IVUS-Guided Wiring Improves the Clinical Outcomes of Angioplasty for Long Femoropopliteal CTO Compared with the Conventional Intraluminal Approach.

AIMS: This study aimed to assess the clinical efficacy of intravascular ultrasound (IVUS)-guided intraplaque wiring for femoropopliteal (FP) chronic total occlusion (CTO). METHODS: This single-center, retrospective, observational study was performed at the Japanese Red Cross Kyoto Daini Hospital. From March 2013 to June 2017, a total of 75 consecutive patients (mean age: 75.4±8.5 years; 59 males), who underwent endovascular treatment (EVT), having 82 de novo FP-CTO lesions, were enrolled in this study. Eleven of the lesions that met the exclusion criteria were excluded, and the remaining 71 lesions were divided into the IVUS-guided wiring group (n=34) and non-IVUS-guided wiring group (n=37). Primary patency, defined as a peak systolic velocity ratio of ＜2.4 on duplex ultrasonography, and freedom from clinically driven target lesion revascularization (CD-TLR) at 12 months were the primary outcomes. RESULTS: The mean lesion length was 21.6±8.9 cm. The frequencies of primary patency and freedom from CD-TLR were significantly higher in the IVUS-guided wiring group than in the non-IVUS-guided wiring group (70.0% vs. 52.2%, p=0.045; 83.9% vs. 62.8%, p=0.036, respectively). The complete clinically true lumen angioplasty rate was also higher in the IVUS-guided wiring group than in the non-IVUS-guided wiring group (91.1% vs. 51.3%, p＜0.001, respectively). The clinically true and false wire passage rates were respectively 97.3% and 2.7% in the IVUS-guided wiring group. CONCLUSION: IVUS-guided wiring improves the clinical outcomes of EVT for FP-CTO by achieving a high clinically true lumen wire passage rate.

The frequency and clinical characteristics of in-stent restenosis due to calcified nodule development after coronary stent implantation.

The purpose of this study was to evaluated the clinical characteristics of calcified nodule-like in-stent restenosis (ISR) lesions using optical coherence tomography (OCT) in vivo. A total of 124 ISR lesions that were treated with a repeat coronary intervention under OCT guidance were included in this analysis. ISR neointimal morphology was classified as "calcified nodule-like ISR", that appeared as a high-backscattering protruding mass with an irregular surface covered by signal-rich bands, or "non-calcified nodule-like ISR". The maximum arc and thickness of calcium behind the stent struts was also measured. Of the 124 ISR lesions, calcified nodule-like ISR was observed in 11 lesions (9%). OCT analysis data showed that the maximum arc of calcium and the maximum calcium thickness behind the stent were significantly larger in the calcified nodule-like ISR lesions than in the non-calcified nodule-like ISR lesions (269 ± 51 vs. 179 ± 92°, p < 0.01 and 989 ± 174 vs. 684 ± 241 µm, p < 0.01, respectively). The enlargement of the stent area was significantly larger in the calcified nodule-like ISR lesions than in the non-calcified nodule-like ISR lesions (1.6 ± 2.3 vs. 0.7 ± 1.3 mm2, p = 0.02). As a result, the enlargement of the lumen area tended to be larger in the calcified group (2.8 ± 1.7 vs. 2.4 ± 1.3 mm2, p = 0.3). Calcified nodule-like neointima within the stent could develop in approximately 10% of all ISR lesions, especially within stents deployed in severely calcified lesions.

Utility of angiography-physiology coregistration maps during percutaneous coronary intervention in clinical practice.

This study aimed to evaluate the utility and feasibility of physiological maps coregistered with angiograms using the pullback of a pressure guidewire with continuous instantaneous wave-free ratio (iFR) measurements. iFR pullback was obtained for 70 lesions from 70 patients with stable angina pectoris using SyncVision (Philips Corp.). Physiological maps were created, whereby the post-intervention iFR (post-iFR) was predicted as iFRpred. The iFR gap was defined if the difference between the iFRpred and post-iFR was ≥ 0.3. The lesion morphology changed from that during the physiological assessment to that during the angiographic assessment in 26 lesions (37.1%). In particular, 22.6% of angiographic tandem lesions changed to physiological focal lesions. The mean pre-intervention iFR, post-iFR, and iFRpred were 0.73 ± 0.17, 0.90 ± 0.06, and 0.93 ± 0.05, respectively. The mean difference between the iFRpred and post-iFR was 0.029 ± 0.099, with 95% limits of agreement of -0.070-0.128. iFR gaps occurred in 28 patients (40%). Notably, a new iFR gradient causing a ≥ 0.03 iFR drop after stenting occurred in 11 (15.7%) cases. The study patients were divided into two groups according to biases between post-iFR and iFRpred < 0.03 (good concordance group) or ≥ 0.03 (poor concordance group). The pre-intervention heart rate was the only independent predictor of poor concordance (odds ratio, 0.936; 95% confidence interval 0.883-0.992; p = 0.027). Physiological maps under resting conditions may contribute to a reduction in unnecessary stent placements without missing lesions requiring treatment. However, the predictive accuracy of post-iFR performance in the present study was slightly lower than that in the previous reports.

A colorimetric assay method for measuring d-glutamate cyclase activity.

In mammals, metabolism of free d-glutamate is regulated by d-glutamate cyclase (DGLUCY), which reversibly converts d-glutamate to 5-oxo-d-proline and H2O. Metabolism of these d-amino acids by DGLUCY is thought to regulate cardiac function. In this study, we established a simple, accurate, and sensitive colorimetric assay method for measuring DGLUCY activity. To this end, we optimized experimental procedures for derivatizing 5-oxo-d-proline with 2-nitrophenylhydrazine hydrochloride. 5-Oxo-d-proline was derivatized with 2-nitrophenylhydrazine hydrochloride in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide as a catalyst to generate the acid hydrazides, whose levels were then determined using a colorimetric method. Under optimized conditions, we examined the sensitivity and accuracy of the colorimetric method and compared our technique with other methods by high-performance liquid chromatography with ultraviolet-visible or fluorescence detection. Moreover, we assessed the suitability of this colorimetric method for measuring DGLUCY activity in biological samples. Our colorimetric method could determine DGLUCY activity with adequate validity and reliability. This method will help to elucidate the relationship among DGLUCY activity, the physiological and pathological roles of d-glutamate and 5-oxo-d-proline, and cardiac function.

Ablation of cardiac TIGAR preserves myocardial energetics and cardiac function in the pressure overload heart failure model.

Despite the advances in medical therapy, the morbidity and mortality of heart failure (HF) remain unacceptably high. HF results from reduced metabolism-contraction coupling efficiency, so the modulation of cardiac metabolism may be an effective strategy for therapeutic interventions. Tumor suppressor p53 (TP53) and its downstream target TP53-induced glycolysis and apoptosis regulator (TIGAR) are known to modulate cardiac metabolism and cell fate. To investigate TIGAR's function in HF, we compared myocardial, metabolic, and functional outcomes between TIGAR knockout (TIGAR-/-) mice and wild-type (TIGAR+/+) mice subjected to chronic thoracic transverse aortic constriction (TAC), a pressure-overload HF model. In wild-type mice hearts, p53 and TIGAR increased markedly during HF development. Eight weeks after TAC surgery, the left ventricular (LV) dysfunction, fibrosis, oxidative damage, and myocyte apoptosis were significantly advanced in wild-type than in TIGAR-/- mouse heart. Further, myocardial high-energy phosphates in wild-type hearts were significantly decreased compared with those of TIGAR-/- mouse heart. Glucose oxidation and glycolysis rates were also reduced in isolated perfused wild-type hearts following TAC than those in TIGAR-/- hearts, which suggest that the upregulation of TIGAR in HF causes impaired myocardial energetics and function. The effects of TIGAR knockout on LV function were also replicated in tamoxifen (TAM)-inducible cardiac-specific TIGAR knockout mice (TIGARflox/flox/Tg(Myh6-cre/Esr1) mice). The ablation of TIGAR during pressure-overload HF preserves myocardial function and energetics. Thus, cardiac TIGAR-targeted therapy to increase glucose metabolism will be a novel strategy for HF. NEW & NOTEWORTHY The present study is the first to demonstrate that TP53-induced glycolysis and apoptosis regulator (TIGAR) is upregulated in the myocardium during experimental heart failure (HF) in mice and that TIGAR knockout can preserve the heart function and myocardial energetics during HF. Reducing TIGAR to enhance myocardial glycolytic energy production is a promising therapeutic strategy for HF.

First-in-Man Clinical Pilot Study Showing the Safety and Efficacy of Intramuscular Injection of Basic Fibroblast Growth Factor With Atelocollagen Solution for Critical Limb Ischemia.

BACKGROUND: Therapeutic angiogenesis with basic fibroblast growth factor (bFGF) with atelocollagen was confirmed in a study using a limb ischemia mouse model. Because the number of elderly patients with critical limb ischemia (CLI) is increasing, particularly that caused by arteriosclerosis obliterans (ASO), the development of less invasive angiogenesis therapies desired. Methods and Results: This first-in-man clinical study was designed to assess the safety and efficacy of i.m. injection of bFGF with atelocollagen. Human recombinant bFGF (200 µg), combined with 4.8 mL 3% atelocollagen solution, was prepared and injected into the gastrocnemius muscle of the ischemic leg. The primary endpoint was safety, evaluated on all adverse events over 48 weeks after this treatment. The secondary endpoint was efficacy, evaluated by improvement of ischemic symptoms. No serious procedure-related adverse events were observed during the follow-up period. Visual analogue scale (VAS) score was significantly improved at 4, 24 and 48 weeks compared with baseline (P<0.05), and 7 patients became pain free during the follow-up period. Fontaine classification was improved in 4 of 10 patients at 48 weeks. Cyanotic lesions disappeared in 2 patients at 4 weeks. CONCLUSIONS: I.m. injection of bFGF with atelocollagen is safe and feasible in patients with CLI. Randomized controlled trials are therefore needed to confirm these results.

Structural and enzymatic properties of mammalian d-glutamate cyclase.

d-Glutamate cyclase (DGLUCY) is a unique enzyme that reversibly converts free d-glutamate to 5-oxo-d-proline and H2O. Mammalian DGLUCY is highly expressed in the mitochondrial matrix in the heart, and its downregulation disrupts d-glutamate and/or 5-oxo-d-proline levels, contributing to the onset and/or exacerbation of heart failure. However, detailed characterisation of DGLUCY has not yet been performed. Herein, the structural and enzymatic properties of purified recombinant mouse DGLUCY were examined. The results revealed a dimeric oligomerisation state, and both d-glutamate-to-5-oxo-d-proline and 5-oxo-d-proline-to-d-glutamate reactions were catalysed in a stereospecific manner. Catalytic activity is modulated by divalent cations and nucleotides including ATP and ADP. Interestingly, the presence of Mn2+ completely abolished the 5-oxo-d-proline-to-d-glutamate reaction but stimulated the d-glutamate-to-5-oxo-d-proline reaction. The optimum pH is ∼8.0, similar to that in the mitochondrial matrix, and the catalytic efficiency for d-glutamate is markedly higher than that for 5-oxo-d-proline. These findings suggest that DGLUCY functions as a metalloenzyme that degrades d-glutamate in the mitochondrial matrix in mammalian cells. The results also provide insight into the correlation between DGLUCY enzyme activity and the physiological and pathological roles of d-glutamate and 5-oxo-d-proline in cardiac function, which is of relevance to the risk of onset of heart failure.

Cardiac-Specific Bdh1 Overexpression Ameliorates Oxidative Stress and Cardiac Remodeling in Pressure Overload-Induced Heart Failure.

BACKGROUND: Energy starvation and the shift of energy substrate from fatty acids to glucose is the hallmark of metabolic remodeling during heart failure progression. However, ketone body metabolism in the failing heart has not been fully investigated. METHODS AND RESULTS: Microarray data analysis and mitochondrial isobaric tags for relative and absolute quantification proteomics revealed that the expression of D-ß-hydroxybutyrate dehydrogenase I (Bdh1), an enzyme that catalyzes the NAD+/NADH coupled interconversion of acetoacetate and ß-hydroxybutyrate, was increased 2.5- and 2.8-fold, respectively, in the heart after transverse aortic constriction. In addition, ketone body oxidation was upregulated 2.2-fold in transverse aortic constriction hearts, as determined by the amount of 14CO2 released from the metabolism of [1-14C] ß-hydroxybutyrate in isolated perfused hearts. To investigate the significance of this augmented ketone body oxidation, we generated heart-specific Bdh1-overexpressing transgenic mice to recapitulate the observed increase in basal ketone body oxidation. Bdh1 transgenic mice showed a 1.7-fold increase in ketone body oxidation but did not exhibit any differences in other baseline characteristics. When subjected to transverse aortic constriction, Bdh1 transgenic mice were resistant to fibrosis, contractile dysfunction, and oxidative damage, as determined by the immunochemical detection of carbonylated proteins and histone acetylation. Upregulation of Bdh1 enhanced antioxidant enzyme expression. In our in vitro study, flow cytometry revealed that rotenone-induced reactive oxygen species production was decreased by adenovirus-mediated Bdh1 overexpression. Furthermore, hydrogen peroxide-induced apoptosis was attenuated by Bdh1 overexpression. CONCLUSIONS: We demonstrated that ketone body oxidation increased in failing hearts, and increased ketone body utilization decreased oxidative stress and protected against heart failure.

D-Glutamate is metabolized in the heart mitochondria.

D-Amino acids are enantiomers of L-amino acids and have recently been recognized as biomarkers and bioactive substances in mammals, including humans. In the present study, we investigated functions of the novel mammalian mitochondrial protein 9030617O03Rik and showed decreased expression under conditions of heart failure. Genomic sequence analyses showed partial homology with a bacterial aspartate/glutamate/hydantoin racemase. Subsequent determinations of all free amino acid concentrations in 9030617O03Rik-deficient mice showed high accumulations of D-glutamate in heart tissues. This is the first time that a significant amount of D-glutamate was detected in mammalian tissue. Further analysis of D-glutamate metabolism indicated that 9030617O03Rik is a D-glutamate cyclase that converts D-glutamate to 5-oxo-D-proline. Hence, this protein is the first identified enzyme responsible for mammalian D-glutamate metabolism, as confirmed in cloning analyses. These findings suggest that D-glutamate and 5-oxo-D-proline have bioactivities in mammals through the metabolism by D-glutamate cyclase.

Activation of PPAR-α in the early stage of heart failure maintained myocardial function and energetics in pressure-overload heart failure.

Failing heart loses its metabolic flexibility, relying increasingly on glucose as its preferential substrate and decreasing fatty acid oxidation (FAO). Peroxisome proliferator-activated receptor α (PPAR-α) is a key regulator of this substrate shift. However, its role during heart failure is complex and remains unclear. Recent studies reported that heart failure develops in the heart of myosin heavy chain-PPAR-α transgenic mice in a manner similar to that of diabetic cardiomyopathy, whereas cardiac dysfunction is enhanced in PPAR-α knockout mice in response to chronic pressure overload. We created a pressure-overload heart failure model in mice through transverse aortic constriction (TAC) and activated PPAR-α during heart failure using an inducible transgenic model. After 8 wk of TAC, left ventricular (LV) function had decreased with the reduction of PPAR-α expression in wild-type mice. We examined the effect of PPAR-α induction during heart failure using the Tet-Off system. Eight weeks after the TAC operation, LV construction was preserved significantly by PPAR-α induction with an increase in PPAR-α-targeted genes related to fatty acid metabolism. The increase of expression of fibrosis-related genes was significantly attenuated by PPAR-α induction. Metabolic rates measured by isolated heart perfusions showed a reduction in FAO and glucose oxidation in TAC hearts, but the rate of FAO preserved significantly owing to the induction of PPAR-α. Myocardial high-energy phosphates were significantly preserved by PPAR-α induction. These results suggest that PPAR-α activation during pressure-overloaded heart failure improved myocardial function and energetics. Thus activating PPAR-α and modulation of FAO could be a promising therapeutic strategy for heart failure.NEW & NOTEWORTHY The present study demonstrates the role of PPAR-α activation in the early stage of heart failure using an inducible transgenic mouse model. Induction of PPAR-α preserved heart function, and myocardial energetics. Activating PPAR-α and modulation of fatty acid oxidation could be a promising therapeutic strategy for heart failure.

Pyk2 aggravates hypoxia-induced pulmonary hypertension by activating HIF-1α.

Pulmonary arterial hypertension (PAH) is a refractory disease characterized by uncontrolled vascular remodeling and elevated pulmonary arterial pressure. Although synthetic inhibitors of some tyrosine kinases have been used to treat PAH, their therapeutic efficacies and safeties remain controversial. Thus, the establishment of novel therapeutic targets based on the molecular pathogenesis underlying PAH is a clinically urgent issue. In the present study, we demonstrated that proline-rich tyrosine kinase 2 (Pyk2), a nonreceptor type protein tyrosine kinase, plays a crucial role in the pathogenesis of pulmonary hypertension (PH) using an animal model of hypoxia-induced PH. Resistance to hypoxia-induced PH was markedly higher in Pyk2-deficient mice than in wild-type mice. Pathological investigations revealed that medial thickening of the pulmonary arterioles, which is a characteristic of hypoxia-induced PH, was absent in Pyk2-deficient mice, suggesting that Pyk2 is involved in the hypoxia-induced aberrant proliferation of vascular smooth muscle cells in hypoxia-induced PH. In vitro experiments using human pulmonary smooth muscle cells showed that hypoxic stress increased the proliferation and migration of cells in a Pyk2-dependent manner. We also demonstrated that Pyk2 plays a crucial role in ROS generation during hypoxic stress and that this Pyk2-dependent generation of ROS is necessary for the activation of hypoxia-inducible factor-1α, a key molecule in the pathogenesis of hypoxia-induced PH. In summary, the results of the present study reveal that Pyk2 plays an important role in the pathogenesis of hypoxia-induced PH. Therefore, Pyk2 may represent a promising therapeutic target for PAH in a clinical setting.

Oxidative post-translational modifications develop LONP1 dysfunction in pressure overload heart failure.

BACKGROUND: Mitochondrial compromise is a fundamental contributor to heart failure. Recent studies have revealed that several surveillance systems maintain mitochondrial integrity. The present study evaluated the role of mitochondrial AAA+ protease in a mouse model of pressure overload heart failure. METHODS AND RESULTS: The fluorescein isothiocyanate casein assay and immunoblotting for endogenous mitochondrial proteins revealed a marked reduction in ATP-dependent proteolytic activity in failing heart mitochondria. The level of reduced cysteine was decreased, and tyrosine nitration and protein carbonylation were promoted in Lon protease homolog (LONP1), the most abundant mitochondrial AAA+ protease, in heart failure. Comprehensive analysis revealed that electron transport chain protein levels were increased even with a reduction in the expression of their corresponding mRNAs in heart failure, which indicated decreased protein turnover and resulted in the accumulation of oxidative damage in the electron transport chain. The induction of mitochondria-targeted human catalase ameliorated proteolytic activity and protein homeostasis in the electron transport chain, leading to improvements in mitochondrial energetics and cardiac contractility even during the late stage of pressure overload. Moreover, the infusion of mitoTEMPO, a mitochondria-targeted superoxide dismutase mimetic, recovered oxidative modifications of LONP1 and improved mitochondrial respiration capacity and cardiac function. The in vivo small interfering RNA repression of LONP1 partially canceled the protective effects of mitochondria-targeted human catalase induction and mitoTEMPO infusion. CONCLUSIONS: Oxidative post-translational modifications attenuate mitochondrial AAA+ protease activity, which is involved in impaired electron transport chain protein homeostasis, mitochondrial respiration deficiency, and left ventricular contractile dysfunction. Oxidatively inactivated proteases may be an endogenous target for mitoTEMPO treatment in pressure overload heart failure.

Inhibition of p53 preserves Parkin-mediated mitophagy and pancreatic ß-cell function in diabetes.

Mitochondrial compromise is a fundamental contributor to pancreatic ß-cell failure in diabetes. Previous studies have demonstrated a broader role for tumor suppressor p53 that extends to the modulation of mitochondrial homeostasis. However, the role of islet p53 in glucose homeostasis has not yet been evaluated. Here we show that p53 deficiency protects against the development of diabetes in streptozotocin (STZ)-induced type 1 and db/db mouse models of type 2 diabetes. Glucolipotoxicity stimulates NADPH oxidase via receptor for advanced-glycation end products and Toll-like receptor 4. This oxidative stress induces the accumulation of p53 in the cytosolic compartment of pancreatic ß-cells in concert with endoplasmic reticulum stress. Cytosolic p53 disturbs the process of mitophagy through an inhibitory interaction with Parkin and induces mitochondrial dysfunction. The occurrence of mitophagy is maintained in STZ-treated p53(-/-) mice that exhibit preserved glucose oxidation capacity and subsequent insulin secretion signaling, leading to better glucose tolerance. These protective effects are not observed when Parkin is deleted. Furthermore, pifithrin-α, a specific inhibitor of p53, ameliorates mitochondrial dysfunction and glucose intolerance in both STZ-treated and db/db mice. Thus, an intervention with cytosolic p53 for a mitophagy deficiency may be a therapeutic strategy for the prevention and treatment of diabetes.

Cytosolic p53 inhibits Parkin-mediated mitophagy and promotes mitochondrial dysfunction in the mouse heart.

Cumulative evidence indicates that mitochondrial dysfunction has a role in heart failure progression, but whether mitochondrial quality control mechanisms are involved in the development of cardiac dysfunction remains unclear. Here we show that cytosolic p53 impairs autophagic degradation of damaged mitochondria and facilitates mitochondrial dysfunction and heart failure in mice. Prevalence and induction of mitochondrial autophagy is attenuated by senescence or doxorubicin treatment in vitro and in vivo. We show that cytosolic p53 binds to Parkin and disturbs its translocation to damaged mitochondria and their subsequent clearance by mitophagy. p53-deficient mice show less decline of mitochondrial integrity and cardiac functional reserve with increasing age or after treatment with doxorubicin. Furthermore, overexpression of Parkin ameliorates the functional decline in aged hearts, and is accompanied by decreased senescence-associated ß-galactosidase activity and proinflammatory phenotypes. Thus, p53-mediated inhibition of mitophagy modulates cardiac dysfunction, raising the possibility that therapeutic activation of mitophagy by inhibiting cytosolic p53 may ameliorate heart failure and symptoms of cardiac ageing.

p53-TIGAR axis attenuates mitophagy to exacerbate cardiac damage after ischemia.

Inhibition of tumor suppressor p53 is cardioprotective against ischemic injury and provides resistance to subsequent cardiac remodeling. We investigated p53-mediated expansion of ischemic damage with a focus on mitochondrial integrity in association with autophagy and apoptosis. p53(-/-) heart showed that autophagic flux was promoted under ischemia without a change in cardiac tissue ATP content. Electron micrographs revealed that ischemic border zone in p53(-/-) mice had 5-fold greater numbers of autophagic vacuoles containing mitochondria, indicating the occurrence of mitophagy, with an apparent reduction of abnormal mitochondria compared with those in WT mice. Analysis of autophagic mediators acting downstream of p53 revealed that TIGAR (TP53-induced glycolysis and apoptosis regulator) was exclusively up-regulated in ischemic myocardium. TIGAR(-/-) mice exhibited the promotion of mitophagy followed by decrease of abnormal mitochondria and resistance to ischemic injury, consistent with the phenotype of p53(-/-) mice. In p53(-/-) and TIGAR(-/-) ischemic myocardium, ROS production was elevated and followed by Bnip3 activation which is an initiator of mitophagy. Furthermore, the activation of Bnip3 and mitophagy due to p53/TIGAR inhibition were reversed with antioxidant N-acetyl-cysteine, indicating that this adaptive response requires ROS signal. Inhibition of mitophagy using chloroquine in p53(-/-) or TIGAR(-/-) mice exacerbated accumulation of damaged mitochondria to the level of wild-type mice and attenuated cardioprotective action. These findings indicate that p53/TIGAR-mediated inhibition of myocyte mitophagy is responsible for impairment of mitochondrial integrity and subsequent apoptosis, the process of which is closely involved in p53-mediated ventricular remodeling after myocardial infarction.

p53 promotes cardiac dysfunction in diabetic mellitus caused by excessive mitochondrial respiration-mediated reactive oxygen species generation and lipid accumulation.

BACKGROUND: Diabetic cardiomyopathy is characterized by energetic dysregulation caused by glucotoxicity, lipotoxicity, and mitochondrial alterations. p53 and its downstream mitochondrial assembly protein, synthesis of cytochrome c oxidase 2 (SCO2), are important regulators of mitochondrial respiration, whereas the involvement in diabetic cardiomyopathy remains to be determined. METHODS AND RESULTS: The role of p53 and SCO2 in energy metabolism was examined in both type I (streptozotocin [STZ] administration) and type II diabetic (db/db) mice. Cardiac expressions of p53 and SCO2 in 4-week STZ diabetic mice were upregulated (185% and 152% versus controls, respectively, P<0.01), with a marked decrease in cardiac performance. Mitochondrial oxygen consumption was increased (136% versus control, P<0.01) in parallel with augmentation of mitochondrial cytochrome c oxidase (complex IV) activity. Reactive oxygen species (ROS)-damaged myocytes and lipid accumulation were increased in association with membrane-localization of fatty acid translocase protein FAT/CD36. Antioxidant tempol reduced the increased expressions of p53 and SCO2 in STZ-diabetic hearts and normalized alterations in mitochondrial oxygen consumption, lipid accumulation, and cardiac dysfunction. Similar results were observed in db/db mice, whereas in p53-deficient or SCO2-deficient diabetic mice, the cardiac and metabolic abnormalities were prevented. Overexpression of SCO2 in cardiac myocytes increased mitochondrial ROS and fatty acid accumulation, whereas knockdown of SCO2 ameliorated them. CONCLUSIONS: Myocardial p53/SCO2 signal is activated by diabetes-mediated ROS generation to increase mitochondrial oxygen consumption, resulting in excessive generation of mitochondria-derived ROS and lipid accumulation in association with cardiac dysfunction.

Systolic blood pressure at admission, clinical manifestations, and in-hospital outcomes in patients with acute myocardial infarction.

BACKGROUND: Several clinical studies have demonstrated an inverse relationship between systolic blood pressure (SBP) at admission and in-hospital mortality in patients hospitalized for acute myocardial infarction (AMI). However, data on the relation between admission SBP and in-hospital prognosis in AMI patients are still lacking in Japan. METHODS AND RESULTS: A total of 1211 AMI patients were classified into quintiles based on SBP at hospital admission (<106 mmHg, n = 241; 106-125 mmHg, n = 239; 126-140 mmHg, n = 244; 141-159 mmHg, n = 238; and ≥ 160 mmHg, n = 249). The patients with SBP < 106 mmHg tended to have higher age, Killip class ≥ 3 at admission, right coronary artery, left main trunk, or multivessels as culprit lesions, larger number of diseased vessels, lower Thrombolysis In Myocardial Infarction grade in the infarct-related artery before primary percutaneous coronary intervention (PCI), and higher value of peak creatine phosphokinase concentration. Patients with SBP <106 mmHg had a significantly higher mortality, while mortality was not significantly different among the other quintiles: 25.7% (<106 mmHg), 5.4% (106-125 mmHg), 5.7% (126-140 mmHg), 2.5% (141-159 mmHg), and 5.6% (≥ 160 mmHg) (p<0.001). On multivariate analysis, Killip class ≥ 3 at admission, admission SBP <106 mmHg, and age were the independent positive predictors of in-hospital mortality, whereas admission SBP 141-159 mmHg and primary PCI were the negative ones, but admission SBP 106-125 mmHg, admission SBP 126-140 mmHg, and admission SBP ≥ 160 mmHg were not. CONCLUSIONS: These results suggest that admission SBP 141-159 mmHg might be correlated with better in-hospital prognosis, whereas admission SBP <106 mmHg was associated with in-hospital death in Japanese patients hospitalized for AMI.

Primary percutaneous coronary intervention for acute myocardial infarction due to possible sequelae of Kawasaki disease in young adults: a case series.

Experience of primary percutaneous coronary intervention (PCI) for young adults with acute myocardial infarction (AMI) due to sequelae of Kawasaki disease (KD) has been extremely limited. In the present report on three young adults (two males and one female; age 20-35 years) with AMI, we performed primary PCI and intravascular ultrasound imaging (IVUS). Case 1 underwent thrombectomy alone in the proximal left circumflex coronary artery, and subsequent IVUS depicted a large aneurysm with an asymmetrically intimal thickening and a residual thrombus in the culprit. Case 2 underwent balloon dilation with adjunctive intracoronary thrombolysis in the proximal left anterior descending coronary artery (LAD), and IVUS during follow-up coronary angiography (CAG) delineated a regressed giant aneurysm with a markedly intimal thickening in the culprit. Case 3, with past history highly suggesting KD, underwent balloon dilation in the proximal LAD, and follow-up CAG as well as IVUS revealed a neoaneurysmal formation in the culprit. In all of the patients, PCI was angiographically effective at the acute phase without complication. Follow-up CAG performed 3-6 months after the procedure revealed no restenosis in all three cases, but a new coronary aneurysm still remained in case 3. Although case 1 and case 2 had no obvious history of KD, the vessel wall morphology from IVUS closely resembled the coronary sequelae after KD, suggesting that they might have antecedent incomplete KD. These cases suggest that primary PCI against coronary sequelae of KD in young AMI patients might be safe and effective in the short term.