Hae Chang Jeong

Mesenchymal stem cells reciprocally regulate the M1/M2 balance in mouse bone marrow-derived macrophages

Mesenchymal stem cells (MSCs) have been widely studied for their applications in stem cell-based regeneration. During myocardial infarction (MI), infiltrated macrophages have pivotal roles in inflammation, angiogenesis and cardiac remodeling. We hypothesized that MSCs may modulate the immunologic environment to accelerate regeneration. This study was designed to assess the functional relationship between the macrophage phenotype and MSCs. MSCs isolated from bone marrow and bone marrow-derived macrophages (BMDMs) underwent differentiation induced by macrophage colony-stimulating factor. To determine the macrophage phenotype, classical M1 markers and alternative M2 markers were analyzed with or without co-culturing with MSCs in a transwell system. For animal studies, MI was induced by the ligation of the rat coronary artery. MSCs were injected within the infarct myocardium, and we analyzed the phenotype of the infiltrated macrophages by immunostaining. In the MSC-injected myocardium, the macrophages adjacent to the MSCs showed strong expression of arginase-1 (Arg1), an M2 marker. In BMDMs co-cultured with MSCs, the M1 markers such as interleukin-6 (IL-6), IL-1β, monocyte chemoattractant protein-1 and inducible nitric oxide synthase (iNOS) were significantly reduced. In contrast, the M2 markers such as IL-10, IL-4, CD206 and Arg1 were markedly increased by co-culturing with MSCs. Specifically, the ratio of iNOS to Arg1 in BMDMs was notably downregulated by co-culturing with MSCs. These results suggest that the preferential shift of the macrophage phenotype from M1 to M2 may be related to the immune-modulating characteristics of MSCs that contribute to cardiac repair.

Protective role of 5-azacytidine on myocardial infarction is associated with modulation of macrophage phenotype and inhibition of fibrosis

We examined whether a shift in macrophage phenotype could be therapeutic for myocardial infarction (MI). The mouse macrophage cell line RAW264.7 was stimulated with peptidoglycan (PGN), with or without 5‐azacytidine (5AZ) treatment. MI was induced by ligation of the left anterior descending coronary artery in rats, and the rats were divided into two groups; a saline‐injection group and a 5AZ‐injection group (2.5 mg/kg/day, intraperitoneal injection). LV function was evaluated and immunohistochemical analyses were performed 2 weeks after MI. Cardiac fibrosis was induced by angiotensin II (AngII) infusion with or without 5AZ (5 mg/kg/day) in mice. Nitric oxide was produced by PGN, which was reduced by 77.87% after 5AZ treatment. Both induction of inducible nitric oxide synthase (iNOS) and iNOS promoter activity by PGN were inhibited by 5AZ. Ejection fraction (59.00 ± 8.03% versus 42.52 ± 2.58%), contractility (LV dP/dt‐max, 8299.76 ± 411.56 mmHg versus 6610.36 ± 282.37 mmHg) and relaxation indices (LV dP/dt‐min, −4661.37 ± 210.73 mmHg versus −4219.50 ± 162.98 mmHg) were improved after 5AZ administration. Cardiac fibrosis in the MI+5AZ was 8.14 ± 1.00%, compared with 14.93 ± 2.98% in the MI group (P < 0.05). Arginase‐1(+)CD68(+) macrophages with anti‐inflammatory phenotype were predominant in the infarct border zone of the MI+5AZ group, in comparison with the MI group. AngII‐induced cardiac fibrosis was also attenuated after 5AZ administration. In cardiac fibroblasts, pro‐fibrotic mediators and cell proliferation were increased by AngII, and these increases were attenuated after 5AZ treatment. 5AZ exerts its cardiac protective role through modulation of macrophages and cardiac fibroblasts.

Red cell distribution width as a novel predictor for clinical outcomes in patients with paroxysmal atrial fibrillation.

AIMS Elevated red cell distribution width (RDW) has been known to be associated with adverse long-term outcomes in patients with cardiovascular diseases. We aimed to evaluate relationship between RDW values and clinical outcomes in patients with paroxysmal atrial fibrillation (AF). METHODS AND RESULTS We analysed 567 patients who were newly diagnosed as paroxysmal AF. Clinical outcomes were analysed after median 4.8 (3.4-6.9) years follow-up. The composite clinical outcomes were defined as the composite of death, hospitalization due to heart failure, and new-onset stroke. Bleeding events were composed of major and minor bleeding. The relationship of RDW with clinical outcomes was assessed using continuous or categorical variables as quartiles: <12.8, 12.8-13.2, 13.3-13.8, and ≥13.9%. Patients with the highest RDW quartile were the oldest and had more frequent history of heart failure. CHA2DS2-VASc score was increased along with increasing RDW quartiles (1.75 ± 1.48 vs. 1.77 ± 1.63 vs. 1.87 ± 1.61 vs. 2.33 ± 1.65, P = 0.008). Incidence of new-onset stroke (log-rank P = 0.032), the composite clinical outcomes (log-rank P = 0.014), and bleeding events (log-rank P = 0.001) were increased as increasing RDW quartiles. Multivariate analysis identified that RDW was a significant predictor for new-onset stroke [adjusted hazard ratio (HR) 1.32, 95% confidence interval (CI) 1.06-1.65, P = 0.015], the composite clinical outcomes (adjusted HR 1.21, 95% CI 1.03-1.41, P = 0.017), and bleeding events (adjusted HR 1.36, 95% CI 1.13-1.64, P = 0.001). CONCLUSIONS RDW can be a new, useful, novel predictor of clinical and safety outcomes in patients with paroxysmal AF.

Statin therapy to reduce stent thrombosis in acute myocardial infarction patients with elevated high-sensitivity C-reactive protein

OBJECTIVE We investigated whether statin therapy and high-sensitivity C-reactive protein (hs-CRP) levels were associated with the risk of stent thrombosis (ST) in acute myocardial infarction (AMI) patients. METHODS A total of 9,162 AMI patients who underwent coronary stent implantation were analyzed in the Korean Acute Myocardial Infarction Registry. The study population was divided into four groups according to level of hs-CRP and peri-procedural statin treatment: low hs-CRP (≤ 2.0mg/L) and high hs-CRP (>2mg/L) with or without statin therapy. We compared the incidence of early ST among the groups. RESULTS Statin therapy did not significantly affect the development of early ST in the low hs-CRP group. In the high hs-CRP group, however, the incidence of early ST was significantly decreased with statin treatment. In a subgroup analysis of the high hs-CRP group, patients aged less than 65 years, without diabetes, with a high body mass index, and with a high Killip class seemed to benefit more from statin therapy. In a multivariable Cox regression analysis of the high hs-CRP group, lack of statin therapy was a significant predictor of ST incidence. CONCLUSIONS Peri-procedural statin treatment had an effect on reduced incidence of early ST in AMI patients with high levels of hs-CRP.

Comparison of Coronary Plaque Components between Non-Culprit Lesions in Patients with Acute Coronary Syndrome and Target Lesions in Patients with Stable Angina: Virtual Histology-Intravascular Ultrasound Analysis

Background and Objectives The differences in plaque characteristics between non-culprit lesions (NCL) in acute coronary syndrome (ACS) patients (ACS-NCL) and target lesions (TL) in stable angina (SA) patients (SA-TL) are not well understood. We used a virtual histology-intravascular ultrasound (VH-IVUS) to compare the plaque components between ACS-NCL and SA-TL. Subjects and Methods We compared VH-IVUS findings between 290 ACS-NCL and 276 SA-TL. VH-IVUS classified the color-coded tissue into four major components: green (fibrotic); yellow-green (fibro-fatty); white {dense calcium (DC)}; and red {necrotic core (NC)}. Thin-cap fibroatheroma (TCFA) was defined as a NC ≥10% of the plaque area in at least 3 consecutive frames without overlying fibrous tissue in the presence of ≥40% plaque burden. Results Although the plaque burden was significantly smaller (52±13% vs. 54±14%, p=0.044), ACS-NCL had a greater %NC area (17.9±11.6% vs. 14.3±8.7%, p<0.001) and %DC area (9.7±9.8% vs. 8.1±8.0%, p=0.032) compared with SA-TL at the minimum lumen site. By volumetric analysis, ACS-NCL had a greater %NC volume (15.8±9.2% vs. 13.9±7.4%, p=0.006) compared with SA-TL. TCFA was observed more frequently in ACS-NCL compared with SA-TL (27.6% vs. 18.1%, p=0.032). Independent predictors of TCFA by multivariate analysis were ACS {odds ratio (OR): 2.204, 95% CI: 1.321-3.434, p=0.021} and high-sensitivity C-reactive protein (OR: 1.101; 95% CI 1.058-1.204, p=0.035). Conclusion Although the plaque burden was significantly smaller, ACL-NCL had more vulnerable plaque components compared with SA-TL, and ACS and high-sensitivity C-reactive protein were the independent predictors of TCFA.

Progressive Dilation of the Left Atrium and Ventricle after Acute Myocardial Infarction Is Associated with High Mortality

Background and Objectives The purpose of this study is to identify the prevalence of progressive dilation in patients with acute myocardial infarction (AMI) combined with heart failure (HF) and determine the prognostic significance and associated factors with a geometric change of an infarcted heart. Subjects and Methods A total of 1310 AMI patients with HF (63.9±12.5 years, 70% male) between November 2005 and April 2011 underwent echocardiography at admission and one year later. Left ventricular (LV) remodeling is defined as 20% progression, and left atria (LA) remodeling is 10% compared with the initial volume index. Results The prevalence of both LA and LV remodeling was 13.9%; LV only was 9.3%, LA only 22.8% and non-remodeling was 55.1%, respectively. In the non-remodeling group, Killip class II was more frequent (83.9%, p<0.001) whereas in other remodeling groups, Killip class III was more frequent. Initial wall motion score index, ejection fraction, maximal cardiac enzyme, high sensitive C-reactive protein, B type natriuretic peptide, and triglyceride serum levels were significantly associated with heart remodeling. All causes of death occurred in 168 cases (12.8%) during the follow-up period. Mortality was the highest in the LV and LA remodeling group (20.9%) and the lowest in the non-remodeling group (11.4%). During the period of follow-up, the cumulative survival rate was significantly lower in the groups of LA and LV remodeling than in others (log rank p=0.006). Conclusion Total mortality was significantly increased in patients AMI with geometrically progressive LA and LV dilatation.

Impact of high admission blood pressure without history of hypertension on clinical outcomes of patients with acute myocardial infarction: From Korea Acute Myocardial Infarction Registry

Impact of high admission blood pressurewithout history of hypertension on clinical outcomes of patients with acute myocardial infarction: From Korea Acute Myocardial Infarction Registry Jae Yeong Cho , Myung Ho Jeong ⁎, Youngkeun Ahn , Hae Chang Jeong , Su Young Jang , Sung Soo Kim , Shi Hyun Rhew , Young Wook Jeong , Ki Hong Lee , Keun-Ho Park , Doo Sun Sim , Nam Sik Yoon , Hyun Ju Yoon , Kye Hun Kim , Young Joon Hong , Hyung Wook Park , Ju Han Kim , Jeong Gwan Cho , Jong Chun Park , Young Jo Kim , Chong Jin Kim , Myeong Chan Cho , Kyoo Rok Han , Hyo Soo Kim , the Korea Acute Myocardial Infarction Registry Investigators

5-Azacytidine modulates interferon regulatory factor 1 in macrophages to exert a cardioprotective effect

Macrophages are actively involved in inflammatory responses during the progression of cardiac injury, including myocardial infarction (MI). A previous study showed that 5-azacytidine (5AZ), a DNA methylation inhibitor, can ameliorate cardiac injury by shifting macrophages toward an anti-inflammatory phenotype via iNOS inhibition. Here, we show that the beneficial effect of 5AZ is associated with sumoylation of interferon regulatory factor-1 (IRF1) in macrophages. IRF1 is a critical transcription factor for iNOS induction and is antagonized by IRF2. In the stimulated macrophages, IRF1 accumulated in the nucleus without degradation by 5AZ treatment. In animal study, 5AZ administration resulted in significant improvements in cardiac function and fibrosis. IRF1-expressing macrophages were more abundant in the 5AZ-treated MI group than in the PBS-treated MI group. Because sumoylated IRF1 is known to mimic IRF2, we examined the IRF1 sumoylation. Sumoylated IRF1 was resistant to degradation and significantly increased in the 5AZ-treated MI group. Collectively, 5AZ had a protective effect after MI by potentiation of IRF1 sumoylation and is suggested as a novel therapeutic intervention for cardiac repair.

Pik3ip1 modulates cardiac hypertrophy by inhibiting PI3K pathway.

Cardiac hypertrophy is an adaptive response to various physiological and pathological stimuli. Phosphoinositide-3 kinase (PI3K) is a highly conserved lipid kinase involved in physiological cardiac hypertrophy (PHH). PI3K interacting protein1 (Pik3ip1) shares homology with the p85 regulatory subunit of PI3K and is known to interact with the p110 catalytic subunit of PI3K, leading to attenuation of PI3K activity in liver and immune cells. However, the role of Pik3ip1 in the heart remains unknown. In the present study, the effects of Pik3ip1 on cardiac hypertrophy were examined. We found that the expression level of Pik3ip1 was markedly higher in cardiomyocytes than in fibroblasts. The interaction of Pik3ip1 with the p110a subunit of PI3K in the heart was identified by immunoprecipitation using neonatal rat cardiomyocytes (NRCM). Approximately 35% knockdown of Pik3ip1 was sufficient to induce myocardial hypertrophy. Pik3ip1 deficiency was shown to lead to activation of PI3K/protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) signaling pathway, increasing protein synthesis and cell size. However, adenovirus-mediated overexpression of Pik3ip1 attenuated PI3K-mediated cardiac hypertrophy. Pik3ip1 was upregulated by PHH due to swimming training, but not by pathological cardiac hypertrophy (PAH) due to pressure-overload, suggesting that Pik3ip1 plays a compensatory negative role for PHH. Collectively, our results elucidate the mechanisms for the roles of Pik3ip1 in PI3K/AKT signaling pathway.

Comparative assessment of angiotensin ii type 1 receptor blockers in the treatment of acute myocardial infarction: surmountable vs. insurmountable antagonist

BACKGROUND The mechanisms of antagonism vary between the angiotensin II type 1 receptor blockers (ARBs): insurmountable antagonism and surmountable antagonism. Recent retrospective observational studies suggest that ARBs may not have equivalent benefits in various clinical situations. The aim of this study was to compare the effect of two categories of ARBs on the long-term clinical outcomes of patients with acute myocardial infarction (AMI). METHODS We analyzed the large-scale, prospective, observational Korea Acute Myocardial Infarction Registry study, which enrolled 2740 AMI patients. They divided by the prescription of surmountable ARBs or insurmountable ARBs at discharge. Primary outcome was major adverse cardiac events (MACEs), defined as a composite of cardiac death, nonfatal MI, and re-percutaneous coronary intervention, coronary artery bypass graft surgery. RESULTS In the overall population, the MACEs rate in 1 year was significantly higher in the surmountable ARB group (14.3% vs. 11.2%, p=0.025), which was mainly due to increased cardiac death (3.3% vs. 1.9%, p=0.031). Matching by propensity-score showed consistent results (MACEs rate: 14.9% vs. 11.4%, p=0.037). In subgroup analysis, the insurmountable ARB treatment significantly reduced the incidence of MACEs in patients with left ventricular ejection fraction greater than 40%, with a low killip class, with ST segment elevation MI, and with normal renal function. CONCLUSIONS In our study, insurmountable ARBs were more effective on long-term clinical outcomes than surmountable ARBs in patients with AMI.