Toshiyuki Nishikido

Outcome of prolonged balloon inflation for the management of coronary perforation.

BACKGROUND Coronary perforation (CP) is a rare, sometimes lethal complication of percutaneous coronary intervention (PCI). OBJECTIVES The purpose of this study was to review the cases of CP and to investigate the management after CP. METHODS A total of 3469 PCIs were performed in our institution from April 1999 to April 2008. All CP cases were identified from our computerized database. RESULTS Thirty patients were identified as having CP (0.86%). According to the Ellis classification, we determined the grade of perforation as type I in 17 cases (56%), type II in 2 cases (7%), and type III in 11 cases (37%). Most CPs were caused by wires (53%), while balloons, stents, and atherectomy devices were responsible for 7%, 37%, and 3%, respectively. Wire caused only 1 case of type III CP (6%), while stent caused 9 type III CPs (82%, p<0.01). Four patients (36%) with type III CP required urgent coronary artery bypass graft surgery (CABG), while no patient with type I/II CP required it (p<0.01). Prolonged balloon inflations were effective for 8 cases out of 11 stent CPs, however, the ballooning duration was significantly longer than that in wire and balloon CP (44±37min vs. 21±13min, p<0.05). CONCLUSIONS Stent CP often causes type III CP and one third of type III CP required urgent CABG. Although stent CP required longer balloon inflations for the management, prolonged balloon inflation might be useful for the management even in the stent CP.

EGCG, a green tea catechin, attenuates the progression of heart failure induced by the heart/muscle-specific deletion of MnSOD in mice.

BACKGROUND Manganese superoxide dismutase (MnSOD) is an important antioxidant enzyme affected in heart/muscle-specific MnSOD-deficient mice (H/M-SOD2-/-), which develop progressive congestive heart failure and exhibit pathology typical of dilated cardiomyopathy. METHODS In this study we investigated the beneficial effects of epigallocatechin gallate (EGCG) on the cardiac remodeling and telomere biology in H/M-SOD2-/- mice. H/M-SOD2-/- mice were divided into three groups: those receiving normal drinking water (KO), a low dose of EGCG (L: 10mg/L), and a high dose of EGCG (H: 100mg/L) beginning at eight weeks of age and lasting for eight weeks. RESULTS The mice in the KO group exhibited significantly dilated cardiac remodeling with reduced contractility, which was prevented by the administration of EGCG. Although the mortality of KO mice was about 50% at 16 weeks of age, the mice that received EGCG had a high survival rate. The cardiac dilatation with reduced cardiac contraction in KO mice was prevented by EGCG treatment. The levels of myocardial oxidative stress and free fatty acids were lower in the group treated with EGCG compared with the KO group. The increased expression of nitric oxide synthase 2, nitrotyrosine, fatty acid synthase, Toll-like receptor 4, and Sirt1 in the KO mice were prevented by EGCG treatment. The shortening of the telomere length, decreased telomerase activity in KO mice were also prevented by EGCG. CONCLUSIONS H/M-SOD2-/- mice receiving EGCG have a lower mortality rate and exhibit less inflammation and a better preserved cardiac function and telomere biology.

Deletion of Apoptosis Inhibitor of Macrophage (AIM)/CD5L Attenuates the Inflammatory Response and Infarct Size in Acute Myocardial Infarction

Background An excessive inflammatory response after myocardial infarction (MI) increases myocardial injury. The toll‐like receptor (TLR)‐4 is activated by the recognition of endogenous ligands and is proinflammatory when there is myocardial tissue injury. The apoptosis inhibitor of the macrophage (AIM) is known to provoke an efflux of saturated free fatty acids (FFA) due to lipolysis, which causes inflammation via the TLR‐4 pathway. Therefore, this study investigated the hypothesis that AIM causes a proinflammatory response after MI. Methods and Results The left anterior descending coronary artery was ligated to induce MI in both AIM‐knockout (AIM−/−) and wild‐type (WT) mice. After 3 days, the inflammatory response from activation of the TLR‐4/NFκB pathway was assessed, and infarct size was measured by staining with triphenyltetrazolium chloride. In addition, left ventricular remodeling was examined after 28 days. Although the area at risk was similar between AIM−/− and WT mice, the infarct size was significantly smaller in AIM−/− mice (P=0.02). The heart weight–to–body weight ratio and myocardial fibrosis were also decreased in the AIM−/− mice, and the 28‐day survival rate was improved (P<0.01). With the reduction of plasma FFA in AIM−/− mice, myocardial IRAK4 and NFκB activity were decreased (all P<0.05). Moreover, there was a reduction in myeloperoxidase activity and inducible nitric oxide synthase as part of the inflammatory response (P<0.01, P=0.03, respectively). Furthermore, NFκB DNA‐binding activation via TLR‐4, neutrophil infiltration, and inflammatory mediators were decreased in AIM−/− mice. Conclusions The deletion of AIM reduced the inflammatory response and infarct size and improved survival after myocardial infarction.

High-dose statin therapy with rosuvastatin reduces small dense LDL and MDA-LDL: The Standard versus high-dose therApy with Rosuvastatin for lipiD lowering (SARD) trial.

BACKGROUND Cardiovascular events (CV) continue to occur due to residual risks in high-risk patients in spite of substantial reductions in the low-density lipoprotein cholesterol (LDL) with statins. It has been reported that the small-dense LDL (sd-LDL) components of high atherogenic particles are associated with an increased risk of CV, more than large buoyant LDL. However, there are few reports regarding the effects of high-dose statin therapy in improving atherogenic lipoproteins. METHODS AND RESULTS In this prospective, randomized, open-label, multicenter study, a total of 111 high-risk patients were randomly assigned to two groups. In the high-dose therapy group, 58 patients were administered 5mg of rosuvastatin per day for four weeks, after which the dose was titrated to 10mg for the following eight weeks. In the low-dose therapy group, 53 patients were given 2.5mg for 12 weeks. We evaluated the lipid profiles, including the levels of sd-LDL, malondialdehyde-modified LDL-cholesterol (C) (MDA-LDL) as oxidized-LDL, and remnant-like particle-cholesterol. The LDL-C, non-high-density lipoprotein (HDL), and LDL-C/HDL-C ratio were decreased in the high-dose therapy group (p<0.01). Moreover, the sd-LDL and MDA-LDL levels were significantly reduced in the high-dose therapy group (p<0.05). There were no serious adverse events in either group. CONCLUSIONS High-dose statin therapy significantly reduced the sd-LDL and MDA-LDL components of atherosclerotic lipoproteins without adverse events in comparison with low-dose statin therapy.

Azelnidipine Inhibits the Differentiation and Activation of THP-1 Macrophages through the L-Type Calcium Channel

Aim: Recently, calcium channel blockers (CCBs) have been reported to reduce atherosclerosis with anti-inflammatory or antiatherosclerotic effects in vivo. It is well established that monocytes and macrophages play important roles in promoting atherosclerosis. However, the effects of CCBs on macrophage activation remain unclear. The aim of this study was to evaluate the effects of azelnidipine, a dihydropyridine L-type CCB, on the activation of macrophages and to clarify the mechanisms of the effects of CCBs on atherosclerosis. Methods: THP-1 monocytes, a human leukemic cell line, were stimulated with 50 ng/mL of phorbol-12-myristate-13-acetate (PMA) 1 h after pretreatment with 10 µM azelnidipine or dimethyl sulfoxide (DMSO), and harvested. Results: Azelnidipine blocked the expression of intercellular adhesion molecule-1 quantified by FACS analysis. The expression levels of Apo E and MMP9, which are markers of macrophage differentiation, were inhibited by azelnidipine as evaluated by quantitative RT-PCR. The level of LOX-1 mRNA, a scavenger receptor, was also reduced significantly by pretreatment with 10 µM azelnidipine. Azelnidipine also lowered the uptake of acetylated LDL. The expression of the L-type calcium channel Cav1.2 was 10-fold higher after 24 h of PMA stimulation. A knockdown of the CACNA1C gene, which encodes Cav1.2 protein in humans, with siRNA blocked the effect of reducing adhesion by azelnidipine, indicating that the effects of azelnidipine on macrophage differentiation were expressed through the CACNA1C gene. Conclusion: Our results suggest that azelnidipine has potent antiatherosclerotic properties by inhibition of macrophage activation through Cav1.2.

PS 13-17 APOPTOSIS INHIBITOR OF MACROPHAGE ACTIVATES INFLAMMATORY RESPONSE AFTER ACUTE MYOCARDIAL INFARCTION

Objective: The persistent inflammation response after myocardial infarction increases myocardial injury, and causes heart failure due to cardiac dysfunction and remodeling. Toll-like receptors (TLR)-4 was activated by the recognition of not only pathogen-associated molecular patterns but also endogenous ligands and it serves as proinflammatory function in circumstances involving myocardial tissue injury. Whereas, it was reported the apoptosis inhibitor of macrophage (AIM) provoke an efflux of saturated free fatty acid (FFA), one of the TLR4 ligands, due to lipolysis, which causes the chronic inflammation via TLR-4 pathway in adipose tissue. This study investigated the hypothesis that AIM activates a proinflammatory response after myocardial infarction. Design and Method: The ligation of the left anterior descending coronary artery to induced myocardial infarction was performed on both AIM-deficient(AIM−/−) mice and wild type (WT) mice. After 3 days, the inflammation responses were assessed in TLR-4/NFkB activation pathway. And infarct size/area-at-risk was measured by staining with Evans blue and triphenyltetrazolium chloride. In addition, the left ventricular remodeling was examined after 28 days. Results: AIM−/− mice showed significantly smaller infarct size compared with WT mice given similar area at risk (20.8 ± 0.6% vs. 27.8 ± 1.9%, p = 0.02). In AIM−/− mice with reduction of plasma FFA, IRAK4 and NFkB activity were decreased on myocardium (p = 0.02, 0.03 vs. WT, respectively). Moreover, there was the reduction of myeloperoxidase activity and iNOS in the inflammation response (p < 0.01, p = 0.03, respectively). We found that the NFkB DNA-binding activation via TLR-4, neutrophil infiltration, and inflammatory mediator were decreased in AIM−/− mice compared with WT mice after 3days. And, the heart weight to body weight ratio, myocardial fibrosis of AIM−/− mice were decreased, and a survival rate improved after 28 days (p < 0.01). Conclusions: AIM−/− mice demonstrated less inflammation response and smaller infarction size after myocardial infarction, suggesting AIM may activate a proinflammatory of TLR-4 after myocardial infarction.

PS 14-04 THE EFFECTS OF THE VILDAGLIPTIN FOR CARDIAC DYSFUNCTION AFTER THE ACUTE MYOCARDIAL INFARCTION

Objective: The diabetes mellitus is one of high risk factors for the acute coronary syndrome. The dipeptidyl-peptidase 4(DPP-4) inhibitors is the antihyperglycemic agents with the possible protective effects for cardiovascular system. It was reported that Glucagon-like peptide-1 had improved left ventricular systolic function, and DPP-4 inhibitors had attenuated post-infarct myocardial remodeling. In contrast, the rate of hospitalization for heart failure was increased by saxagliptin in SAVOR-TIMI 53 trial. The purpose of this study was evaluating effects of DPP-4 inhibitors on the cardiac function by DPP-4 inhibitors in patients with myocardial infarction. Design and Method: We performed an open-label, parallel-group comparison study between vildagliptin treatment group and non-incretin treatment group. A total of 28 patients of type2 diabetes without use of insulin were enrolled and 21 patients were assigned to vildagliptin treatment group and non-incretin treatment group randomly within 48 hours after the acute myocardial infarction onset. Eleven patients had been taken 100 mg of vildagliptin per-day and/or another antihyperglycemic agent in vildagliptin treatment group, and 10 patients had been taken antihyperglycemic agents without incretin agents in non-incretin group. We evaluated the effects and safety for cardiac function by vildagliptin 6 months later. Results: The glycated hemoglobin levels were lower with vidagliptin (5.95 ± 0.94%vs 6.99 ± 1.63%; p = 0.04), and glycemic standard deviation (SD) and J-index without mean amplitude of glycemic excursions (MAGE) in glycemic variability were improved significantly in most of vildagliptin treatment group. (p < 0.05, p = 0.03) There were no serious adverse events such as hypoglycemia, pancreatitis, and the hospitalization for heart failure in either group. There were the protective tendencies but no statistically significant changes of the ejection fraction, deceleration time, E/A, E/e’, and BNP levels between two groups. (p = 0.24, p = 0.10, p = 0.40, p = 0.37, and p = 0.25, respectively). Conclusions: Our results suggest that vildagliptin did not improved cardiac dysfunction statistically including the systolic and diastolic functions significantly after myocardial infarction so far.

PS 13-13 EGCG, A GREEN TEA CATECHIN, ATTENUATES THE PROGRESSION OF HEART FAILURE INDUCED BY THE HEART/MUSCLE-SPECIFIC DELETION OF MnSOD IN MICE

Objective: Manganese superoxide dismutase (MnSOD) is an important antioxidant enzyme affected in heart/muscle-specific MnSOD-deficient mice (H/M-SOD2−/−), which develop progressive congestive heart failure and exhibit pathology typical of dilated cardiomyopathy. Design and Method: In this study we investigated the beneficial effects of epigallocatechin gallate (EGCG) on the cardiac remodeling and telomere biology in H/M-SOD2 −/−mice. Methods: H/M-SOD2−/− mice were divided into three groups: those receiving normal drinking water (KO), a low dose of EGCG (L: 10 mg/L) and a high dose of EGCG (H: 100 mg/L) beginning at eight weeks of age and lasting for eight weeks. Results: The mice in the KO group exhibited significantly dilated cardiac remodeling with reduced contractility, which was prevented by the administration of EGCG. Although the mortality of KO mice was about 50% at 16 weeks of age, the mice that received EGCG had a high survival rate. The cardiac dilatation with reduced cardiac contraction in KO mice was prevented by EGCG treatment. The levels of myocardial oxidative stress and free fatty acids were lower in the group treated with EGCG compared with the KO group. The increased expression of nitric oxide synthase 2, nitrotyrosine, fatty acid synthase, Toll-like receptor 4 and Sirt1 in the KO mice were prevented by EGCG treatment. The shortening of the telomere length, decreased telomerase activity in KO mice were also prevented by EGCG. Conclusions: H/M-SOD2−/− mice receiving EGCG have a lower mortality rate and exhibit less inflammation and a better preserved cardiac function and telomere biology.

Radiation Exposure Associated with Preoperative Multidetector Computed Tomography of Pulmonary Vein Isolation

Background: Multidetector computed tomography (MDCT) visualization of the pulmonary veins (PV) and left atrium provides the necessary anatomic information for successful left atrial ablation and PV isolation. However, the potential risks due to exposure to ionizing radiation associated with MDCT have raised concerns. Objectives: The purpose of this study was to compare radiation exposure between prospective and retrospective ECG-gated CT angiography (hereafter, prospective CTA, retrospective CTA). Methods: The 64-slice MDCT (Discovery CT 750HD, GE Healthcare) was performed 78 consecutive patients. Twenty-eight patients were analyzed by prospective CTA using step-and-shoot protocol, and 50 patients were analyzed by retrospective CTA. Results: Mean (±SD) effective radiation exposure in the prospective CTA group was 2.2±0.8 mSv compared to 15.4±5.9 mSv in the retrospective CTA group (p<0.001). Conclusion: In preoperative evaluation of PV isolation, prospective CTA can reduce radiation exposure than retrospective CTA.