratifying factors, 30 ≤ Lp(a) < 50 mg/dL and Lp(a) ≥50 mg/dL were associated with significantly higher risk of subsequent CVEs in pre-DM (2.181 [1.099-4.327] and 2.668 [1.383-5.415], respectively; all P < 0.05) and DM (3.088 [1.535-5.895] and 3.470 [1.801-6.686], all P < 0.05). Moreover, adding Lp(a) to the Cox model increased the C-statistic by 0.022 and 0.029 in pre-DM and DM, respectively, while the C-statistic was not statistically improved when Lp(a) was included for CVEs prediction in NGR. CONCLUSIONS: Our findings, for the first time, indicated that elevated Lp(a) levels might affect the prognosis in patients with pre-DM with stable CAD, suggesting that Lp(a) may help further stratify stable CAD patients with mild impaired glucose metabolism.

Impact of Non-Alcoholic Fatty Liver Disease on Cardiovascular Outcomes in Patients With Stable Coronary Artery Disease: A Matched Case-Control Study.

INTRODUCTION: Whether non-alcoholic fatty liver disease (NAFLD) is associated with cardiovascular risk has still been controversial. The reasons for this disparity may be associated with subject selection, events definition, diagnostic criteria of NAFLD, or research methods. The aim of this study was to determine the relationship of NAFLD to cardiovascular disease (CVD) outcomes in patients with stable, new-onset coronary artery disease (CAD). METHODS: A matched case-control study based on the cohort with stable, new-onset CAD was implemented in 162 cases (patients who developed all-cause death, non-fatal myocardial infarction and stroke during an average of 11,484 patient-years of follow-up) and 162 controls without cardiovascular events matched with the same sex, the age difference ≤3 years old, and the admission date within 3 months. Abdominal ultrasonography and coronary angiography were performed at admission. COX proportional hazard models and conditional logistic regression analysis were used to assess the effect of NAFLD on CVD outcomes. RESULTS: NAFLD was more common in the event group than in the control group (P = 0.012). Kaplan-Meier analysis showed a significant association between NAFLD and CVD outcomes (P = 0.007). Moreover, Cox regression (hazard ratios 1.56; 95% confidence interval, 1.04-2.34, P = 0.031) and conditional logistic regression (odds ratio 2.72, 95% confidence interval, 1.16-6.39, P = 0.022) analyses further demonstrated that NAFLD was an independent risk factor for CVD outcomes. CONCLUSIONS: NAFLD is indeed an independent predictor of CVD outcomes in patients with stable, new-onset CAD. Further randomized controlled trials may be needed to confirm our findings.

Severe aortic valve stenosis in a 14-year-old boy with sitosterolemia.

We report a 14-year-old boy finally diagnosed with sitosterolemia, presenting with severe aortic valve stenosis. Genetic analysis revealed homozygous null mutation c.1336 C > T (p.R446X) in ABCG5 gene. His cardiac ultrasound presented aortic valve stenosis and moderate aortic regurgitation. His whole aorta computed tomography angiogram scan revealed aortic stenosis superior to the aortic valve, followed by ascending aorta dilation, whereas his coronary and peripheral arteries appeared normal. His maximum total cholesterol and low-density lipoprotein-cholesterol levels dropped dramatically after diet control, and ezetimibe was prescribed for treatment. The current case indicated that sitosterolemia may be a heterogeneous disease in clinical phenotype.

Application of expanded genetic analysis in the diagnosis of familial hypercholesterolemia in patients with very early-onset coronary artery disease.

BACKGROUND: Patients with monogenic familial hypercholesterolemia (FH) have high risk for coronary artery disease (CAD). A recent FH Expert Panel suggested that FH was underdiagnosed and undertreated which needs early diagnosis. Moreover, the proportion of DNA-confirmed FH patients hospitalized with very early-onset (≤ 35 years) CAD remains uncertain. METHODS: One hundred and five patients with age ≤ 35 years and LDL-C ≥ 3.4 mmol/L were tested for 9 genes (LDLR, APOB, PCSK9, APOE, STAP1, LIPA, LDLRAP1, ABCG5/8). Dutch Lipid Clinic Network (DLCN) and Simon Broome (SB) criteria for FH were also performed. RESULTS: The prevalence of genetically confirmed FH was 38.1% (n = 40) in 105 patients. DLCN categorized 26.7% patients to probable and definite FH while SB identified 17.1% of patients with possible to definite FH. Twenty-five (62.5%) and seventeen (42.5%) patients with pathogenic mutations were undiagnosed according to SB and DLCN criteria. FH variant carriers, especially homozygotes, had significantly higher plasma LDL-C levels. The best LDL-C threshold for genetically confirmed FH was 4.56 mmol/L in the present study. CONCLUSIONS: FH is really a common cause for very young CAD patients (≤ 35 years) with a 38.1% of causative mutations in China and best LDL-C threshold for predicting mutations was 4.56 mmol/L. The underdiagnostic rate of clinical criteria was around 42.5-62.5%, suggesting that the expanded genetic testing could indeed promote the diagnosis of FH.

Intensive genetic analysis for Chinese patients with very high triglyceride levels: Relations of mutations to triglyceride levels and acute pancreatitis.

BACKGROUND: Severe hypertriglyceridemia (SHTG, TG ≥5·65 mmol/L), a disease, usually resulting from a combination of genetic and environmental factors, may increase the risk of acute pancreatitis (AP). However, previous genetic analysis has been limited by lacking of related observation of gene to AP. METHODS: The expanding genetic sequencing including 15 TG-related genes (LPL, LMF1, APOC2, GPIHBP1, GCKR, ANGPTL3, APOB, APOA1-A4-C3-A5, TRIB1, CETP, APOE, and LIPI) was performed within 103 patients who were diagnosed with primary SHTG and 46 age- and sex-matched normal controls. FINDINGS: Rare variants were found in 46 patients and 12 controls. The detection rate of rare variants in SHTG group increased by 19·5% via intensive genetic analysis. Presence of rare variants in LPL, APOA5, five LPL molecular regulating genes and all the sequenced genes were found to be associated with SHTG (p < 0·05). Of noted, patients with history of AP presented higher frequency of rare variants in LPL gene and all the LPL molecular regulating genes (27·8% vs.4·7% and 50·0% vs. 20·0%). The risk scores for SHTG determined by common TG-associated variants were increased in subgroups according to the extent of SHTG when they were compared with that of controls. Finally, patients without rare variants within SHTG group also presented higher risk scores than control group (p < 0·05). INTERPRETATION: Expanding genetic analysis had a higher detection rate of rare variants in patients with SHTG. Rare variants in LPL and its molecular regulating genes could increase the risk of AP among Chinese patients with SHTG. FUND: This work was partially supported by the Capital Health Development Fund (201614035) and CAMS. Major Collaborative Innovation Project (2016-I2M-1-011) awarded to Dr. Jian-Jun Li, MD, PhD.

Triglyceride glucose and haemoglobin glycation index for predicting outcomes in diabetes patients with new-onset, stable coronary artery disease: a nested case-control study.

AIM: Previous studies have shown that both triglyceride glucose (TyG) and haemoglobin glycation indexes (HGI) are predictors of cardiovascular risk. However, the prognostic value of TyG index and HGI in patients with type 2 diabetes mellitus (T2DM) and stable coronary artery disease (CAD) is not determined. METHODS: We conducted a nested case-control study among 1282 T2DM patients with stable CAD. Patients were followed up for 3846 person-years. A total of 160 patients with events (12.5%) were identified and matched individually on age, gender, previous use of lipid lowering agents and duration of follow-up with 640 controls. RESULTS: In Kaplan-Meier analysis, the upper tertiles of TyG index and HGI had a significant lower event-free survival (p = .002; p = .036, respectively). Of the note, both TyG index and HGI were associated with increased risk of MACCEs after adjusting for confounding risk factors [adjusted HR (95% CI): 1.693 (1.238-2.316); 1.215 (1.046-1.411), respectively]. Moreover, adding TyG index to the Cox model increased the C-statistic to 0.638 (95%CI: 0.595-0.683, p = .002) while the C-statistic was not statistically improved when HGI was included (p = .240). CONCLUSIONS: Both TyG index and HGI could predict cardiovascular outcomes in T2DM patients with new-onset, stable CAD while TyG index might be better. Key messages Both TyG and HGI are predictors of cardiovascular risk. The prognostic value of TyG index and HGI in T2DM patients with stable coronary artery disease is not determined. Our study firstly indicates that TyG index might have better prognostic value than HGI in T2DM patients with new-onset, stable CAD.

Impacts of Prediabetes Mellitus Alone or Plus Hypertension on the Coronary Severity and Cardiovascular Outcomes.

Whether prediabetes mellitus (Pre-DM) alone or combined with hypertension is an independent risk factor for cardiovascular disease has not been fully clarified. This study aimed to further confirm whether the relation of Pre-DM to cardiovascular disease differs between individuals with or without hypertension. A total of 7121 consecutive patients with angina-like chest pain who received coronary angiography were evaluated and 4193 patients with angiography-proven stable, new-onset coronary artery disease were enrolled into the study. They were divided into 3 groups according to diabetes mellitus status and further stratified by hypertension. The severity of coronary artery disease was assessed by number of diseased vessels and Gensini score. All subjects were regularly followed up for the occurrence of the composite end points. Comparisons of coronary artery disease severity and outcomes were performed among these groups. During an average of 11 338 patient-years of follow-up, 434 (10.35%) cardiovascular events occurred. No significant difference was observed in coronary severity and composite end point events between Pre-DM and normal glucose regulation groups (both P>0.05). However, when hypertension was also incorporated as a stratifying factor, cardiovascular disease risk, assessed by coronary severity and clinical prognosis, was significantly elevated in Pre-DM plus hypertension and diabetes mellitus plus hypertension groups, compared with the reference group with normal glucose regulation and normal blood pressure (all P<0.05). The present study indicated that among patients with stable, new-onset coronary artery disease, the increased cardiovascular risk with Pre-DM is largely driven by the coexistence of hypertension rather than Pre-DM per se.

Impact of glucose and lipid markers on the correlation of calculated and enzymatic measured low-density lipoprotein cholesterol in diabetic patients with coronary artery disease.

BACKGROUND AND AIMS: Low-density lipoprotein cholesterol (LDL-C) is widely estimated by Friedewald equation (FE) and Enzymatic test (ET), which are affected by several factors. The aim of this study was to observe the impact of diabetic lipid and glucose patterns on the correlation between FE LDL-C (F-LDL) and ET LDL-C (E-LDL) in patients with coronary artery disease (CAD). METHODS AND RESULTS: A total of 8155 CAD patients were consecutively enrolled and their lipid profiles were measured. The impacts of triglyceride (TG), glycosylated hemoglobin A1c (HbA1c), and high-density lipoprotein cholesterol (HDL-C) on the correlation of F-LDL and E-LDL were examined. The difference value (DV) between F-LDL and E-LDL was compared using ANOVA test. The CAD patients with DM were elder and had higher body mass index, plasma TG compared with those without DM (P < .05 separately). In the whole population, F-LDL was lower than E-LDL but showed a high correlation with E-LDL (r = .970, P = .000). Moreover, as the TG concentrations increased, the DV increased accordingly but the correlation between F-LDL and E-LDL decreased (P < .01). The similar trend was also found in both DM and non-DM patients comparing with different TG groups. However, in patients with DM, there was no significant difference of DV in different HbA1c groups or HDL-C concentrations (P > .05). CONCLUSION: Although F-LDL might underestimate the value of LDL-C, the correlation between F-LDL and E-LDL was clinically acceptable (r = .97), suggesting the LDL-C values measured by two methods were similarly reliable in CAD patients with or without DM.

Effect of proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies on new-onset diabetes mellitus and glucose metabolism: A systematic review and meta-analysis.

AIMS: To investigate the effect of two clinically applied proprotein convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9-mAbs) on glycaemia and new-onset diabetes mellitus (NODM). MATERIALS AND METHODS: PubMed, MEDLINE, Embase, Cochrane databases and ClinicalTrials.gov websites were systematically searched for randomized controlled trials that reported data on fasting plasma glucose (FPG), glycated haemoglobin (HbA1c) or NODM incidence. Risk ratios (RRs) for NODM and mean difference (MD) for FPG and HbA1c with 95% confidence intervals (CIs) were calculated using a fixed-effect model. Heterogeneity was examined using the I2 statistic and potential publication bias was assessed using funnel plots and Egger's test. RESULTS: A total of 18 studies including 26 123 participants without diabetes were identified. No significant difference was observed in the PCSK9-mAb treatment groups in terms of NODM (RR 1.05, 95% CI 0.95-1.16), FPG (MD 0.00 mmol/L, 95% CI -0.02 to 0.02) or HbA1c (MD 0.00% [0 mmol/L], 95% CI -0.01 to 0.01) compared with control groups. Subgroup (PCSK9-mAb type, participant characteristics, treatment duration, treatment method and differences in control treatment) and sensitivity analyses did not significantly alter the results. Meta-regression analyses showed that risk of NODM was not associated with baseline age, baseline body mass index (BMI), proportion of men, treatment duration or percent LDL cholesterol reduction. CONCLUSIONS: Alirocumab and evolocumab, two types of PCSK9-mAb approved by the US Food and Drug Administration and the European Medicines Agency, had no significant impact on NODM and glucose homeostasis, regardless of PCSK9-mAb type, participant characteristics, treatment duration, treatment method and differences in control treatment. Baseline age, BMI, proportion of men, treatment duration, and percent change of LDL cholesterol did not influence diabetes risk.

Triglyceride glucose index for predicting cardiovascular outcomes in patients with coronary artery disease.

BACKGROUND: Triglyceride glucose (TyG) index is a novel marker for metabolic disorders and recently it has been reported to be associated with cardiovascular disease (CVD) risk in apparently healthy individuals. However, the prognostic value of TyG index in patients with stable coronary artery disease (CAD) is not determined. METHODS: We conducted a nested case-control study among 3,745 patients with stable CAD. Patients were followed up for 11,235 person-years. The cardiovascular events (CVEs) were defined as all-cause death, non-fatal myocardial infarction (MI), stroke and post-discharge revascularization [percutaneous coronary intervention (PCI) coronary artery bypass grafting (CABG)]. In total, 290 (7.7%) patients with CVEs and 1,450 controls were matched according to age, gender, previous history of PCI or CABG and the duration of follow-up. TyG index was calculated as formula: ln[fasting triglycerides (mg/dL) × fasting plasma glucose (mg/dL)/2]. RESULTS: Multivariable Cox proportional hazards models revealed that TyG index was positively associated with CVEs risk (hazard ratio: 1.364, 95% confidence interval: 1.100-1.691, P=0.005). The Kaplan-Meier analysis indicated that patients within the highest quartile of TyG index presented the lowest event-free survival (P=0.029). Moreover, a 1-standard deviation (SD) increment in TyG index was associated with 23.2% [hazard ratio (HR): 1.232, 95% confidence interval (95% CI): 1.084-1.401] higher risk of CVEs, which was superior to other triglyceride or glycemic related markers. CONCLUSIONS: The present study, firstly, showed that TyG index was positively associated with future CVEs, suggesting that TyG may be a useful marker for predicting clinical outcomes in patients with CAD.

Quantitative Proteomics Analysis of Ischemia/Reperfusion Injury-Modulated Proteins in Cardiac Microvascular Endothelial Cells and the Protective Role of Tongxinluo.

BACKGROUND: The protection of endothelial cells (ECs) against reperfusion injury has received little attention. In this study, we used Tandem Mass Tag (TMT) labeling proteomics to investigate the modulated proteins in an in vitro model of cardiac microvascular endothelial cells (CMECs) subjected to ischemia/reperfusion (I/R) injury and their alteration by traditional Chinese medicine Tongxinluo (TXL). METHODS: Human CMECs were subjected to 2 h of hypoxia followed by 2 h of reoxygenation with different concentrations of TXL Protein expression profiles of CMECs were determined using tandem mass spectrometry. We evaluated several proteins with altered expression in I/R injury and summarized some reported proteins related to I/R injury. RESULTS: TXL dose-dependently decreased CMEC apoptosis, and the optimal concentration was 800 µg/mL. I/R significantly altered proteins in CMECs, and 30 different proteins were detected between a normal group and a hypoxia and serum deprivation group. In I/R injury, TXL treatment up-regulated 6 types of proteins including acyl-coenzyme A synthetase ACSM2B mitochondrial (ACSM2B), cyclin-dependent kinase inhibitor 1B (CDKN1B), heme oxygenase 1 (HMOX1), transcription factor SOX-17 (SOX17), sequestosome-1 isoform 1 (SQSTM1), and TBC1 domain family member 10B (TBC1D10B). Also, TXL down-regulated 5 proteins including angiopoietin-2 isoform c precursor (ANGPT2), cytochrome c oxidase assembly factor 5 (COA5), connective tissue growth factor precursor (CTGF), cathepsin L1 isoform 2 (CTSL), and eukaryotic elongation factor 2 kinase (LOC101930123). These types of proteins mainly had vital functions, including cell proliferation, stress response, and regulation of metabolic process. CONCLUSIONS: The study presented differential proteins upon I/R injury through a proteomic analysis. TXL modulated the expression of proteins in CMECs and has a protective role in response to I/R.

AMPK-mediated cardioprotection of atorvastatin relates to the reduction of apoptosis and activation of autophagy in infarcted rat hearts.

Atorvastatin (ATV) has an important pro-survival role in cardiomyocytes after acute myocardial infarction (AMI). The objectives of this study were to: 1) determine whether ATV could affect autophagy of cardiomyocytes via the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway, and 2) investigate the balance between autophagy and apoptosis pathways. Male Wistar rats (n = 100) were randomly divided into sham, control, ATV, Compound C, and ATV+ Compound C groups. In this AMI model, drug treatments were administered for 1 week before induction of MI by surgical ligation, and measurements were taken 1 and 4 weeks after AMI induction. Transthoracic echocardiography showed that the ejection fraction in the ATV group increased by 11.7% ± 6.83% over the control group 4 weeks after AMI. The fibrosis, infarcted area, and inflammatory level were determined by pathological and histological studies; these were found to be decreased substantially with ATV treatment (P<0.05). The expression of apoptotic, autophagic, and AMPK pathway proteins was detected by immunohistochemical staining and western blotting, while expression of their corresponding genes was measured with real-time polymerase chain reaction (PCR). ATV treatment increased AMPK/mTOR activity and the expression of autophagic protein LC3 in infarcted myocardium (P<0.05). The treatment also inhibited induction of pro-apoptotic protein Bax. AMPK inhibitor Compound C reversed these beneficial effects. In conclusion, ATV improves survival of cardiomyocytes and decreases alterations in morphology and function of infarcted hearts by inducing autophagy and inhibiting apoptosis through the activation of AMPK/mTOR pathway.

Costs and Benefits Associated With Transradial Versus Transfemoral Percutaneous Coronary Intervention in China.

BACKGROUND: Transradial percutaneous coronary intervention (PCI) has been increasingly adopted in clinical practice, given its potential advantages over transfemoral intervention; however, the impact of different access strategies on costs and clinical outcomes remains poorly defined, especially in the developing world. METHODS AND RESULTS: Using data from a consecutive cohort of 5306 patients undergoing PCI in China in 2010, we compared total hospital costs and in-hospital outcomes for transradial intervention (TRI) and transfemoral intervention. Patients receiving TRI (n=4696, 88.5%) were slightly younger (mean age 57.4 versus 59.5 years), less often women (21.6% versus 33.1%), more likely to undergo PCI for single-vessel disease, and less likely to undergo PCI for triple-vessel or left main diseases. The unadjusted total hospital costs were 57 900 Chinese yuan (¥57 900; equivalent to 9190 US dollars [$9190]) for TRI and ¥67 418 ($10,701) for transfemoral intervention. After adjusting for all observed patient and procedural characteristics using the propensity score inverse probability weighting method, TRI was associated with a lower total cost (adjusted difference ¥8081 [$1283]). More than 80% of the cost difference was related to lower PCI-related costs (adjusted difference -¥5162 [-$819]), which were likely driven by exclusive use of vascular closure devices in transfemoral intervention, and lower hospitalization costs (-¥1399 [-$222]). Patients receiving TRI had shorter length of stay and were less likely to experience major adverse cardiac events or post-PCI bleeding. These differences were consistent among clinically relevant subgroups with acute myocardial infarction, acute coronary syndrome, and stable angina. CONCLUSIONS: Among patients undergoing PCI, TRI was associated with lower cost and favorable clinical outcomes compared with transfemoral intervention.

Intravenous administration of atorvastatin-pretreated mesenchymal stem cells improves cardiac performance after acute myocardial infarction: role of CXCR4.

BACKGROUND: The interaction between stromal cell-derived factor 1 (SDF-1) and its receptor CXC chemokine receptor 4 (CXCR4) plays an important role in mesenchymal stem cells (MSCs) migration and engraftment. Statins can increase the survival of MSCs. However, whether statins could enhance MSCs migration and engraftment is still unknown. Therefore, we designed the study to investigate whether atorvastatin (ATV) could enhance CXCR4 expression of MSCs and promote them homing toward the injured myocardium. METHODS AND RESULTS: Expression of CXCR4 was evaluated by flow cytometry and real time PCR. A transwell system was used to assess MSCs migration ability. Recruitment of systematically delivered MSCs to the infarcted heart was evaluated in Sprague-Dawley rats with acute myocardial infarction (AMI). ATV pretreatment enhanced the expression of CXCR4 and stimulated MSCs migration in vitro. However, the effect was largely abolished by CXCR4 neutralizing antibody. In AMI models, we found much more ATV-pretreated MSCs homing toward the infarcted myocardium than non-treated cells and this was accompanied by improved cardiac performance. CONCLUSIONS: ATV increases the migration ability of MSCs and improves cardiac performance due to up-regulated expression of CXCR4. These results suggest that ATV pretreatment of donor MSCs is an effective way to promote cell therapeutic potential for AMI.

Atorvastatin treatment improves the effects of mesenchymal stem cell transplantation on acute myocardial infarction: the role of the RhoA/ROCK/ERK pathway.

BACKGROUND: Statins protect mesenchymal stem cells (MSCs) against the harsh microenvironment and improve the efficacy of MSC transplantation after acute myocardial infarction (AMI); however, the mechanism remains uncertain. Furthermore, the transdifferentiation potential of MSCs in the post-infarct heart remains highly controversial. The RhoA/Rho-associated coiled-coil-forming kinase (ROCK) pathway participates in many aspects of the damaged heart after AMI and related to the "pleiotropic" effects of statins. This study aimed to explore whether atorvastatin (ATV) facilitates the survival and therapeutic efficacy of MSCs via the inhibition of RhoA/ROCK pathway and subsequently its downstream molecular extracellular regulated protein kinase (ERK1/2), and to investigate the transdifferentiation potential of MSCs in vivo. METHODS AND RESULTS: Female rats received myocardial injections of male rat MSCs 30 min after AMI. Four weeks after AMI, ATV combined with MSC treatment resulted in improved cardiac function and reduced infarct area. ATV facilitated the MSC survival, as revealed by the increased expression of Y chromosomal genes and the increased number of Y chromosome-positive cells; however, no transdifferentiation markers were observed. ATV inhibited the production of inflammatory cytokines both in vitro and vivo, accompanied by suppression of ROCK and ERK activities. Geranylgeranyl pyrophosphate (GGPP) abrogated the effects of ATV in the H9c2 cells under hypoxia/serum deprivation (H/SD), while the ROCK inhibitor fasudil mimicked the benefits of ATV after AMI. CONCLUSIONS: ATV improves the post-infarct microenvironment via RhoA/ROCK/ERK inhibition and thus facilitates the survival and efficacy of implanted MSCs. Transdifferentiation may be not responsible for the cardiac benefits that follow MSC transplantation.