TAK1 Limits Death Receptor Fas-Induced Proinflammatory Cell Death in Macrophages.

Fas, a member of the death receptor family, plays a central role in initiating cell death, a biological process crucial for immune homeostasis. However, the immunological and pathophysiological impacts to which enhanced Fas signaling gives rise remain to be fully understood. Here we demonstrate that TGF-ß-activated kinase 1 (TAK1) works as a negative regulator of Fas signaling in macrophages. Upon Fas engagement with high concentrations of FasL, mouse primary macrophages underwent cell death, and, surprisingly, Fas stimulation led to proteolytic cleavage of gasdermin (GSDM) family members GSDMD and GSDME, a hallmark of pyroptosis, in a manner dependent on caspase enzymatic activity. Remarkably, TAK1-deficient macrophages were highly sensitive to even low concentrations of FasL. Mechanistically, TAK1 negatively modulated RIPK1 kinase activity to protect macrophages from excessive cell death. Intriguingly, mice deficient for TAK1 in macrophages (TAK1mKO mice) spontaneously developed tissue inflammation, and, more important, the emergence of inflammatory disease symptoms was markedly diminished in TAK1mKO mice harboring a catalytically inactive RIPK1. Taken together, these findings not only revealed an unappreciated role of TAK1 in Fas-induced macrophage death but provided insight into the possibility of perturbation of immune homeostasis driven by aberrant cell death.

Combination therapy of modified electroconvulsive therapy and long-acting injectable aripiprazole for dopamine supersensitivity psychosis: a case report.

In the treatment of schizophrenia, long-term pharmacotherapy with D2-receptor antagonists can induce dopamine supersensitivity psychosis (DSP). We report a male patient with schizophrenia with suspected DSP due to excessive polypharmacy. He was hospitalized for several years. Most psychotropic drugs were reduced and subsequently stopped without the exacerbation of symptoms by administering modified electroconvulsive therapy (mECT). Aripiprazole was then selected as the main drug for treatment, which was subsequently changed to the long-acting injection formulation. He was eventually discharged and returned home. Combination therapy with mECT and aripiprazole, especially the long-acting injectable formulation, may help improve and prevent DSP.

Subjective achievement from psychiatry rotation in the Japanese postgraduate residency system: a longitudinal questionnaire study.

BACKGROUND: Psychiatry rotation has been mandatory in the Japanese postgraduate residency system since 2020. Some psychiatry-related competency items are stipulated as mandatory for residents. The current study aimed to clarify whether psychiatry rotation affected residents' subjective achievement of these competency items. METHODS: This longitudinal study was conducted among postgraduate residents who completed a rotation in the psychiatry department at Nagasaki University Hospital across two academic years (2020-2021). The survey was administered at the start and at the end of the psychiatry rotation. Residents evaluated their subjective understanding and confidence regarding initiating treatment for these competency items using a six-point Likert scale. The average scores for each item were compared between pre-rotation and post-rotation. RESULTS: In total, 99 residents (91.7%) responded to this survey. Residents had significantly higher scores at post-rotation compared with pre-rotation in all psychiatry-related competency items in both subjective understanding and confidence in initiating treatment. Additionally, strong effect sizes were found for many items. CONCLUSION: Residents improved learning about psychiatry-related competency items through psychiatry rotation. This finding suggests that it is reasonable for psychiatry rotation to be mandatory in the current Japanese postgraduate residency system. The importance of psychiatry is likely to increase in both undergraduate and postgraduate medical education in the future. It is necessary to continuously update educational strategies to meet changing social needs over time. As this study was conducted at a single institution, a multi-center study is needed to expand the current findings.

Neuropathology of the spinal nerve roots, spinal cord, and brain in the first autopsied case of Charcot-Marie-Tooth disease 4F with a D651N mutation in the periaxin gene.

Charcot-Marie-Tooth disease (CMT) 4F is an autosomal recessive, hereditary peripheral neuropathy, mostly caused by mutations in the periaxin gene (PRX). This article reports neuropathological findings of the spinal nerve roots, spinal cord, and brain of a patient with CMT4F and a D651N missense mutation in PRX. The patient was a 74-year-old woman who had a history of peripheral neuropathy with onset at the age of 30 years. She also had a history of infantile paralysis at the age of 18 months. The most pronounced autopsy finding was diffuse enlargement of anterior and posterior nerve roots, accentuated at the lumbo-sacral levels. On microscopy, the swollen nerve roots showed a loss of large-diameter myelinated fibers and formation of numerous onion bulbs. Most of the onion bulbs lacked the central, regenerating thin myelin sheaths, and in large-diameter nerve fibers whose axons had been lost, collagen fibers occupied the center of the onion bulbs. Some nerve roots formed glial bundles at the proximal end. The spinal cord showed degeneration of the gracile fascicles, and the lumbar segment anterior horn showed an asymmetric neuronal loss with rarefaction of the neuropil. The brain did not show any notable changes except for multiple foci of a radial microcolumnar arrangement of neurons in the cerebral cortex. Degeneration of the lumbar segment anterior horn is most likely secondary to the anterior radiculopathy, but a localized circulatory disturbance is another possibility.

Dystypia Associated with Diaschisis of the Middle Frontal Gyri after Left Angular Infarction.

Dystypia without aphasia, agraphia, or apraxia is a rare symptom and has been suggested to result from a lesion in the left middle frontal cortex. We herein describe a man with dystypia with agraphia due to infarction of the left angular gyrus. His dystypia seemed to result from the convergence failure of the kana into the alphabetical spellings. During dystypia, hypoperfusion of the bilateral middle frontal cortices was discovered. However, after his symptoms improved, blood flow in the middle frontal cortices returned to normal. This case suggests that the middle frontal cortex is downstream of the angular gyrus in the dictating pathway and a lesion in the left middle frontal cortex could cause pure dystypia.

Akinetopsia on Driving.

Akinetopsia is a quite rare symptom. Two types of akinetopsia have been reported: one is cinematographic vision, and the other is invisibility of moving objects. These symptoms are thought to occur due to dysfunction of the MT/V5 area at the occipitoparietal region. I herein describe a 54-year-old man who collided with a car parked on the left side of the road while driving. He complained that the parked car looked to be moving forwards and he could not stop his car when he noticed that it was parked. Magnetic resonance imaging disclosed the fresh infarction on the right temporoparietal region involving the MT/V5 area. His symptom during driving was considered cinematographic vision and it was the cause of the traffic accident. Akinetopsia resulted in illusory kinetopsia on driving and the traffic accident.

Clinical and genetic features of Charcot-Marie-Tooth disease 2F and hereditary motor neuropathy 2B in Japan.

Mutations in small heat shock protein beta-1 (HspB1) have been linked to Charcot-Marie-Tooth (CMT) disease type 2F and distal hereditary motor neuropathy type 2B. Only four cases with HSPB1 mutations have been reported to date in Japan. In this study between April 2007 and October 2014, we conducted gene panel sequencing in a case series of 1,030 patients with inherited peripheral neuropathies (IPNs) using DNA microarray, targeted resequencing, and whole-exome sequencing. We identified HSPB1 variants in 1.3% (13 of 1,030) of the patients with IPNs, who exhibited a male predominance. Based on neurological and electrophysiological findings, seven patients were diagnosed with CMT disease type 2F, whereas the remaining six patients were diagnosed with distal hereditary motor neuropathy type 2B. P39L, R127W, S135C, R140G, K141Q, T151I, and P182A mutations identified in 12 patients were described previously, whereas a novel K123* variant with unknown significance was found in 1 patient. Diabetes and impaired glucose tolerance were detected in 6 of the 13 patients. Our findings suggest that HSPB1 mutations result in two phenotypes of inherited neuropathies and extend the phenotypic spectrum of HSPB1-related disorders.

New endoplasmic reticulum stress regulator, Gipie, regulates the survival of vascular smooth muscle cells and the neointima formation after vascular injury.

OBJECTIVE: The accumulation of unfolded protein in the endoplasmic reticulum (ER) initiates an adaptive stress response, termed the unfolded protein response. Previous studies suggested that ER stress might be involved in the formation of neointima after vascular injury. We recently discovered a novel regulator of ER stress, 78-kDa glucose-regulated protein-interacting protein induced by ER stress (Gipie). The objective of this study was to elucidate the role of Gipie using models of vascular disease. APPROACH AND RESULTS: We investigated the functions of Gipie in cultured vascular smooth muscle cells (VSMCs) and in a vascular injury model of a rat carotid artery. The expression of Gipie was predominantly detected in synthetic VSMCs and to a much lesser extent in contractile VSMCs, which was augmented by treatment with thapsigargin. Gipie knockdown increased the phosphorylation levels of c-Jun N-terminal kinase and the number of apoptotic cells under ER stress. Moreover, Gipie knockdown decreased the mature form of collagen I in synthetic VSMCs. The expression of Gipie was rarely detected in the medial VSMCs of the intact carotid artery, whereas it was detected in most of the neointimal cells and some of the medial VSMCs after balloon injury. Depletion of Gipie in the rat carotid artery attenuated the neointimal thickening, which was accompanied by increased cell death in the neointima. Conversely, overexpression of Gipie augmented the neointimal thickening. CONCLUSIONS: Gipie participates in the ER stress response in VSMCs and plays an important role in neointima formation after vascular injury.

Serum uric acid as a predictor of future hypertension: Stratified analysis based on body mass index and age.

BACKGROUND: Serum uric acid level is a predictor of future hypertension. However, its dependence on body mass index or age is unclear. METHODS: We examined 26,442 Japanese males aged 18-60years free from hypertension or diagnosed cardiovascular disease at baseline followed up between 2000 and 2010. Participants were categorized into three groups according to the tertile of serum uric acid levels [mg/dL; 1st (reference): 0.1-5.3; 2nd: 5.4-6.2; 3rd: 6.3-11.6]. Incident hypertension was defined as newly detected blood pressure≥140/90mmHg and/or antihypertensive drugs initiation. Body mass index (<25kg/m(2) vs. ≥25kg/m(2)) and age (<40years vs. ≥40years) were stratified into two groups. RESULTS: During a mean follow-up of 7.2years, there were 11,361 (43%) hypertension cases. Mean serum uric acid levels (mg/dL) at baseline in each group were 1st tertile, 4.6; 2nd tertile, 5.8; and 3rd tertile, 7.0. The cumulative incident hypertension rate was significantly higher in the 3rd tertile (50.8%) than in the 1st (37.4%). Multiple-adjusted hazard ratios (95% confidence interval) for incident hypertension compared with 1st tertile were 1.01 (0.96-1.05) and 1.15 (1.10-1.21) in the 2nd and 3rd tertile, respectively. There was a significant interaction between age and serum uric acid level (p for interaction=0.035). In subjects aged ≥40years, the 3rd serum uric acid group showed higher hazard ratios [1.48 (1.38-1.59)]. CONCLUSION: High serum uric acid level was associated with future hypertension in young and middle-aged Japanese males. This association was stronger among subjects ≥40years old.

Wnt11 gene therapy with adeno-associated virus 9 improves the survival of mice with myocarditis induced by coxsackievirus B3 through the suppression of the inflammatory reaction.

The wnt signaling pathway plays important roles in development and in many diseases. Recently several reports suggest that non-canonical Wnt proteins contribute to the inflammatory response in adult animals. However, the effects of Wnt proteins on virus-induced myocarditis have not been explored. Here, we investigated the effect of Wnt11 protein in a model of myocarditis induced by coxsackievirus B3 (CVB3) using recombinant adeno-associated virus 9 (rAAV9). The effect of Wnt11 gene therapy on a CVB3-induced myocarditis model was examined using male BALB/c mice. Mice received a single intravenous injection of either rAAV9-Wnt11 or rAAV9-LacZ 2 weeks before intraperitoneal administration of CVB3. Intravenous injection of the rAAV9 vector resulted in efficient, durable, and relatively cardiac-specific transgene expression. Survival was significantly greater among rAAV9-Wnt11 treated mice than among mice treated with rAAV9-LacZ (87.5% vs. 54.1%, P < 0.05). Wnt11 expression also reduced the infiltration of inflammatory cells, necrosis of the myocardium, and suppressed the mRNA expression of inflammatory cytokines. This is the first report to show that Wnt11 expression improves the survival of mice with CVB3-induced myocarditis. AAV9-mediated Wnt11 gene therapy produces beneficial effects on cardiac function and increases the survival of mice with CVB3-induced myocarditis through the suppression of both infiltration of inflammatory cells and gene expression of inflammatory cytokines.

Akt-dependent Girdin phosphorylation regulates repair processes after acute myocardial infarction.

Myocardial infarction is a leading cause of death, and cardiac rupture following myocardial infarction leads to extremely poor prognostic feature. A large body of evidence suggests that Akt is involved in several cardiac diseases. We previously reported that Akt-mediated Girdin phosphorylation is essential for angiogenesis and neointima formation. The role of Girdin expression and phosphorylation in myocardial infarction, however, is not understood. Therefore, we employed Girdin-deficient mice and Girdin S1416A knock-in (Girdin(SA/SA)) mice, replacing the Akt phosphorylation site with alanine, to address this question. We found that Girdin was expressed and phosphorylated in cardiac fibroblasts in vitro and that its phosphorylation was crucial for the proliferation and migration of cardiac fibroblasts. In vivo, Girdin was localized in non-cardiomyocyte interstitial cells and phosphorylated in α-smooth muscle actin-positive cells, which are likely to be cardiac myofibroblasts. In an acute myocardial infarction model, Girdin(SA/SA) suppressed the accumulation and proliferation of cardiac myofibroblasts in the infarcted area. Furthermore, lower collagen deposition in Girdin(SA/SA) mice impaired cardiac repair and resulted in increased mortality attributed to cardiac rupture. These findings suggest an important role of Girdin phosphorylation at serine 1416 in cardiac repair after acute myocardial infarction and provide insights into the complex mechanism of cardiac rupture through the Akt/Girdin-mediated regulation of cardiac myofibroblasts.

Girdin/GIV regulates transendothelial permeability by controlling VE-cadherin trafficking through the small GTPase, R-Ras.

Vascular permeability is regulated by intercellular junction organization of endothelial cells, the dysfunction of which is implicated in numerous pathological conditions. Molecular mechanisms of how endothelial cells regulate intercellular junction in response to extracellular signals, however, have so far remained elusive. This study identified that Girdin (also termed GIV), an Akt substrate functioning in post natal angiogenesis, was expressed in a mature endothelial monolayer, where it regulated VE-cadherin trafficking to maintain vascular integrity. Girdin depletion abrogated VEGF-induced VE-cadherin endocytosis and the disassembly of adherens junctions in a monolayer of endothelial cells, thus leading to a significant decrease in the permeability. We also showed that activated R-Ras, a member of the Ras family GTPase, known to be a master regulator of transendothelial permeability, interacts with Girdin, and facilitates the complex formation between Girdin and VE-cadherin in endothelial cells. However, the increased permeability mediated by the loss of R-Ras was rescued by Girdin depletion, thus suggesting that the interaction of Girdin with R-Ras functions in VE-cadherin trafficking pathways distinct from endocytosis. The recycling of VE-cadherin was promoted by the exogenous expression of the active mutant of R-Ras, which was attenuated in the Girdin-depleted endothelial cells. These results show that Girdin regulates transendothelial permeability in synergy with R-Ras and VE-cadherin in an endothelial monolayer.

Persistent superconductor currents in holographic lattices.

We consider a persistent superconductor current along the direction with no translational symmetry in a holographic gravity model. Incorporating a lattice structure into the model, we numerically construct novel solutions of hairy charged stationary black branes with momentum or rotation along the latticed direction. The lattice structure prevents the horizon from rotating, and the total momentum is only carried by matter fields outside the black brane horizon. This is consistent with the black hole rigidity theorem, and it suggests that in dual field theory with lattices, superconductor currents are made up of "composite" fields, rather than "fractionalized" degrees of freedom. We also show that our solutions are consistent with the superfluid hydrodynamics.

Therapeutic reendothelialization by induced pluripotent stem cells after vascular injury--brief report.

OBJECTIVE: Endothelial damage is an early requisite step for atherosclerosis after vascular injury. It has been reported that vascular wall cells can develop from induced pluripotent stem (iPS) cell-derived fetal liver kinase-1-positive (Flk-1(+)) cells. Here, we investigated the efficacies of intravenously administered iPS cell-derived Flk-1(+) cells on reendothelialization and neointimal hyperplasia in a mouse model of vascular injury. APPROACH AND RESULTS: Femoral arteries of KSN nude mice were injured using a steel wire. Mouse iPS cell-derived Flk-1(+) or Flk-1(-) cells were intravenously injected into those mice at 24 hours after vascular injury. Delivery of iPS cell-derived Flk-1(+) cells significantly attenuated neointimal hyperplasia compared with controls. Evans blue staining of the injured vessel revealed that administration of iPS cell-derived Flk-1(+) significantly enhanced reendothelialization compared with the Flk-1(-) cell control group. Recruitment of PKH26-labeled iPS cell-derived Flk-1(+) cells to the site of injury was also detectable. Expression level of CXCR4 in iPS cell-derived Flk-1(+) cells was 7.5-fold higher than that of iPS cell-derived Flk-1(-) cells. Stromal cell-derived factor-1α treatment significantly enhanced adhesion and migration of iPS cell-derived Flk-1(+) cells to the endothelia, but these were not observed in Flk-1(-) cells. CONCLUSIONS: Intravenously administered iPS cell-derived Flk-1(+) cells are recruited to the site of vascular injury, thereby enhancing reendothelialization followed by suppression of neointimal hyperplasia. Administration of iPS cell-derived Flk-1(+) cells is a potentially useful therapeutic means for vascular dysfunction and prevention of restenosis after angioplasty.

Associations of proteinuria and the estimated glomerular filtration rate with incident hypertension in young to middle-aged Japanese males.

OBJECTIVE: To investigate the independent associations of proteinuria and the estimated glomerular filtration rate (eGFR) with incident hypertension. METHODS: We investigated 29,181 Japanese males 18-59years old without hypertension in 2000 and examined whether proteinuria and the eGFR predicted incident hypertension independently over 10years. Incident hypertension was defined as a newly detected blood pressure of ≥140/90mmHg and/or the initiation of antihypertensive drugs. Proteinuria and the eGFR were categorized as dipstick negative (reference), trace or ≥1+ and ≥60 (reference), 50-59.9 or <50ml/min/1.73m(2), respectively. Cox proportional hazards models were used to estimate the hazard ratios (HRs) of incident hypertension. RESULTS: At baseline, 236 (0.8%) and 477 (1.6%) participants had trace and ≥1+ dipstick proteinuria, while 1416 (4.9%) and 129 (0.4%) participants had an eGFR of 50-59.9 and <50ml/min/1.73m(2), respectively. The adjusted HRs were significant for proteinuria ≥1+ (HRs 1.20, 95% CI: 1.06-1.35) and an eGFR of <50ml/min/1.73m(2) (1.29, 1.03-1.61). When two non-referent categories were combined (dipstick≥trace vs. negative and eGFR<60 vs. ≥60ml/min/1.73m(2)), the association was more significant for proteinuria (1.15, 1.04-1.27) than for eGFR (0.99, 0.92-1.07). CONCLUSIONS: Proteinuria and a reduced eGFR are independently associated with future hypertension in young to middle-aged Japanese males.

Renal dysfunction and atherosclerosis of the neointima following bare metal stent implantation.

BACKGROUND: Recently, neoatherosclerosis within the neointima after bare metal stent (BMS) implantation, which could cause late restenosis and very late stent thrombosis, has been a cause of concern. Renal dysfunction has been related to late cardiovascular events after coronary intervention. The present study was conducted focusing on the relationship between renal dysfunction and neointimal tissue characteristics with BMS restenosis using integrated backscatter intravascular ultrasound (IB-IVUS). METHODS: We prospectively performed IB-IVUS in 80 consecutive patients requiring target lesion revascularization after BMS implantation; the patients were divided into two groups according to the estimated glomerular filtration [eGFR: ≥60 (n = 49) and <60 ml/min/1.73 m(2) (n = 31)]. RESULTS: Patients with eGFR <60 ml/min/1.73 m(2) had a significantly higher percentage of lipid tissue volume within the neointima and a lower percentage of fibrous tissue volume than those with eGFR ≥60 ml/min/1.73 m(2) (23.2 ± 9.4 vs. 18.0 ± 7.0%, p = 0.005, and 75.3 ± 9.3 vs. 80.4 ± 7.0%, p = 0.007, respectively). Using logistic regression analysis, eGFR <60 ml/min/1.73 m(2) and duration from stent implantation ≥48 months were independent predictors of increased lipid tissue volume within the neointima (odds ratio, 3.93; 95% confidence interval, 1.15-13.46, p = 0.03, and odds ratio, 7.56; 95% confidence interval, 2.02-28.30, p = 0.003, respectively). CONCLUSIONS: Lower eGFR levels were associated with greater lipid tissue volume within the neointima after BMS deployment, suggesting the development of atherosclerosis. Renal dysfunction may affect neointimal tissue characteristics and thus leading to an increased risk of late stent failure.

The actin-binding protein Girdin and its Akt-mediated phosphorylation regulate neointima formation after vascular injury.

RATIONALE: It is well established that the migration and proliferation of vascular smooth muscle cells (VSMCs) have major roles in the vascular remodeling process. Our previous study showed that the Akt substrate Girdin, which is expressed in VSMCs and endothelial cells, is essential for postnatal angiogenesis. However, the function of Girdin and its Akt-mediated phosphorylation in VSMCs and their in vivo roles in vascular remodeling remain to be elucidated. OBJECTIVE: We investigated the function of Girdin and its Akt-mediated phosphorylation using cultured VSMCs and animal models of vascular remodeling. METHODS AND RESULTS: The depletion of Girdin by RNA interference disrupted the rearrangement of the actin cytoskeleton in VSMCs, resulting in impaired cell migration. The depletion of Girdin also inhibited VSMC proliferation. Girdin expression was highly upregulated and its serine at position 1416 was phosphorylated in the neointima of carotid arteries after balloon injury in a rat model. The introduction of an adenovirus harboring short hairpin RNA against Girdin attenuated the proliferation of VSMCs and neointima formation without affecting reendothelialization. Furthermore, we found that neointima formation after femoral wire injury was significantly attenuated in Girdin S1416A knock-in mice, in which the Akt phosphorylation site of Girdin was mutated, thus indicating a major role for Girdin phosphorylation in vascular remodeling. CONCLUSIONS: These findings indicate that Girdin and its Akt-mediated phosphorylation have major roles in the migration and proliferation of VSMCs and vascular remodeling, making the Akt/Girdin signaling pathway a potential target for the development of new therapeutics for vascular diseases.

Impact of adiponectin and leptin on long-term adverse events in Japanese patients with acute myocardial infarction. Results from the Nagoya Acute Myocardial Infarction Study (NAMIS).

BACKGROUND: Low adiponectin levels and high leptin levels are associated with a high incidence of developing cardiovascular disease. However, the relationship between the levels of these adipokines and the development of adverse events after acute myocardial infarction (AMI) remains unclear. METHODS AND RESULTS: This study enrolled 724 Japanese subjects with AMI who underwent successful emergency percutaneous coronary intervention (PCI). Their serum adiponectin and leptin levels were measured 7 days after AMI onset. There were 63 adverse events during the 3-year follow-up. The levels of adiponectin and leptin and the leptin to adiponectin ratio, were significantly associated with adverse events [hazard ratio 2.08 (95% confidence interval (CI) 1.33-3.24), P=0.001; hazard ratio 0.62 (95% CI 0.43-0.90), P=0.012; hazard ratio 0.59 (95% CI 0.45-0.76), P<0.001, respectively]. The leptin to adiponectin ratio remained a significant independent predictor of adverse events during long-term follow-up in a multivariable analysis [adjusted hazard ratio 0.60 (95% CI 0.43-0.83), P=0.002]. CONCLUSIONS: Higher adiponectin and lower leptin levels are associated with a high incidence of adverse events in Japanese patients after AMI, and the leptin to adiponectin ratio independently predicts prognosis after AMI.

Long-term outcome of drug-eluting vs. bare-metal stents in patients with acute myocardial infarction. Subgroup analysis of the nagoya acute myocardial infarction study (NAMIS).

BACKGROUND: The purpose of the present study was to compare the 5-year clinical outcomes after implantation of drug-eluting stent (DES) and bare-metal stent (BMS) in Japanese patients with acute myocardial infarction (AMI). METHODS AND RESULTS: This study was a subgroup analysis of the Nagoya Acute Myocardial Infarction Study (NAMIS). It included 658 AMI patients, of which 280 were treated with a DES and 378 with a BMS. The major adverse cardiac event (MACE)-free rates during the 5-year follow-up period were similar between the 2 groups (95.7% vs. 96.8%, P=0.482). A significant difference was seen, however, in the target lesion revascularization (TLR) rates (7.9% vs. 17.7%, P<0.0001). Interestingly, there was no significant difference between the 2 groups from year 1 to 5 with regard to late TLR (2.5% vs. 2.1%, P=0.906), despite the markedly lower incidence of TLR within the first year in the DES group compared with the BMS group (5.4% vs. 15.6%, P<0.0001). CONCLUSIONS: In this long-term follow-up analysis of DES compared to BMS in Japanese patients with AMI, there was no significant difference in the incidence of MACE. Although a lower rate of TLR was observed in DES group within the first year, the superiority of DES in relation to the incidence of TLR disappeared after the first year following primary percutaneous coronary intervention.