Lei Gao

Comparative performance of warfarin pharmacogenetic algorithms in Chinese patients

INTRODUCTIONnMultiple warfarin pharmacogenetic algorithms have been confirmed to predict warfarin dose more accurately than clinical algorithm or the fixed-dose approach. However, their performance has never been objectively evaluated in patients under low intensity warfarin anticoagulation, which is optimal for prevention of thromboembolism in Asian patients.nnnMATERIAL AND METHODSnWe sought to compare the performances of 8 eligible pharmacogenetic algorithms in a cohort of Chinese patients (n=282) under low intensity warfarin anticoagulation with target international normalized ratio (INR) ranged from 1.6 to 2.5. The performance of each algorithm was evaluated by calculating the percentage of patients whose predicted dose fell within 20% of their actual therapeutic dose (percentage within 20%), and the mean absolute error (MAE) between each predicted dose and actual stable dose.nnnRESULTSnIn the entire cohort, the pharmacogenetic algorithms could predict warfarin dose with the average MAE of 0.87 ± 0.17 mg/day (0.73-1.17 mg/day), and the average percentage within 20% of 43.8% ± 8.1% (29.1% - 52.1%). By pairwise comparison, warfarin dose prediction was significantly more accurate with the algorithms derived from Asian patients (48.6% - 50.0%) than those from Caucasian patients (29.1% - 39.7%; odds ratio [OR]: 1.61-3.36, p ≤ 0.02). Algorithms with additional covariates of INR values or CYP4F2*3 performed better than those without the covariates (adding INR: OR: 1.71 (1.08-2.72), p =0.029; adding CYP4F2*3: OR: 2.67(1.41-5.05), p =0.004). When the patients were stratified according to the dose range, the algorithms from Caucasian and racially mixed populations tended to perform better in higher dose group (≥ 4.5mg/day), and algorithms from Asian populations performed better in intermediate dose group (1.5-4.5mg/day). None of the algorithms performed well in lower dose group (≤ 1.5mg/day).nnnCONCLUSIONSnNo eligible pharmacogenetic algorithm could perform the best for all dosing range in the Chinese patients under low intensity warfarin anticoagulation. Construction of a refinement pharmacogenetic algorithm integrating 3 genotypes (CYP2C9, VKORC1 and CYP4F2) and INR data should be warranted to improve the warfarin dose prediction in such patients.

Influence of warfarin dose-associated genotypes on the risk of hemorrhagic complications in Chinese patients on warfarin

This study was designed to evaluate the effect of the warfarin dose-associated genotypes, CYP2C9*3 (rs1057910), VKORC1 −1639 G/A (rs9923231), and CYP4F2 1347 C/T (rs2108622), on hemorrhagic complications in Han Chinese patients. Consecutively recruited patients requiring more than 1xa0year of warfarin treatment were followed from the initiation of warfarin anticoagulation for at least 3xa0months. CYP2C9*3, VKORC1 −1639 G/A, and CYP4F2 1347 C/T were genotyped by sequencing. The association between genotypes and warfarin hemorrhagic complications was evaluated using Cox proportional hazard regression, adjusted for demographic and clinical factors. Of 312 eligible patients obtaining stable warfarin anticoagulation in 3xa0months, 11 major and 69 minor hemorrhages occurred over 147 person-years. The CYP2C9*3 genotype conferred an increased risk of all [hazard ratio (HR) 3.07, 95xa0% confidence interval (CI) 1.57–6.01] and minor hemorrhage (HR 3.28, 95xa0% CI 1.62–6.65), but not major hemorrhage (HR 0.44, 95xa0% CI 0.04–4.72). CYP2C9*3 also conferred an increased risk of over-anticoagulation with international normalization ratio (INR) ≥4 (HR 2.92, 95xa0% CI 1.08–7.85). VKORC1 −1639 G/A, and CYP4F2 rs2108622 did not confer significant increase in risk for hemorrhage or over-anticoagulation. Kaplan–Meier curves showed that time to all hemorrhagic events was significantly shorter for patients with CYP2C9*3 genotype than non-carriers (Pxa0=xa00.001), but not for patients with VKORC1 −1639 G/A or CYP4F2 rs2108622 genotype (Pxa0=xa00.3 and 0.2). CYP2C9*3 may be the main genetic factor in hemorrhagic complications in Chinese patients under warfarin anticoagulation.

Cutting-balloon angioplasty before drug-eluting stent implantation for the treatment of severely calcified coronary lesions.

Background Severely calcified coronary lesions respond poorly to balloon angioplasty, resulting in incomplete and asymmetrical stent expansion. Therefore, adequate plaque modification prior to drug-eluting stent (DES) implantation is the key for calcified lesion treatment. This study was to evaluate the safety and efficacy of cutting balloon angioplasty for severely calcified coronary lesions. Methods Ninety-two consecutive patients with severely calcified lesions (defined as calcium arc ≥ 180° calcium length ratio ≥ 0.5) treated with balloon dilatation before DES implantation were randomly divided into two groups based on the balloon type: 45 patients in the conventional balloon angioplasty (BA) group and 47 patients in the cutting balloon angioplasty (CB) group. Seven cases in BA group did not satisfactorily achieve dilatation and were transferred into the CB group. Intravascular ultrasound (IVUS) was performed before balloon dilatation and after stent implantation to obtain qualitative and quantitative lesion characteristics and evaluate the stent, including minimum lumen cross-sectional area (CSA), calcified arc and length, minimum stent CSA, stent apposition, stent symmetry, stent expansion, vessel dissection, and branch vessel jail. In-hospital, 1-month, and 6-month major adverse cardiac events (MACE) were reported. Results There were no statistical differences in clinical characteristics between the two groups, including calcium arc (222.2° ± 22.2° vs. 235.0° ± 22.1°, P = 0.570), calcium length ratio (0.67 ± 0.06 vs. 0.77 ± 0.05, P = 0.130), and minimum lumen CSA before PCI (2.59 ± 0.08 mm2 vs. 2.52 ± 0.08 mm2, P = 0.550). After stent implantation, the final minimum stent CSA (6.26 ± 0.40 mm2 vs. 5.03 ± 0.33 mm2; P = 0.031) and acute lumen gain (3.74 ± 0.38 mm2 vs. 2.44 ± 0.29 mm2, P = 0.015) were significantly larger in the CB group than that of the BA group. There were not statistically differences in stent expansion, stent symmetry, incomplete stent apposition, vessel dissection and branch vessel jail between two groups. The 30-day and 6-month MACE rates were also not different. Conclusions Cutting balloon angioplasty before DES implantation in severely calcified lesions appears to be more efficacies including significantly larger final stent CSA and larger acute lumen gain, without increasing complications during operations and the MACE rate in 6-month.

Efficacy and safety of limus-eluting versus paclitaxel-eluting coronary artery stents in patients with diabetes mellitus: A meta-analysis

BACKGROUND/OBJECTIVESnThe relative efficacy and safety of limus-eluting stent (LES) versus paclitaxel-eluting stent (PES) in DM patients remain unclear.nnnMETHODSnThe PubMed, EMBASE, and Cochrane Central Register of Controlled Trials electronic databases were searched from January 2001 to December 2013. Clinical trials that performed head-to-head comparisons of LES versus PES implantation in patients with DM were considered for inclusion.nnnRESULTSnThis meta-analysis included 28 clinical trials involving 23,678 patients: 9953 who underwent sirolimus-eluting stent (SES) implantation, 4209 underwent everolimus-eluting stent (EES) or zotarolimus-eluting stent (ZES) implantation, and 9516 underwent PES implantation. The short-term target lesion revascularization (TLR) rate was significantly lower after SES implantation than after PES implantation (3.6% vs 6.3%; odds ratio (OR): 0.659; P=0.014), but there were no significant differences in the rates of target vessel revascularization (TVR), stent thrombosis (ST), myocardial infarction (MI), all-cause mortality, or major adverse cardiac events (MACE). There were no differences in the longer-term rates of TLR, TVR, ST, MI, all-cause mortality, or MACE between SES versus PES. Second-generation LES (EES or ZES) implantation resulted in lower rates of ST (2.1% vs 3.3%; OR: 0.586; P<0.001), MI (2.3% vs 4.1%; OR: 0.527; P=0.001), and MACE (8.0% vs 10.3%; OR: 0.796; P=0.007) than PES implantation.nnnCONCLUSIONSnIn patients with DM, short- and longer-term MACE rates were similar after first-generation LES and PES implantation. The second-generation LES may be better than PES implantation in rates of ST, MI, and MACE.

Percutaneous coronary intervention in the elderly with ST-segment elevation myocardial infarction

As a result of increased life expectancy, octogenarians constitute an increasing proportion of patients admitted to hospital for ST-segment elevation myocardial infarction (STEMI). Primary percutaneous coronary intervention is currently the treatment of choice for octogenarians presenting with STEMI. The recent literature on this topic has yielded controversial results, even though advances in drug-eluting stents and new types of antithrombotic agents are improving the management of STEMI and postoperative care. In this paper, we review the current status of percutaneous coronary intervention in the elderly with STEMI, including the reasons for their high mortality and morbidity, predictors of mortality, and strategies to improve outcomes.

Impact of renal dysfunction on long-term outcomes of elderly patients with acute coronary syndrome: a longitudinal, prospective observational study

BackgroundThis study investigated the impact of renal dysfunction (RD) on long-term outcomes in elderly patients with acute coronary syndrome (ACS), and evaluated prognostic factors in elderly patients with ACS and RD.MethodsThis longitudinal prospective study included 184 consecutive patients who were admitted with ACS between January 2009 and January 2010 and also had RD. Patients were divided into five groups according to their estimated glomerular filtration rate (eGFR): 1) eGFRu2009≥u200990xa0mL/min/1.73xa0m2 with evidence of kidney damage, 2) 60u2009≤u2009eGFRu2009<u200990xa0mL/min/1.73xa0m2, 3) 30u2009≤u2009eGFRu2009<u200960xa0mL/min/1.73xa0m2, 4) 15u2009≤u2009eGFRu2009<u200930xa0mL/min/1.73xa0m2, and 5) eGFRu2009<u200915xa0mL/min/1.73xa0m2. The primary endpoints were death and complications during hospitalization. The secondary endpoint was any major adverse cardiac event (MACE) during follow-up.ResultsThe mean follow-up period was 502.2u2009±u2009203.6xa0days. The mean patient age was 73.7u2009±u20099.4xa0years, and 61.4% of the patients were men. Severe RD (eGFRu2009<u200930xa0mL/min/1.73xa0m2) was an independent predictor of MACE. Severe RD was associated with a low hemoglobin level, low left ventricular ejection fraction, and high levels of high-sensitivity C-reactive protein, N-terminal pro-B-type natriuretic peptide, and cystatin C. Survival was significantly poorer in patients with severe RD than in patients with mild RD.ConclusionsAmong patients with ACS, severe RD was associated with advanced age, diabetes, hypertension, and cardiac dysfunction. Severe RD was an independent risk factor for MACE, and was associated with poor prognosis.

The Coexistence of Multiple Cardiovascular Diseases is an Independent Predictor of the 30‐Day Mortality of Hospitalized Patients With Congestive Heart Failure: A Study in Beijing

Congestive heart failure (CHF) has become a major clinical and public health challenge with the aging of the population in China. However, the effect of the coexistence of multiple cardiovascular diseases on the prognosis of hospitalized patients with CHF remains unclear. A comparative analysis was performed to explore the etiology and comorbidities of CHF and in‐hospital mortality in patients with CHF.

Voltage-dependent anion channel involved in the mitochondrial calcium cycle of cell lines carrying the mitochondrial DNA A4263G mutation

In this study, we investigated the effects of the voltage-dependent anion channel (VDAC) on the mitochondrial calcium cycle in cell lines carrying the mitochondrial DNA A4263G mutation. We established lymphoblastoid cell lines from three symptomatic individuals and one asymptomatic individual from the large Chinese Han family carrying the A4263G mutation; these were compared with three control cell lines. The mitochondrial Ca(2+) concentration and membrane potential were detected by loading cells with Rhod-2 and JC-1, respectively. Confocal images showed the average Rhod-2 and JC-1 fluorescence levels of individuals carrying the tRNA(Ile) A4263G mutation were lower than those of the control group (P<0.05). The baseline Rhod-2 fluorescence in the control group increased after exposure to atractyloside (an opener of the adenine nucleotide translocator, P<0.05), but no significant change was detected in the cell line harboring the A4263G mutation (P>0.05). The baseline JC-1 fluorescence in both the mutated and control cell lines decreased after subsequent exposure to atractyloside (P<0.05), whereas this effect of atractyloside was inhibited by Cyclosporin A (CsA, a VDAC blocker). We conclude that the mitochondrial VDAC is involved in both the increase of mitochondrial permeability to Ca(2+) and the decrease of mitochondrial membrane potential in cell lines carrying the mtDNA A4263G mutation.

Incomplete revascularization in the drug eluting stent era permits meaningful long-term (12-78 months) outcomes in patients ≥ 75 years with acute coronary syndrome

Objective To compare long-term prognosis between complete revascularization (CR) and incomplete revascularization (IR) in elderly patients with acute coronary syndrome (ACS) who underwent percutaneous coronary intervention (PCI). Methods We prospectively enrolled patients ≥ 75 years with ACS and multi-lesion disease between January 2005 and December 2010 at our center (Institute of Geriatric Cardiology, Chinese PLA General Hospital). Baseline clinical characteristics, PCI parameters and long-term (12 to 78 months) outcomes including main adverse cardiac and cerebral events (MACCE) were compared between CR and IR groups. We used the Kaplan-Meier curve to describe the survival rates, and variables reported to be associated with prognosis were included in Cox regression. Results Of the 502 patients, 230 patients obtained CR, and the other 272 patients underwent IR. Higher SYNTAX score was an independent predictor of IR [Odds ratio (OR): 1.141, 95% confidence interval (95% CI): 1.066–1.221, P = 0.000]. A total of 429 patients (85.5%) were followed with a duration ranging from 12 months to 78 months. There were no significant differences in cumulative survival rates and event free survival rates between the two groups, even for patients with multi-vessel disease. Older age (OR: 1.079, 95% CI: 1.007–1.157, P = 0.032), prior myocardial infarction (OR: 1.440, 95% CI: 1.268–2.723, P = 0.001) and hypertension (OR: 1. 653, 95% CI: 1.010-2.734, P = 0.050) were significant independent predictors of long-term MACCE. Conclusions Given that both clinical and coronary lesion characteristics are much more complex in patients ≥75 years with ACS and multi-lesion disease, IR may be an option allowing low risk hospital results and meaningful long-term (12 to 78 months) outcomes.

Single Cell Gene Profiling Revealed Heterogeneity of Paracrine Effects of Bone Marrow Cells in Mouse Infarcted Hearts

It is now recognized that transplantation of bone marrow cells (BMCs) into infarcted hearts has the capacity to improve the cardiac function through paracrine effects. However, detailed expression levels of paracrine factors in BMCs in infarcted hearts are poorly described. By use of laser capture microdissection combined with real-time PCR, we depicted the expression profiles of paracrine factors in infarcted hearts versus normal hearts. Consistent with the in vivo observation, a similar expression pattern was evidenced in cultured BMCs. Furthermore, BMCs displayed heterogeneity of paracrine effects in infarcted hearts as analyzed at the single cell level using single cell PCR. Interestingly, the CD45+ subpopulation showed higher expression levels of angiogenic factors compared to other subpopulations. Finally, most angiogenic factors were induced under the microenvironment of infarction. Our study demonstrated the heterogeneity of paracrine effects in BMCs at single cell level in infarcted hearts, highlighting preferential expression of angiogenic factors in the CD45+ subpopulation. These findings broaden our understanding of paracrine effects of BMCs in vivo, and offer new insights into BMCs therapy in myocardial infarction (MI).