Hun-Jun Park

Cell therapy with embryonic stem cell-derived cardiomyocytes encapsulated in injectable nanomatrix gel enhances cell engraftment and promotes cardiac repair

A significant barrier to the therapeutic use of stem cells is poor cell retention in vivo. Here, we evaluate the therapeutic potential and long-term engraftment of cardiomyocytes (CMs) derived from mouse embryonic stem cells (mESCs) encapsulated in an injectable nanomatrix gel consisting of peptide amphiphiles incorporating cell adhesive ligand Arg-Gly-Asp-Ser (PA-RGDS) in experimental myocardial infarction (MI). We cultured rat neonatal CMs in PA-RGDS for 7 days and found that more than 90% of the CMs survived. Next, we intramyocardially injected mouse CM cell line HL-1 CMs with or without PA-RGDS into uninjured hearts. Histologic examination and flow cytometry analysis of digested heart tissues showed approximately 3-fold higher engraftment in the mice that received CMs with PA-RGDS compared to those without PA-RGDS. We further investigated the therapeutic effects and long-term engraftment of mESC-CMs with PA-RGDS on MI in comparison with PBS control, CM-only, and PA-RGDS only. Echocardiography demonstrated that the CM-only and CM+PA-RGDS groups showed higher cardiac function at week 2 compared to other groups. However, from 3 weeks, higher cardiac function was maintained only in the CM+PA-RGDS group; this was sustained for 12 weeks. Confocal microscopic examination of the cardiac tissues harvested at 14 weeks demonstrated sustained engraftment and integration of mESC-CMs into host myocardium in the CM+PA-RGDS group only. This study for the first time demonstrated that PA-RGDS encapsulation can enhance survival of mESC-derived CMs and improve cardiac function post-MI. This nanomatrix gel-mediated stem cell therapy can be a promising option for treating MI.

High-density lipoprotein cholesterol as a predictor of clinical outcomes in patients achieving low-density lipoprotein cholesterol targets with statins after percutaneous coronary intervention

Background A low level of high-density lipoprotein cholesterol (HDL-C) is strongly associated with cardiovascular events. However, the significance of HDL-C after statin therapy on the outcome of patients who have undergone percutaneous coronary intervention (PCI) with drug eluting stents (DES) is unclear. Objectives To investigate the significance of HDL-C after statin therapy on cardiovascular events in patients with coronary artery disease after DES implantation. Methods Patients who underwent PCI with DES from January 2004 to December 2009 were prospectively enrolled. The follow-up lipid panel of 2693 patients (median lab follow-up duration 225 days) who had continued using statins after PCI and who attained low-density lipoprotein cholesterol (LDL-C) <100 mg/dl was analysed. Major adverse cardiac events (MACE), including all-cause death, non-fatal myocardial infarction, and target vessel revascularisation according to follow-up HDL-C level (40 mg/dl for men or 50 mg/dl for women) were compared with the use of propensity scores matching. Results Median follow-up duration was 832 days. 1585 (58.9%) patients had low follow-up HDL-C and 1108 had high follow-up HDL-C. The low follow-up HDL-C group had significantly higher rates of MACE. Low follow-up HDL-C was a significant independent predictor of MACE (adjusted HR 1.404, 95% CI 1.111 to 1.774, p=0.004). In further analysis with propensity scores matching, overall findings were consistent. Conclusions Raising HDL-C levels may be a subsequent goal after achieving target LDL-C levels in patients with DES implantation.

Purification of Cardiomyocytes From Differentiating Pluripotent Stem Cells Using Molecular Beacons That Target Cardiomyocyte-Specific mRNA

Background— Although methods for generating cardiomyocytes from pluripotent stem cells have been reported, current methods produce heterogeneous mixtures of cardiomyocytes and noncardiomyocyte cells. Here, we report an entirely novel system in which pluripotent stem cell–derived cardiomyocytes are purified by cardiomyocyte-specific molecular beacons (MBs). MBs are nanoscale probes that emit a fluorescence signal when hybridized to target mRNAs. Method and Results— Five MBs targeting mRNAs of either cardiac troponin T or myosin heavy chain 6/7 were generated. Among 5 MBs, an MB that targeted myosin heavy chain 6/7 mRNA (MHC1-MB) identified up to 99% of HL-1 cardiomyocytes, a mouse cardiomyocyte cell line, but <3% of 4 noncardiomyocyte cell types in flow cytometry analysis, which indicates that MHC1-MB is specific for identifying cardiomyocytes. We delivered MHC1-MB into cardiomyogenically differentiated pluripotent stem cells through nucleofection. The detection rate of cardiomyocytes was similar to the percentages of cardiac troponin T– or cardiac troponin I–positive cardiomyocytes, which supports the specificity of MBs. Finally, MHC1-MB–positive cells were sorted by fluorescence-activated cell sorter from mouse and human pluripotent stem cell differentiating cultures, and ≈97% cells expressed cardiac troponin T or cardiac troponin I as determined by flow cytometry. These MB-based sorted cells maintained their cardiomyocyte characteristics, which was verified by spontaneous beating, electrophysiological studies, and expression of cardiac proteins. When transplanted in a myocardial infarction model, MB-based purified cardiomyocytes improved cardiac function and demonstrated significant engraftment for 4 weeks without forming tumors. Conclusions— We developed a novel cardiomyocyte selection system that allows production of highly purified cardiomyocytes. These purified cardiomyocytes and this system can be valuable for cell therapy and drug discovery.

Long-term outcomes of percutaneous coronary intervention versus coronary artery bypass grafting for unprotected left main coronary bifurcation disease in the drug-eluting stent era

Objectives There are limited data on long-term outcomes (ie, beyond 4 years) for patients with unprotected left main bifurcation disease who underwent percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) in the drug-eluting stent (DES) era. This study therefore compared the treatment effects of PCI and CABG in unprotected left main bifurcation disease. Methods 865 patients with unprotected left main bifurcation disease treated with either PCI using DES (n=556) or CABG (n=309) were evaluated between May 2003 and December 2009. PCI-treated patients were further categorised into simple stenting (n=360) or complex stenting (n=196). Results Median follow-up was 4.2 years (IQR 2.9–5.2 years). After adjusting covariates with multivariate Cox hazard regression model and inverse probability of treatment weighting, the long-term cumulative rates of death (HR 0.95; 95% CI 0.62 to 1.45) or composite of death, Q-wave myocardial infarction, or stroke (HR 0.97, 95% CI 0.64 to 1.48) were not significantly different for patients undergoing PCI or CABG except for target-vessel revascularisation (TVR) (HR 4.42, 95% CI 2.39 to 8.18). The complex stenting group had similar long-term clinical outcomes compared with the simple stenting group except for TVR (HR 1.94, 95% CI 1.22 to 3.10). In further analysis with propensity score matching, overall findings were consistent. Conclusions In patients with unprotected left main bifurcation disease, PCI using DES provides similar long-term (up to 5.2 years) clinical outcomes except for TVR compared with CABG. Complex and simple stenting yielded similar outcomes except for a higher TVR rate in complex stenting.

Impact of the Stent Length on Long-Term Clinical Outcomes Following Newer-Generation Drug-Eluting Stent Implantation

Stent length has been considered an important predictor of adverse events after percutaneous coronary intervention, even with the first-generation drug-eluting stents (DESs). The introduction of newer-generation DES has further reduced the rates of adverse clinical events such as restenosis, myocardial infarction, and stent thrombosis. The aim of this study was to compare the impact of stent length on the long-term clinical outcomes between first- and newer-generation DESs. The effects of stent length (≥32 vs <32 mm) on the clinical outcomes were evaluated in 8,445 patients who underwent percutaneous coronary intervention using either a first-generation DES (sirolimus- and paclitaxel-eluting stents, n = 6,334) or a newer-generation DES (everolimus- and zotarolimus-eluting stents, n = 2,111) from January 2004 to December 2009. The 3-year adverse outcomes (composite of all-cause death, nonfatal myocardial infarction, target vessel revascularization, and stent thrombosis) were compared using the inverse probability of treatment-weighted method according to the stent length. After adjustment for differences in the baseline risk factors, a stent length of ≥32 mm was significantly associated with higher cumulative rates of target vessel revascularization and stent thrombosis in the patients treated with a first-generation DES (adjusted hazard ratio 1.875, 95% confidence interval 1.531 to 2.297, p <0.001; adjusted hazard ratio 2.964, 95% confidence interval 1.270 to 6.917, p = 0.012), but it was not associated with the clinical outcomes in patients treated with a newer-generation DES. In conclusion, stent length might not be associated with long-term clinical outcomes in newer-generation DES era, whereas stent length might be associated with long-term clinical outcomes in the first-generation DESs.

Long-Term Percutaneous Coronary Intervention Rates and Associated Independent Predictors for Progression of Nonintervened Nonculprit Coronary Lesions

After successful percutaneous coronary intervention (PCI), unpredictable coronary events occur that are caused by in-stent restenosis and the progression of preexisting nonculprit coronary lesions. However, little is known about the long-term clinically driven PCI rates for the progression of nonculprit coronary lesions discovered during culprit-lesion PCI or its independent predictors, including several biomarkers. In this study, the clinical and angiographic data of 1,395 PCI patients treated from January 2004 to May 2007 were retrospectively analyzed. Of these patients, 507 were eligible for this study. After baseline PCI (i.e., culprit-lesion PCI), 81 patients (16%) underwent additional clinically driven PCI to treat preexisting nonculprit coronary lesions during the study period. The cumulative rates of clinically driven PCI for nonculprit coronary lesions were 7.7% (n = 39) at 1 year, 14% (n = 70) at 2 years, and 16% (n = 81) at 3 years. The independent predictors of clinically driven PCI included a larger number of significant coronary lesions (odds ratio [OR] 2.29, 95% confidence interval [CI] 1.5 to 3.5, p <0.001), low high-density lipoprotein (<40 mg/dl; OR 2.01, 95% CI 1.01 to 3.98, p = 0.046), hypercholesterolemia (total cholesterol >200 mg/dl; OR 1.46, 95% CI 1.22 to 1.97, p = 0.04), history of PCI (OR 1.24, 95% CI 1.09 to 1.60, p = 0.003), and increased triglyceride levels (OR 1.003, 95% CI 1.001 to 1.007, p = 0.038) at the time of baseline PCI. In conclusion, PCI patients with nonculprit coronary lesions underwent additional clinically driven PCI at rates of 7.7% at 1 year, 14% at 2 years, and 16% at 3 years because of the progression of preexisting nonculprit coronary lesions. Overall coronary artery disease burden and poor lipid profiles at baseline PCI confer significant risks for clinically driven PCI.

Direct comparison of B-type natriuretic peptide and N-terminal pro-BNP for assessment of cardiac function in a large population of symptomatic patients

BACKGROUNDS B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NTproBNP) levels showed frequent discrepancies in individual patients. OBJECTIVES The aims were 1) to compare the abilities of BNP and NTproBNP for the detection of left ventricular systolic dysfunction (LVSD) or diastolic dysfunction (LVDD) in the symptomatic patients, and 2) to assess the direct correlation and its independent determinants between them. METHODS 1032 patients with dyspnea underwent BNP and NTproBNP measurements simultaneously. 967/1032 (93.7%) patients underwent echocardiography. Using the receiver operation characteristic curve analyses for the detection of LVSD (EF<45%) or advanced LVDD, the area under the curves (AUC) of both biomarkers was compared according to age, gender, body mass index (BMI), hemoglobin (Hb), and glomerular filtration rate (eGFR). Using multiple regression analysis, the direct correlation and its independent determinants were identified between them. RESULTS In the entire population, the AUCs of BNP and NTproBNP had no significant differences (LVSD: 0.909 vs. 0.893, p=0.20; advanced LVDD: 0.897 vs. 0.879, p=0.13). In patients with BMI<25, the AUCs of BNP were significantly higher than those of NTproBNP (LVSD: 0.897 vs. 0.869, p=0.03; advanced LVDD: 0.916 vs. 0.885, p=0.02). They had strong correlation (r=0.895, p<0.001) and LVEF, eGFR<60 ml/min, Hb<12 g/dl and use of diuretics were the independent determinants between them. CONCLUSION BNP and NTproBNP displayed strong correlation and near-identical performances for the screening of cardiac dysfunction. However, LVEF, renal function, Hb and use of diuretics should be considered for clinical interpretation.

Improved anemia is associated with favorable long-term clinical outcomes in patients undergoing PCI.

BackgroundAnemia is associated with an increased risk of mortality in patients who underwent percutaneous coronary intervention (PCI) in the bare-metal stent era. However, there have been no data concerning the clinical importance of anemia improvement during the follow-up period after discharge from the hospital during the drug-eluting stent era. Methods and resultsTo assess anemia, the hemoglobin level was measured at the time of index PCI with drug-eluting stents and at the subsequent outpatient visit between 3 and 12 months later. Improvement of anemia was defined by the normalization of the hemoglobin level at the follow-up laboratory examination. We analyzed 4300 patients who were tested for initial and follow-up hemoglobin levels. We compared major adverse cardiac and cerebrovascular events (MACCE) between the normal group and the anemia group and between the improved anemia group and the sustained anemia group. The median follow-up period was 25.4 months. There was poorer clinical outcome in the anemia group than in the normal group in terms of MACCE (adjusted hazard ratio 1.479, 95% confidence interval 1.025–2.134, P=0.037). Furthermore, the sustained anemia group showed poorer MACCE than did the improved anemia group (hazard ratio 3.558, 95% confidence interval 2.285–5.539, P<0.0001). On the basis of the multivariate Cox hazard regression model and propensity-score matching, the overall findings were consistent between sustained and improved anemia groups. ConclusionThe follow-up of hemoglobin level is important, and improvement of anemia is associated with favorable long-term clinical outcomes.

Impact of the CYP2C19*17 polymorphism on the clinical outcome of clopidogrel therapy in Asian patients undergoing percutaneous coronary intervention.

The impact of the CYP2C19*17 polymorphism on the clinical outcome in Asians undergoing percutaneous coronary intervention (PCI) is unknown. We sought to assess the long-term impact of CYP2C19*17 on the risk for adverse clinical events in 2188 Korean patients taking clopidogrel after PCI. The prevalence of the CYP2C19*17 allele [*wt/*17: 2.4% (n=53), *17/*17: 0%] was very low. The 2-year cumulative event rates for bleeding [*wt/*17 vs. *wt/*wt: 2 vs. 2.3%; adjusted hazard ratio (HR), 1.23; 95% confidence interval (CI), 0.16–9.45], stent thrombosis (2 vs. 1.1%; HR, 3.98; 95% CI, 0.49–31.6) or composite of any death, and myocardial infarction or stroke (5.4 vs. 7.1%; HR, 1.37; 95% CI, 0.32–5.73) did not differ on the basis of the presence of CYP2C19*17. In conclusion, in our study population of Asian patients, the CYP2C19*17 polymorphism was not associated with adverse clinical outcomes after PCI because of its low prevalence, the rarity of homozygotes, and the relatively low rate of adverse clinical events.

Optimal antithrombotic strategy in patients with atrial fibrillation after coronary stent implantation.

Background and Objectives Little evidence is available on the optimal antithrombotic therapy following percutaneous coronary intervention (PCI) in patients with atrial fibrillation (AF). We investigated the outcomes of antithrombotic treatment strategies in AF patients who underwent PCI. Subjects and Methods Three hundred sixty-two patients (68.0% men, mean age: 68.3±7.8 years) with AF and who had undergone PCI with stent implantation between 2005 and 2007 were enrolled. The clinical, demographic and procedural characteristics were reviewed and the stroke risk factors as well as antithrombotic regimens were analyzed. Results The accompanying comorbidities were as follows: hypertension (59.4%), diabetes (37.3%) and congestive heart failure (16.6%). The average number of stroke risk factors was 1.6. At the time of discharge after PCI, warfarin was prescribed for 84 patients (23.2%). Cilostazol was used in addition to dual antiplatelet therapy in 35% of the patients who did not receive warfarin. The mean follow-up period was 615±385 days. The incidences of major adverse cardiac events (MACE), stroke and major bleeding were 11.3%, 3.6% and 4.1%, respectively. By Kaplan-Meier survival analysis, warfarin treatment was not associated with a lower risk of MACE (p=0.886), but it was associated with an increased risk of major bleeding (p=0.002). Conclusion Oral anticoagulation therapy after PCI may increase hemorrhagic events in Korean AF patients.