Jae Yeong Cho

Tubastatin A suppresses renal fibrosis via regulation of epigenetic histone modification and Smad3-dependent fibrotic genes.

Inflammation and fibrosis are implicated in the pathogenesis of hypertensive kidney damage. We previously demonstrated that a nonspecific histone deacetylase (HDAC) inhibitor attenuates cardiac fibrosis in deoxycorticosterone acetate-salt hypertensive rats, which induces HDAC6 protein and enzymatic activity. However, the HDAC inhibitors effect and mechanism have not yet been demonstrated. We sought to determine whether an HDAC6-selective inhibitor could treat hypertension and kidney damage in angiotensin II-infused mice. Hypertension was induced by infusion of ANG in mice. Tubastatin A, an HDAC6 selective inhibitor, did not regulate blood pressure. Hypertensive stimuli enhanced the expression of HDAC6 in vivo and in vitro. We showed that the inhibition of HDAC6 prevents fibrosis and inflammation as determined by quantitative real-time PCR, western blot, and immunohistochemistry. Small interfering RNA (siRNA) against HDAC6 or Smad3 attenuated hypertensive stimuli-induced fibrosis and inflammation, whereas Smad2 siRNA failed to inhibit fibrosis. Interestingly, the combination of the HDAC6 inhibitor and Smad3 knockdown synergistically blocked transforming growth factor β (TGF-β) or ANG-induced fibrosis. We also demonstrated for the first time, to our knowledge, that acetylation of collagen type I can be regulated by HDAC6/p300 acetyltransferase. The chromatin immunoprecipitation assay revealed that the HDAC6 inhibitor suppressed TGF-β-induced acetylated histone H4 or phospho-Smad2/3 to Smad3 binding elements in the fibrosis-associated gene promoters including collagen type I. These results suggest that HDAC6 may be a valuable therapeutic target for the treatment of hypertension-induced kidney fibrosis and inflammation.

Effect of contrast-induced nephropathy on cardiac outcomes after use of nonionic isosmolar contrast media during coronary procedure

Contrast-induced nephropathy (CIN) has been increasing and seems to be associated with clinical outcomes in ischemic heart disease. This study aimed to assess the incidence, predictors, and cardiac outcomes of CIN when nonionic isosmolar contrast media (iodixanol, Visipaque(®), GE Healthcare, Cork, Ireland) was used. Between January 2005 and July 2008, 510 patients (69.2 ± 9.0 years of age, 384 men) undergoing diagnostic coronary angiography (CAG) or percutaneous coronary intervention (PCI) were divided into two groups according to the development of CIN (CIN group: n=74; non-CIN group: n=436). CIN developed in 74 patients (14.5%). They were more likely to have diabetes (55.4% vs. 42.9%, p=0.045), decreased left ventricular ejection fraction (LVEF) (50.1 ± 12.6% vs. 57.7 ± 13.9%, p<0.001), and lower baseline hematocrit level (32.4 ± 5.3% vs. 36.6 ± 5.5%, p<0.001). Multiple logistic regression analysis revealed baseline hematocrit (odds ratio 0.900, 95% confidence interval 0.851-0.952, p<0.001), decreased LVEF (odds ratio 0.967, 95% confidence interval 0.949-0.986, p=0.001), and baseline creatinine level (odds ratio 2.317, 95% confidence interval 1.252-4.286, p=0.007) as independent predictors of CIN. At 1-year follow-up, patients with CIN were found to have more adverse outcomes than without CIN in Cox proportional hazards analysis (hazard ratio 13.068, 95% confidence interval 2.425-70.434, p=0.003). CIN was mostly associated with baseline creatinine level rather than CM amount using nonionic isosmolar CM. We found that patients with CIN had worse event-free survival than patients without CIN after multifactorial adjustment.

Gallic acid prevents isoproterenol-induced cardiac hypertrophy and fibrosis through regulation of JNK2 signaling and Smad3 binding activity

Gallic acid, a type of phenolic acid, has been shown to have beneficial effects in inflammation, vascular calcification, and metabolic diseases. The present study was aimed at determining the effect and regulatory mechanism of gallic acid in cardiac hypertrophy and fibrosis. Cardiac hypertrophy was induced by isoproterenol (ISP) in mice and primary neonatal cardiomyocytes. Gallic acid pretreatment attenuated concentric cardiac hypertrophy. It downregulated the expression of atrial natriuretic peptide, brain natriuretic peptide, and beta-myosin heavy chain in vivo and in vitro. Moreover, it prevented interstitial collagen deposition and expression of fibrosis-associated genes. Upregulation of collagen type I by Smad3 overexpression was observed in cardiac myoblast H9c2 cells but not in cardiac fibroblasts. Gallic acid reduced the DNA binding activity of phosphorylated Smad3 in Smad binding sites of collagen type I promoter in rat cardiac fibroblasts. Furthermore, it decreased the ISP-induced phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal regulated kinase (ERK) protein in mice. JNK2 overexpression reduced collagen type I and Smad3 expression as well as GATA4 expression in H9c2 cells and cardiac fibroblasts. Gallic acid might be a novel therapeutic agent for the prevention of cardiac hypertrophy and fibrosis by regulating the JNK2 and Smad3 signaling pathway.

Gallic acid attenuates hypertension, cardiac remodeling, and fibrosis in mice with NG-nitro-L-arginine methyl ester-induced hypertension via regulation of histone deacetylase 1 or histone deacetylase 2

Objective: Gallic acid, a natural chemical found in plants, has been reported to show antioxidant, anticancer, and anti-inflammatory effects. We investigated the efficacy of a short-term or long-term treatment with gallic acid in NG-nitro-L-arginine methyl ester (L-NAME)-induced hypertensive mice and the underlying regulatory mechanism. Methods: Hypertension was sufficiently induced after 2 weeks of L-NAME administration. Cardiac remodeling was assessed by echocardiography. Hypertrophic markers, transcription factors, and fibrosis-related gene expression were evaluated by quantitative real-time polymerase chain reaction and western blotting. Results: Gallic acid effectively lowered SBP, regardless of the administration route (intraperitoneal or oral). L-NAME increased the left ventricular (LV) thickness without an increase in the total heart weight. Weekly echocardiography demonstrated that gallic acid significantly reduced LV posterior wall and septum thickness in chronic L-NAME mice from 3 to 7 weeks. The administration of gallic acid to mice showed a dual preventive and therapeutic effect on the L-NAME-induced LV remodeling. The effect was associated with the suppression of the gene expression of hypertrophy markers and the GATA-binding factor 6 (GATA6) transcription factor. Short-term or long-term treatment with gallic acid attenuated cardiac fibrosis and reduced the expression of histone deacetylase 1 and 2 in H9c2 cells and in rat primary cardiac fibroblasts, as well as in vivo. Small interfering RNA knockdown confirmed the association of these enzymes with L-NAME-induced cardiac remodeling and fibrosis. Conclusion: These results suggested that gallic acid may be a potential therapeutic agent for the treatment of cardiovascular diseases with hypertension and cardiac fibrosis.

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.

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.

High Lipoprotein(a) Levels are Associated With Long-Term Adverse Outcomes in Acute Myocardial Infarction Patients in High Killip Classes

Background and Objectives An elevated concentration of lipoprotein(a) {Lp(a)} is associated with an increased prevalence and increased severity of coronary artery disease. However, the relationship between Lp(a) levels and outcomes after acute myocardial infarction (AMI) is unclear. Subjects and Methods Between October 2005 and June 2007, we measured serum Lp(a) levels in 832 consecutive AMI patients (age, 62.8±12.4 years, 600 men) on admission. They were divided into tertiles according to their serum Lp(a) levels {Tertile 1 (n=276), Lp(a)<13.8 mg/dL; Tertile 2 (n=279), Lp(a)=13.8-30.6 mg/dL; Tertile 3 (n=277), Lp(a)>30.6 mg/dL}. Results There were no differences in baseline clinical characteristics among Tertiles 1, 2, and 3, except for proportions of Killip class III-IV patients (5.8% vs. 10.0% vs. 18.8%, respectively, p<0.001). There were significant differences in left ventricular ejection fractions (57.3±11.4% vs. 55.9±12.3% vs. 53.1±13.1%, p<0.001). Among the laboratory findings, there were significant differences in total cholesterol (173.3±37.2 vs. 183.5±38.9 vs. 185.3±43.8 mg/dL, p=0.001), low density lipoprotein-cholesterol (111.3±34.3 vs. 122.9±34.7 vs. 123.3±39.4 mg/dL, p<0.001), apolipoprotein B (92.8±25.4 vs. 100.8±26.0 vs. 101.9±28.8 mg/dL, p<0.001), and amino-terminal pro-brain natriuretic peptide levels (1805.2±4343.3 vs. 2607.9±5216.3 vs. 3981.5±7689.7 pg/mL, p<0.001). After adjusting for multiple variables in the high Killip class (III-IV) subgroup, the risk estimate for major adverse cardiovascular events (MACE) at 1-year follow-up was significantly higher in Tertile 3 than in Tertiles 1 or 2 (hazard ratio 6.723, 95% confidence interval 1.037-43.593, p=0.046). Conclusion In patients in high Killip classes, high serum levels of Lp(a) were significantly associated with long-term adverse outcomes after AMI.

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

Clinical, angiographic, and intravascular ultrasound predictors of early stent thrombosis in patients with acute myocardial infarction.

Risk factors reported for early stent thrombosis (EST) included acute coronary syndrome, suboptimal antiplatelet therapy, procedural factors such as residual dissection and underexpansion of stents, and smaller final lumen area and inflow/outflow disease (residual stenosis or dissection) by intravascular ultrasound (IVUS) [1–4]. However, the predictors of EST including all variables such as baseline characteristics, laboratory data, angiographic and IVUS findings in patients with acute myocardial infarction (AMI) are still not well known. From January 2007 to December 2009, we identified 418 consecutive patients with a first AMI who underwent pre-percutaneous coronary intervention (PCI) IVUS within 24 h from symptom onset, were stented successfully, and had post-PCI IVUS imaging. EST included acute (b24 h) and subacute ST (1 to 30 days) after stent implantation. Cardiac-specific troponin I (cTnI) levels were measured by a paramagnetic particle, chemiluminescent immunoenzymatic assay (Beckman, Coulter Inc., Fullerton, California). No-reflow was defined as postPCI TIMI grade 0, 1, or 2 flow. Tissue prolapse was defined as tissue extrusion through the stent strut at post-PCI. The baseline characteristics, angiographic and IVUS findings are summarized in Table 1. EST occurred in 16 patients (3.8%). Glycoprotein IIb/IIIa inhibitor was used more frequently in patients with EST compared with those without EST. Pre-PCI peak creatine kinase-MB and cTnI were significantly higher in patients with EST compared with those without EST. Pre-PCI TIMI flow grade was significantly lower in patients with EST compared with those without EST. More stents were deployed in patients with EST compared with those without EST. Noreflow during or after PCI was developed more frequently in EST group than in non-EST group (87.5% vs. 12.2%, p b 0.001). Plaque burden at the minimum lumen site was significantly greater in patients with EST compared with those without EST. Pre-PCI plaque rupture and IVUSdetected thrombuswere observedmore frequently in patients with EST compared with those without EST. Post-stenting tissue prolapse was observed more frequently in patients with EST compared with those without EST (68.8% vs. 32.6%, p= 0.003). Independent predictors of EST are summarized in Table 2. Multivariate analysis showed that noreflow, pre-PCI peak cTnI, and tissue prolapse were the independent predictors of EST. No-reflow can occur easily in lesions with various kinds of vulnerable plaque including plaque rupture and thrombus and this no-reflow is associated with microvascular damage which is likely to slow the epicardial coronary blood flow and to stagnate blood flow which may accelerate local thrombus formation [5]. The mechanism underlying the association between pre-PCI peak cTnI level and EST is not clear, although cTnI is associated with high thrombus grade with promoted thrombus formation in patients with AMI, who already have heightened systemic and intracoronary platelet reactivity, thrombin generation, and inflammation. Tissue prolapse may represent a source for thrombus accumulation in an environment that already has a high potential for thrombogenesis. Impaired arterial healing and ST have been associated with the prolapse of the necrotic core between stent struts. This is especially relevant in the setting of AMI, because such patients already have an increased risk for this devastating event [6]. In conclusion, the incidence of EST after stenting of infarct-related arteries was 3.8%. No-reflow, pre-PCI peak cTnI and tissue prolapse were associated with the development of EST after stent implantation in patients with AMI.