Caiyi Lu

Hybrid Coronary Revascularization by Endoscopic Robotic Coronary Artery Bypass Grafting on Beating Heart and Stent Placement

BACKGROUND Hybrid revascularization has been used in minimally invasive coronary artery bypass grafting and percutaneous coronary intervention for multivessel coronary artery disease (CAD). Very few endoscopic robotic coronary bypasses on the beating heart have been reported. The aim of this study was to assess hybrid revascularization by endoscopic robotic coronary artery bypass on the beating heart with percutaneous coronary intervention in a staged approach. METHODS Forty-two patients underwent selective robotic coronary artery bypass grafting on the beating heart. Ten patients with right coronary artery or circumflex coronary stenosis underwent stent placement after robotic left internal mammary artery (LIMA) anastomosis to the left anterior descending (LAD) artery surgery in a separate session. The average age of the patients was 62.3 +/- 12.1 years old. Coronary arteriography showed significant stenosis or total occlusion of the LAD in all patients and significant stenosis in the right coronary or circumflex arteries. The LIMA was harvested by the da Vinci S robotic surgical system (Intuitive Surgical, Sunnyvale, CA) and manually anastomosed to the LAD off-pump in 6 patients, and by totally endoscopic bypass on the beating heart in 4 patients. Percutaneous coronary intervention with placement of a stent to stenotic non-LAD targets was performed 4 to 5 days after operation. All LIMA-LAD grafts were assessed angiographically. RESULTS All 10 patients had off-pump robotic bypass surgery and stent placement using a staged approach without complications. CONCLUSIONS Our preliminary study shows that hybrid coronary revascularization by endoscopic robotic coronary artery bypass grafting on a beating heart and subsequent stent placement is a feasible integrated approach for patients with multivessel CAD.

Influence of CYP2C9 and VKORC1 genotypes on the risk of hemorrhagic complications in warfarin-treated patients: a systematic review and meta-analysis.

BACKGROUND The main challenge for warfarin anticoagulation is the risk for hemorrhagic complications. Although certain pharmacogenetic factors may explain the individual variabilities about the therapeutic warfarin dose requirement, the genetic factors to warfarin hemorrhagic complications due to over-anticoagulation are largely unknown. To interpret the potential role of warfarin-related genotypes on over-anticoagulation and hemorrhagic complications, we conducted a meta-analysis based on 22 published studies. METHODS A comprehensive search was applied to the reports on over-anticoagulation and hemorrhagic complications published prior to December 31, 2012 in PubMed and EMBASE. References were identified by strict inclusion and exclusion criteria, with additional information obtained by consulting with the authors of primary studies. The roles of genotypes in CYP2C9 and VKORC1 on over-anticoagulation (INR > 4) and hemorrhagic complications were analyzed by Revman 5.0.2 software. RESULTS A total of 6272 patients in 22 reports were included in the meta-analysis, including studies of 18 from Caucasians (3 from both Caucasian and African-American), 3 from Asians, and 1 from Brazilians. Compared to CYP2C9 wild genotype (CYP2C9*1), both CYP2C9*2 (rs 1799853, c. 430 C > T, p. Arg144Cys) and *3 (rs 1057910, c. 1075 A >C, p. Ile359Leu) confer significantly higher risk for warfarin over-anticoagulation and hemorrhagic complications. After stratification by CYP2C9 allele status, significantly higher risk for hemorrhagic complications was found only in carriers of at least 1 copy of CYP2C9*3 [For total hemorrhages: *1/*3 HR: 2.05 (1.36-3.10), p < 0.001; *3/*3 HR: 4.87 (1.38-17.14), p = 0.01; For major hemorrhages: *1/*3 HR: 2.43 (1.17-5.06), p = 0.02; *3/*3 HR: 4.81 (0.95-24.22), p = 0.06]. Furthermore, similar susceptibility of total hemorrhage by CYP2C9 genotypes was observed in Caucasians and Asians. After stratification by the occurrence time, both CYP2C9*2 and *3 are risk factors for over-anticoagulation within 30 days of warfarin treatment [*2 HR: 1.64 (1.11-2.43), p = 0.01; *3 HR: 2.48 (1.56-3.96), p < 0.001], and only CYP2C9*3 showed higher risk for over-anticoagulation after 30 days [HR: 1.86 (1.08-3.20), P = 0.03]. For VKORC1 c. -1639G > A (rs 9923231) genotypes, GA and AA contributed significantly higher risk for over-anticoagulation within 30 days [HR: 2.14 (1.75-2.62), p < 0.001], but not for over-anticoagulation after 30 days [HR:0.78 (0.46-1.33), p = 0.36]. No significant association was found between VKORC1 genotypes and hemorrhagic complications. CONCLUSIONS Both CYP2C9 and VKORC1 genotypes are associated with an increased risk for warfarin over-anticoagulation, with VKORC1 c. -1639G > A more sensitive early in the course of anticoagulation. CYP2C9*3 is the main genetic risk factor for warfarin hemorrhagic complications.

Genetic determinants of high on-treatment platelet reactivity in clopidogrel treated Chinese patients

INTRODUCTION Cytochrome P450 (CYP), ATP-binding cassette transporters (ABCB1), and paraoxonase-1 (PON1) play crucial roles in clopidogel absorption and bioactivation. Genetic polymorphisms in these genes have been associated with the variability of the response to clopidogrel, however their contribution to high on-treatment platelet reactivity (HPR) in clopidogrel treated Chinese patients is less known. MATERIALS AND METHODS Five-hundred Chinese-Han patients treated with clopidogrel for acute coronary syndrome (ACS) were consecutively recruited from the Department of Geriatric Cardiology, General Hospital of Chinese Peoples Liberation Army, from September 2010 to September 2012. We assessed the relations of CYP2C19*2 (rs4244285), CYP2C19*3 (rs4986893), CYP2C19*17 (rs12248560), PON1Q129R (rs662) and ABCB1C3435T (rs1045642) to the platelet aggregation after 5 days maintenance dose of clopidogrel administration, and the risk for HPR. The cutoff of HPR was defined as 20 μmol/L adenosine diphosphate (ADP)-induced platelet aggregation>50%. RESULTS Both CYP2C19*2 and *3 alleles were significantly associated with higher platelet aggregation after 5 days maintenance dose of clopidogrel administration (P<0.00001 and P=0.042, respectively). The platelet aggregation in carriers of at least one CYP2C19 loss-of-function allele (*2 or *3, accounted for 58% of the study population) was obviously higher than that in non-carriers (P<0.00001). Patients with the CYP2C19*2 allele had a higher risk of HPR than those with the CYP2C19 wild-type genotype [adjusted hazard ratio (HR), 1.56; 95% confidence interval(CI), 1.04-2.33, P=0.03]. The carriers of at least one CYP2C19 loss-of-function allele could also predict significantly greater risk of HPR compared with non-carriers (adjusted HR1.79,95% CI: 1.33-2.4,P=0.003). However, the carriage of CYP2C19*3 alone could not predict the risk of HPR significantly (adjusted HR, 1.5; 95% CI: 0.83-3, P=0.16). Significant relation of CYP2C19*17, PON1Q129R and ABCB1C3435T to the platelet aggregation was not found. CONCLUSION In clopidogrel treated Chinese patients with ACS, carriers of at least one CYP2C19 loss-of-function allele could predict greater risk of HPR, with the impact mainly attributing to CYP2C19*2. Neither ABCB1 nor PON1 genotype could influence the antiplatelet response of clopidogrel in the cohort of Chinese patients.

Comparative performance of warfarin pharmacogenetic algorithms in Chinese patients

INTRODUCTION Multiple 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. MATERIAL AND METHODS We 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. RESULTS In 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). CONCLUSIONS No 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.

PON1 Q192R genotype influences clopidogrel responsiveness by relative platelet inhibition instead of on-treatment platelet reactivity

BACKGROUND paraoxonase-1 (PON1) was recently identified as the crucial enzyme for clopidogrel bioactivation, with PON1 Q192R (rs662) polymorphism determining the clopidogel antiplatelet efficacy. However, subsequent studies showed controversies over the findings. This study aimed to evaluate the impact of PON1 Q192R in parallel to that of CYP2C19*2 (rs4244285) on clopidogrel responsiveness in a cohort of Chinese patients with unstable angina pectoris. MATERIAL AND METHODS One hundred and eighty Chinese-Han patients diagnosed with unstable angina pectoris and treated with clopidogrel were consecutively recruited. Clopidogrel responsiveness, measured by relative platelet inhibition {RI=[(pretreatment aggregation-posttreatment aggregation at 5days)/(pretreatment aggregation)] x100%}, was assessed in relation to PON1 Q192R and CYP2C19*2 genotypes. RI values were stratified into four quartiles, with patients in quartile 1 defined as individuals of clopidogrel non-responsiveness. The contributions of PON1 Q192R and CYP2C19*2 to on-treatment platelet reactivity (OTPR) at 5days maintenance dose of clopidogrel were also evaluated. RESULTS For PON1 Q192R genotypes, RI values were significantly lower in patients with QR and RR alleles than in patients with QQ alleles (p=0.01). OTPR values at 5days maintenance dose of clopidogrel were similar across all the PON1 Q192R genotypes (p=0.41). PON1 192 QR and RR conferred increased risks for clopidogrel non-responsiveness [OR 3.64; 95% CI (1.21-10.92), p=0.02]. For CYP2C19*2 genotypes, compared to CYP2C19*1/*1 wild type carriers, CYP2C19*2 carriers showed a significantly higher OTPR (p=0.009), and a trend for lower RI values (p=0.06). An increased risk for clopidogrel non-responsiveness was found in patients with CYP2C19*2 genotype [OR 2.02; 95% CI (1.03-3.96), p=0.04]. CONCLUSIONS Both PON1 Q192R and CYP2C19*2 genotypes influence clopidogrel responsiveness, with the impact of PON1 Q192R mainly on relative platelet inhibition instead of OTPR of clopidogrel.

Effects of sleep deprivation on action potential and transient outward potassium current in ventricular myocytes in rats.

Background Sleep deprivation contributes to the development and recurrence of ventricular arrhythmias. However, the electrophysiological changes in ventricular myocytes in sleep deprivation are still unknown. Material/Methods Sleep deprivation was induced by modified multiple platform technique. Fifty rats were assigned to control and sleep deprivation 1, 3, 5, and 7 days groups, and single ventricular myocytes were enzymatically dissociated from rat hearts. Action potential duration (APD) and transient outward current (Ito) were recorded using whole-cell patch clamp technique. Results Compared with the control group, the phases of APD of ventricular myocytes in 3, 5, and 7 days groups were prolonged and APD at 20% and 50% level of repolarization (APD20 and APD50) was significantly elongated (The APD20 values of control, 1, 3, 5, and 7 days groups: 5.66±0.16 ms, 5.77±0.20 ms, 8.28±0.30 ms, 11.56±0.32 ms, 13.24±0.56 ms. The APD50 values: 50.66±2.16 ms, 52.77±3.20 ms, 65.28±5.30 ms, 83.56±7.32 ms, 89.24±5.56 ms. P<0.01, n=18). The current densities of Ito significantly decreased. The current density-voltage (I–V) curve of Ito was vitally suppressed downward. The steady-state inactivation curve and steady-state activation curve of Ito were shifted to left and right, respectively, in sleep deprivation rats. The inactivation recovery time of Ito was markedly retarded and the time of closed-state inactivation was markedly accelerated in 3, 5, and 7 days groups. Conclusions APD of ventricular myocytes in sleep deprivation rats was significantly prolonged, which could be attributed to decreased activation and accelerated inactivation of Ito.

Additional manual thrombus aspiration for ST-segment elevation myocardial infarction during percutaneous coronary intervention: an updated meta-analysis

Background The clinical efficacy and safety of adjunctive thrombus aspiration (TA) in patients with ST-segment elevation myocardial infarction (STEMI) during percutaneous coronary intervention (PCI) remain controversial. Methods Twenty five eligible randomized controlled trials were included to compare the use of thrombus aspiration (TA) with PCI and PCI-only for STEMI. The primary endpoint was all-cause mortality and death. The secondary endpoints were major adverse cardiac events (MACE), recurrent infarction (RI), target vessel revascularization (TVR), stent thrombosis (ST), perfusion surrogate markers and stroke. Results TIMI flow grade 3 and MBG 2–3 were significantly increased in the TA plus PCI arm compared with the PCI-only arm [relative risk (RR): 1.05, 95% confidence intervals (CI): 1.02–1.09, P = 0.004] and (RR: 1.68, 95% CI: 1.40–2.00, P < 0.001), respectively. There were no significant differences in all-cause mortality, MACEs, TVR and ST rates between the two groups. The RI rate was lower in the TA plus PCI arm than that in the PCI-only arm with short-term follow-up duration (RR: 0.60, 95% CI: 0.38–0.96, P = 0.03), but there was no significant difference in RI incidence over the medium- or long-term follow-up periods (RR: 1.00, 95% CI: 0.77–1.29, P = 0.98), and (RR: 0.96, 95% CI: 0.81–1.15, P = 0.69), respectively. There were statistically significant differences in the rates of crude stroke and stroke over the medium- or long-term follow-up periods and the crude stroke rate in the TA plus PCI (RR: 1.60, 95% CI: 1.08–2.38, P = 0.02) and (RR: 1.43, 95% CI: 1.03–1.98, P = 0.03), respectively; this was not observed between the two arms during the short-term follow-up period (RR: 1.47, 95% CI: 0.97–2.21, P = 0.07). Conclusions Routine TA-assisted PCI in STEMI patients can improve myocardial reperfusion and get limited benefits related to the clinical endpoints, which may be associated with stroke risk.

Electrophysiological Characteristics of the LQT2 Syndrome Mutation KCNH2-G572S and Regulation by Accessory Protein KCNE2

Mutations in hERG cause long QT syndrome type 2 which is characterized by a prolonged QT interval on electrocardiogram and predisposition to life-threatening ventricular tachyarrhythmia, syncope, and sudden death. hERG-G572S induces trafficking defects of hERG channel protein from Golgi to the plasma membrane and results in a dominant negative suppression of hERG current density. As an accessory β subunit, KCNE2 promotes hERG migration from Golgi to cellular membrane. In this study, we investigated the rescue effect of KCNE2 in a G572S mutation of hERG. Transfection was performed into HEK293 cells. Patch clamp technique, western blotting analyses and confocal microscopic examination were used. Results showed that KCNE2 had a significantly enhanced effect on G572S mutation current. The increase of current was largest at KCNH2:KCNE2 of 1:3. Confocal images showed co-expressing G572S and KCNE2 could cause a substantial up-regulated membrane protein (155 kDa) expression. Expression of membrane protein accumulated markedly with increasing ratio of KCNH2:KCNE2. G572S defective mutant could be restored by both KCNE2 and lower temperature (27°C), which suggested that the lower temperature could be the favorable circumstances for the rescue function of KCNE2. In this study, we successfully set up “the action potential” on the HEK 293 cells by genetically engineered to express Kir2.1, Nav1.5, and Kv11.1, wherein on reaching over an excitation threshold by current injection. The results suggested that KCNE2 could shorten action potential duration which was prolonged by G572S. These findings described electrophysiological characteristics of the LQT2 syndrome mutation KCNH2-G572S and regulation by accessory protein KCNE2, and provided a clue about LQT2 and relative rescue mechanism.

Hypotensive effects of renal denervation in spontaneously hypertensive rat based on ultrasonic contrast imaging

BACKGROUND Sympathetic nerves-fire rate is generally enhanced in some types of hypertension models. Renal sympathetic denervation(RSD) by the radiofrequency ablation was used to treat the hypertension has achieved curative effect.HTN-1 and HTN-2 trial reported catheter-based renal denervation may cause substantial and sustained blood-pressure reduction in patients with resistant hypertension. However, recent controlled HTN-3 trial questioned the BP lowering effect of Renal denervation treatment. The controversial results maybe arised from the incompleted RSD which implemented inside the renal artery. Now renal denervation therapy for resistant hypertension is in attractive and controversial status. Our aim is to define the hyotensive value of complete renal denervation in adult spontaneous hypertensive rats. METHODS Male spontaneous hypertensive rats(SHR) aged 12 weeks were randomly selected for either unilateral renal artery sympathetic nerves ablation (URSNA), or conventional technique of renal denervation (CRD), or bilateral renal artery sympathetic nerves ablation (BRSNA) and sham operation. Blood pressure, sodium and water balance,serum reninangiotensin II and Norepinephrine concentration were measured during 20 weeks after renal denervation operation. Internal diameters of renal arteries and renal blood flow rate was tested by ultrasonic contrast imaging. RESULTS The continued increased blood pressure in SHR was delayed and significantly reduced by conventional renal denervation over a period of 8 weeks. Both the bilateral and unilateral renal sympathetic nerve ablation procedure did not prevent the development of hypertension in SHR. The attenuation of hypertension was accompanied with the increase of urinary sodium excretion and depression of rennin angiotensin system (RAS). CONCLUSIONS We concluded that renal denervation may not be an effective therapeutic method in the long-term control of hypertension in adult SHR.

GW25-e0540 Pharmacogenetics of clopidogrel responsiveness in Chinese patients with acute coronary syndrome

Cytochrome P450 (CYP), ATP-binding cassette transporters (ABCB1), and paraoxonase-1 (PON1) play crucial roles in clopidogel metabolism. Genetic polymorphisms in these genes have been associated with the variability of the response to clopidogrel, however, there are controversies over the findings.