Eun-Seok Jeon

Decreased Number and Impaired Angiogenic Function of Endothelial Progenitor Cells in Patients With Chronic Renal Failure

Objective—Increased risk of cardiovascular disease in patients with chronic renal failure (CRF) has been explained by accelerated atherosclerosis and impaired angiogenesis, in which endothelial progenitor cells (EPCs) may play key roles. We hypothesized that altered EPC biology may contribute to the pathophysiology of CRF. Methods and Results—EPCs were isolated from CRF patients on maintenance hemodialysis (n=44) and from a normal control group (n=30). CRF patients showed markedly decreased numbers of EPC (44.6%) and colonies (75.3%) when compared with the controls (P <0.001). These findings were corroborated by 30.5% decrease in EPC migratory function in response to vascular endothelial growth factor (VEGF) (P =0.040) and 48.8% decrease in EPC incorporation into human umbilical vein endothelial cells (HUVEC) (P <0.001). In addition, Framingham’s risk factor score of both CRF (r = −0.461, P =0.010) and normal group (r = −0.367, P =0.016) significantly correlated with the numbers of EPC. Indeed, the number of circulating EPC was significantly lower in CRF patients than in normal group under the same burden of risk factors (P <0.001). A significant correlation was also observed between dialysis dose (Kt/V) and EPC incorporation into HUVEC (r =0.427, P =0.004). Conclusions—EPC biology, which is critical for neovascularization and the maintenance of vascular function, is altered in CRF. Our data strongly suggest that dysfunction of circulating EPC has a role in the progression of cardiovascular disease in patients with CRF.

Extracorporeal cardiopulmonary resuscitation in patients with inhospital cardiac arrest: A comparison with conventional cardiopulmonary resuscitation*

Objective:We investigated whether the survival of patients with inhospital cardiac arrest could be extended by extracorporeal cardiopulmonary resuscitation supported with extracorporeal membrane oxygenation compared with those of conventional cardiopulmonary resuscitation. Design:A retrospective, single-center, observational study. Setting:A tertiary care university hospital. Patients:We retrospectively analyzed a total of 406 adult patients with witnessed inhospital cardiac arrest receiving cardiopulmonary resuscitation for >10 mins from January 2003 to June 2009 (85 in the extracorporeal cardiopulmonary resuscitation group and 321 in the conventional cardiopulmonary resuscitation group). Interventions:None. Measurements and Main Results:The primary end point was a survival discharge with minimal neurologic impairment. Propensity score matching was used to balance the baseline characteristics and cardiopulmonary resuscitation variables that could potentially affect prognosis. In the matched population (n = 120), the survival discharge rate with minimal neurologic impairment in the extracorporeal cardiopulmonary resuscitation group was significantly higher than that in the conventional cardiopulmonary resuscitation group (odds ratio of mortality or significant neurologic deficit, 0.17; 95% confidence interval, 0.04–0.68; p = .012). In addition, there was a significant difference in the 6-month survival rates with minimal neurologic impairment (hazard ratio, 0.48; 95% confidence interval, 0.29–0.77; p = .003; p <.001 by stratified log-rank test). In the subgroup based on cardiac origin, extracorporeal cardiopulmonary resuscitation also showed benefits for survival discharge (odds ratio, 0.19; 95% confidence interval, 0.04–0.82; p = .026) and 6-month survival with minimal neurologic impairment (hazard ratio, 0.56; 95% confidence interval, 0.33–0.97; p = .038; p = .013 by stratified log-rank test). Conclusions:Extracorporeal cardiopulmonary resuscitation showed a survival benefit over conventional cardiopulmonary resuscitation in patients who received cardiopulmonary resuscitation for >10 mins after witnessed inhospital arrest, especially in cases with cardiac origins.

Transplantation of endothelial progenitor cells accelerates dermal wound healing with increased recruitment of monocytes/macrophages and neovascularization

Endothelial progenitor cells (EPCs) act as endothelial precursors that promote new blood vessel formation and increase angiogenesis by secreting growth factors and cytokines in ischemic tissues. These facts prompt the hypothesis that EPC transplantation should accelerate the wound‐repair process by facilitating neovascularization and the production of various molecules related to wound healing. In a murine dermal excisional wound model, EPC transplantation accelerated wound re‐epithelialization compared with the transplantation of mature endothelial cells (ECs) in control mice. When the wounds were analyzed immunohistochemically, the EPC‐transplanted group exhibited significantly more monocytes/macrophages in the wound at day 5 after injury than did the EC‐transplanted group. This observation is consistent with enzyme‐linked immunosorbent assay results showing that EPCs produced in abundance several chemoattractants of monocytes and macrophages that are known to play a pivotal role in the early phase of wound healing. At day 14 after injury, the EPC‐transplanted group showed a statistically significant increase in vascular density in the granulation tissue relative to that of the EC‐transplanted group. Fluorescence microscopy revealed that EPCs preferentially moved into the wound and were directly incorporated into newly formed capillaries in the granulation tissue. These results suggest that EPC transplantation will be useful in dermal wound repair and skin regeneration, because EPCs both promote the recruitment of monocytes/macrophages into the wound and increase neovascularization.

Preoperative NT-proBNP and CRP predict perioperative major cardiovascular events in non-cardiac surgery

Objective: To investigate whether simple and non-invasive measurement of N-terminal pro-brain natriuretic peptide (NT-proBNP) and/or C-reactive protein (CRP) can predict perioperative major cardiovascular event (PMCE). Design: Prospective, single-centre, cohort study. Setting: A 1900-bed tertiary-care university hospital in Seoul, Korea Design and patients: The predictive power of NT-proBNP, CRP and Revised Cardiac Risk Index (RCRI) for the risk of PMCE (myocardial infarction, pulmonary oedema or cardiovascular death) were evaluated from a prospective cohort of 2054 elective major non-cardiac surgery patients. Optimal cut-off values were derived from receiver operating characteristic curve (ROC) analysis. Main outcome measurement: PMCE (myocardial infarction, pulmonary oedema or cardiovascular death) within postoperative 30 days. Results: PMCE developed in a total of 290 patients (14.1%). Each increasing quartile of NT-proBNP or CRP level was associated with a greater risk of PMCE after adjustment for traditional clinical risk factors. The relative risk (RR) of highest versus lowest quartile was 5.2 for NT-proBNP (p<0.001) and 3.7 for CRP (p<0.001). Both NT-proBNP (cut-off  = 301 ng/l) and CRP (cut-off  = 3.4 mg/l) predicted PMCE better than RCRI (cut-off  = 2) by ROC analysis (p<0.001). Moreover, the predictive power of RCRI (adjusted RR  = 1.5) could be improved significantly by addition of CRP and NT-proBNP to RCRI (adjusted RR 4.6) (p<0.001). Conclusions: High preoperative NT-proBNP or CRP is a strong and independent predictor of perioperative major cardiovascular event in non-cardiac surgery. The predictive power of current clinical risk evaluation system would be strengthened by these biomarkers.

Enhanced dermal wound neovascularization by targeted delivery of endothelial progenitor cells using an RGD-g-PLLA scaffold

Endothelial progenitor cells (EPCs), endothelial precursors that promote neovascularization in ischemic tissues, have shown the limited vascular regeneration efficacy due to their poor homing into injured sites and low survival, so that a variety of biosynthetic scaffolds have been employed as cell delivery vehicles to overcome the current cell transplantation methods. However, few paralleled studies that directly compare the efficacy of EPCs seeded within synthetic scaffolds to that of EPCs delivered by the conventional transplantation techniques used for EPC therapies have been performed. To address these issues, RGD-g-PLLA biosynthetic scaffold was developed for the targeted EPC delivery and was found to successfully support the in vitro growth and endothelial functions of EPCs. This scaffold also appeared to be good as in vivo targeted delivery carriers of EPCs as it promoted vascular regeneration in a murine dermal wound models. Furthermore, direct comparison with the intradermal EPC injection revealed that the targeted delivery of EPCs by using the RGD-g-PLLA scaffold was superior to their conventional local injection method in terms of the localization and survival/retention of the transplanted EPCs, and their vascular repairing potential. These results suggest that the development of an effective stem cell delivery system may help to maximize the tissue-repairing efficacy with a limited number of stem cells, thereby resolving the limited clinical success of current stem cell therapies that have utilized simple cell injections or infusions.

PICOT Attenuates Cardiac Hypertrophy by Disrupting Calcineurin–NFAT Signaling

PICOT (protein kinase C–interacting cousin of thioredoxin) was previously shown to inhibit pressure overload-induced cardiac hypertrophy, concomitant with an increase in ventricular function and cardiomyocyte contractility. The combined analyses of glutathione S-transferase pull-down experiments and mass spectrometry enabled us to determine that PICOT directly interacts with muscle LIM protein (MLP) via its carboxyl-terminal half (PICOT-C). It was also shown that PICOT colocalizes with MLP in the Z-disc. MLP is known to play a role in anchoring calcineurin to the Z-disc in the sarcomere, which is critical for calcineurin–NFAT (nuclear factor of activated T cells) signaling. We, therefore, suggested that PICOT may affect calcineurin–NFAT signaling through its interaction with MLP. Consistent with this hypothesis, PICOT, or more specifically PICOT-C, abrogated phenylephrine-induced increases in calcineurin phosphatase activity, NFAT dephosphorylation/nuclear translocation, and NFAT-dependent transcriptional activation in neonatal cardiomyocytes. In addition, pressure overload–induced upregulation of NFAT target genes was significantly diminished in the hearts of PICOT-overexpressing transgenic mice. PICOT interfered with MLP–calcineurin interactions in a dose-dependent manner. Moreover, calcineurin was displaced from the Z-disc, concomitant with an abrogated interaction between calcineurin and MLP, in the hearts of PICOT transgenic mice. Replenishment of MLP restored the hypertrophic responses and the increase in calcineurin phosphatase activity that was inhibited by PICOT in phenylephrine-treated cardiomyocytes. Finally, PICOT-C inhibited cardiac hypertrophy to an extent that was comparable to that of full-length PICOT. Taken together, these data suggest that PICOT inhibits cardiac hypertrophy largely by negatively regulating calcineurin–NFAT signaling via disruption of the MLP–calcineurin interaction.

Two-year survival and neurological outcome of in-hospital cardiac arrest patients rescued by extracorporeal cardiopulmonary resuscitation☆

BACKGROUND The clinical benefit of extracorporeal cardiopulmonary resuscitation (E-CPR) has been proved in short-term follow-up studies. However, the benefit of E-CPR beyond 1 year has been not known. We investigated 2-year outcome of patients who received E-CPR or conventional CPR (C-CPR). METHODS We analyzed a total of 406 adult in-hospital cardiac arrest victims who underwent CPR for more than 10 min from 2003 to 2009. The two-year survival and neurological outcome of E-CPR (n=85) and C-CPR (n=321) were compared using propensity score-matched analysis. RESULTS The 2-year survival with minimal neurological impairment was 4-fold higher in the E-CPR group than the C-CPR group (23.5% versus 5.9%, hazard ratio (HR)=0.57, 95% confidence interval (CI)=0.43-0.75, p<0.001) by unadjusted analysis. After propensity-score matching, it was still 4-fold higher in the E-CPR group than the C-CPR group (20.0% versus 5.0%, HR=0.53, 95% CI=0.36-0.80, p=0.002). In the E-CPR group, the independent predictors associated with minimal neurological impairment were age ≤65 years (HR=0.46; 95% CI=0.26-0.81; p=0.008), CPR duration ≤35 min (HR=0.37; 95% CI=0.18-0.76; p=0.007), and subsequent cardiovascular intervention including coronary intervention or cardiac surgery (HR=0.36; 95% CI=0.18-0.68; p=0.002). CONCLUSIONS The initial survival benefit of E-CPR for cardiac arrest patients persisted at 2 years.

Improvement of hyponatraemia during hospitalisation for acute heart failure is not associated with improvement of prognosis: an analysis from the Korean Heart Failure (KorHF) registry

Objective Hyponatraemia predicts poor prognosis in patients hospitalised for acute heart failure (AHF). Yet, the association of hyponatraemia improvement with better postdischarge outcome has not been elucidated. Here, we determined the clinical impact of hyponatraemia improvement during hospitalisation on postdischarge outcome in patients admitted for AHF. Design Prospective cohort study. Setting Nation-wide twenty-four academic hospitals in Korea (mean follow-up of 1.7 years after discharge). Patients 2888 patients hospitalised for AHF. Main outcome measures Primary endpoints were composite of death or rehospitalisation due to heart failure. Results Hyponatraemia was present in 575 of total 2888 patients hospitalised for AHF at admission. Hyponatraemia was normalised in 274 patients (47.7%) at discharge. During mean follow-up of 1.7 years total 735 rehospitalisations and 397 deaths were documented. Persistent hyponatraemia during hospitalisation was significantly associated with increased incidence of composite endpoint of death or rehospitalisation in multivariate analysis compared with normonatraemia at admission (HR 1.345, 95% CI 1.075 to 1.683, p=0.010). However, improvement of hyponatraemia during hospitalisation was not significantly associated with lower incidence of composite endpoint of death or rehospitalisation in multivariate analysis (HR 1.084, 95% CI 0.709 to 1.659, p=0.709). Improved hyponatraemia was not associated with better prognosis in analysis with propensity score matching, either (HR 1.111, 95% CI 0.588 to 2.100, p=0.746). Conclusions In patients hospitalised for AHF, hyponatraemia on admission is associated with a worse prognosis compared with normonatraemia, irrespective of whether hyponatraemia improves during hospitalisation.

Prognostic value of NT-proBNP in heart failure with preserved versus reduced EF

Objective Plasma level of N-terminal–pro-brain natriuretic peptide (NT-proBNP) is a reliable prognostic factor in patients with heart failure (HF). However, it is unclear how differently the biomarker predicts adverse outcomes in HF with preserved EF (HFpEF) versus HF with reduced EF (HFrEF). Methods From the Korean Heart Failure registry, a prospective multicentre cohort for consecutive patients who were hospitalised for acute HF syndrome, those with available NT-proBNP and LVEF measurements were extracted. Patients with LVEF ≥50% were categorised as the HFpEF group (N=528) and those with ≤40% as the HFrEF group (N=1142). Results Patients with HFpEF had significantly lower NT-proBNP level than those with HFrEF (median 2723 vs 5644 ng/L, p<0.001). Event-free survival did not differ between the two groups either in terms of death from any cause (88.4% vs 86.9%; p=0.471) or the composite of death or HF readmission at 1 year (73.8% vs 70.6%; p=0.225). High levels of NT-proBNP were significantly associated with poor outcomes. However, the relationship was not different among the HFpEF and HFrEF groups (interaction p=0.956 for all-cause death; p=0.351 for the composite of all-cause death or HF hospitalisation). Conclusions Plasma level of NT-proBNP is the most powerful prognostic factor in both HFpEF and HFrEF. Although patients with HFpEF have lower NT-proBNP levels, the prognosis of a patient with HFpEF expected from a given NT-proBNP level is similar with his/her counterpart with HFrEF.

Plasma transforming growth factor β1 as a biochemical marker to predict the persistence of atrial fibrillation after the surgical maze procedure

OBJECTIVES The Cox maze procedure was developed as a surgical treatment for atrial fibrillation. However, atrial fibrillation recurs in some patients, and atrial remodeling in the form of fibrosis can lead to perpetuation of atrial fibrillation. To identify the predictor of the persistence of atrial fibrillation after the maze procedure using cryoablation, we evaluated the preoperative plasma transforming growth factor beta1. We also examined the correlations between plasma transforming growth factor beta1 levels and the degree of atrial fibrosis. METHODS Preoperative plasma transforming growth factor beta1 levels were measured in 86 consecutive patients (age, 54 +/- 12 years) who underwent both the open heart operation for valvular heart disease and the surgical maze procedure with cryoablation for persistent atrial fibrillation. We measured the degree of fibrosis from the tissue of the left atrium. RESULTS At 1 years follow-up, 10 of 86 patients had persistent atrial fibrillation. Patients with persistent atrial fibrillation had higher preoperative plasma transforming growth factor beta1 levels than the patients with sinus rhythm (0.44 +/- 0.29 vs 0.32 +/- 0.15 ng/mL, P = .03). Patients with persistent atrial fibrillation had higher mRNA expressions of collagen III and lower mRNA expressions of atrial natriuretic peptide than those with sinus rhythm, and the plasma transforming growth factor beta1 levels correlated with the degree of fibrosis in the left atrium (r = 0.497, P = .022). Multiple logistic regression analysis revealed that plasma transforming growth factor beta1 levels were independently associated with the postoperative persistence of atrial fibrillation at 1 years follow-up. CONCLUSIONS Preoperative plasma transforming growth factor beta1 levels could be used to predict the persistence of atrial fibrillation at 1 years follow-up after the surgical maze procedure by using cryoablation. Preoperative plasma transforming growth factor beta1 levels were correlated with the degree of fibrosis in the left atria of patients with mitral valvular heart disease.