小林 欣夫

Accumulating evidence has suggested a role for p53 activation in various age-associated conditions. Here, we identified a crucial role of endothelial p53 activation in the regulation of glucose homeostasis. Endothelial expression of p53 was markedly upregulated when mice were fed a high-calorie diet. Disruption of endothelial p53 activation improved dietary inactivation of endothelial nitric oxide synthase that upregulated the expression of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha in skeletal muscle, thereby increasing mitochondrial biogenesis and oxygen consumption. Mice with endothelial cell-specific p53 deficiency fed a high-calorie diet showed improvement of insulin sensitivity and less fat accumulation, compared with control littermates. Conversely, upregulation of endothelial p53 caused metabolic abnormalities. These results indicate that inhibition of endothelial p53 could be a novel therapeutic target to block the vicious cycle of cardiovascular and metabolic abnormalities associated with obesity.

In Japan, a lower maintenance dose of ticlopidine is used than in the United States and Europe. Therefore a lower maintenance dose of clopidogrel may also be considered appropriate in Japanese patients. The present randomized pilot study evaluated the efficacy and safety of 50 mg clopidogrel in Japanese patients who underwent drug-eluting stent (DES) implantation. A total of 200 patients with 277 lesions who underwent intravascular ultrasound-guided DES implantation were enrolled. The subjects were allocated to the 50- or 75-mg clopidogrel group. All patients received 100 mg aspirin daily before the procedure, and this continued indefinitely. The duration of clinical follow-up was 21.8 +/- 5.7 months in the 75-mg group and 21.9 +/- 6.1 months in the 50-mg group (P = 0.96). During follow-up, no cardiac death, myocardial infarction, or stent thrombosis was observed in either group. Side effects of clopidogrel were observed in 4 patients (4.0 %) in the 75-mg group and in 4 patients (4.0 %) in the 50-mg group. Following this randomized pilot study, it may be justified to perform a large-scale randomized study comparing 50- and 75-mg dosing of clopidogrel in Japanese patients undergoing coronary stent implantation.

Side branch compromise after stenting in bifurcation lesions is a matter of concern. It may happen that even low-profile balloon catheters do not cross stent struts after rewiring. The Corsair catheter is a hybrid catheter that has features of a microcatheter and a support catheter. The present study evaluated usefulness of the Corsair catheter to facilitate advancing a low-profile balloon catheter through stent struts in bifurcation lesions. After rewiring, low-profile balloon catheters failed to cross stent struts of 29 bifurcation lesions. The Corsair microcatheter successfully crossed stent struts in all lesions except one (97 %) where a stent was implanted to treat in-stent restenosis (stent-in-stent). Low-profile balloon catheters were able to advance into the side branch of all bifurcation lesions where the Corsair microcatheter crossed stent struts. In conclusion, the Corsair microcatheter may be utilized if low-profile balloon catheters are unable to cross stent struts in bifurcation lesions. © 2013 Japanese Association of Cardiovascular Intervention and Therapeutics.

A 78-year-old woman complained of experiencing dyspnea (New York Heart Association II) and faintness. Echocardiography revealed she had asymmetric left ventricular hypertrophy, and a dynamic left ventricular outflow tract (LVOT) obstruction due to systolic anterior motion of the mitral valve. It also revealed calcification of the noncoronary cusp and a high-flow velocity in the LVOT (6.3m/s). The planimetry measurement with transesophageal echocardiography was 0.89cm2 (aortic valve area/body surface area: 0.69cm2/m2). Later, she was diagnosed with hypertrophic obstructive cardiomyopathy (HOCM) and aortic stenosis (AS). However, during the catheterization, the transvalvular pressure gradient (PG) was only 25mmHg. In order to solve this, we performed a percutaneous transluminal septal myocardial ablation. As a result, the PG of the LVOT decreased from 152mmHg to 25mmHg.We first thought that the LVOT obstruction had reduced the flow passing through the aortic valve, and restricted the motion of the aortic valve leaflets. We also considered the possibility that the aortic valve area had been underestimated. The hemodynamic study played an important role in the decision for the treatment plan. The present case was a combination of HOCM and "mild" AS.&lt . Learning objective: We know that we can distinguish between a left ventricular outflow tract obstruction and aortic stenosis using continuous-wave Doppler according to the phase of the peak gradient. However, if both are present, it is uncertain whether we can distinguish between them. It is necessary to measure the subaortic pressure and flow passing through the aortic valve accurately by catheterization in order to know which is the chief pathology.&gt . © 2013 Japanese College of Cardiology.

心臓MRI(CMR)と12誘導Holter心電図を3ヵ月以内に受診した、肥大型心筋症(HCM)の連続患者30名(男性21名、女性9名、平均62±14歳)を対象として、HCM患者で頻繁に観察される断片化QRS波を伴う様々な形態型の心室期外収縮(VPB)の臨床的意義をレトロスペクティブに調査した。全VPBと断片化VPBの形態型数は各々4.7±3.6と2.3±1.8であった。CMR上で左室壁厚、LV重量、左室駆出率は各々17.6±3.6mm、151.6±46.3g、66.2±8.8%であった。26名の左室筋(LVM)に後期亢進(LE)が認められ、LEの平均容積は38.1±22.4mlであった。HCM患者においては、12誘導Holter心電図上の断片化VPBの形態型はCMR上のLVMにおけるLE容積と特異的な正相関を有し、その影響は全VPBよりも大きいことが示された。

3ヵ月以内に12誘導Holster心電図(ECG)と強調ECGゲートCTを受診した、肥大型心筋症(HCM)の連続患者47名(男性36名、女性11名、平均61±13歳)を対象として、冠状動脈と左室筋(LVM)の特性をレトロスペクティブに評価した。CT上で29名の患者に線維症が認められた。冠動脈狭窄を有する患者においては、無狭窄患者と比較して全心室期外収縮(VPB)と断片化VPBの形態型数は有意に低かった。CT上で線維症を有する患者においては、線維症を有しない患者と比較して全VPBと断片化VPBの形態型数は有意に高かった。全VPBまたは断片化VPBの形態型数とCT上の冠動脈内の≧50%内腔狭窄との間には負の相関係数が認められ、一方全VPBまたは断片化VPBの形態型数とCT上のLVM線維症の間には正の相関係数が認められた。

BACKGROUND: Autonomic ganglionated plexi (GPs) play a significant role in the initiation and maintenance of atrial fibrillation (AF). GPs are key targets for a maze procedure. The purpose of this study was to identify the location of the left atrial GPs based on dense epicardial mapping during a maze procedure in patients with concomitant AF. METHODS: Sixteen patients (age, 68 ± 10 years; 11 males, 69%) with heart failure and concomitant AF (duration 55 ± 86 months) underwent intraoperative epicardial electrophysiological mapping and a GP ablation using the maze procedure at our institution. Twenty-four-site, high-frequency stimulation (1,000/min; output, 18 V; pulse width, 0.75 ms) was performed by placing tweezers directly onto the potential GP sites on the left atrial epicardium. RESULTS: Active GPs were found in 13 (81%) of the 16 patients, and 12 (92%) of 13 patients had active GPs between the right pulmonary veins (PVs) and the interatrial groove. For those patients with active locations, a 7-day event-loop recording demonstrated that 12 (92%) of 13 patients were maintained in sinus rhythm 3 months after the operation. CONCLUSION: Dense epicardial mapping in the potential GP areas identified active GP locations in a high percentage of patients. GPs between the PVs and interatrial groove have a high potential as ablation targets for treatment of concomitant AF.

Purpose: To reduce radiation-exposure, prospective-ECG-gating without padding is preferable. To evaluate diagnostic-accuracy of coronary 320-slice-CT angiography using various-acquisition-methods, we compared retrospective-ECG-gated with dose-modulation and "virtual" prospective-ECG-gating with and without padding. Materials-and-methods: We retrospectively selected seventy-seven consecutive symptomatic subjects (52-males, 62 +/- 12 years) with normal-sinus-rhythm who underwent both retrospective-ECG-gated 320-slice-CT and conventional-coronary-angiograms (CCAG) within 3-months. CT images were reconstructed at 5% from 0 to 95% of RR-interval. Three-methods were used to assess >50% coronary-stenosis; 1) using only 75% of data named virtual prospective-ECG-gating without padding, 2) using 70-100% of data if heart-rate (HR) was <66 beats/minute (bpm), or using 35-100% of data if HR was >65 bpm, named as virtual prospective-ECG- gating with padding, and 3) using all-phase-data named retrospective-ECG-gating. Results: In 42-subjects with HR <66 bpm, there were zero unevaluable-segments in virtual prospective-ECG-gating with and without padding and retrospective-ECG-gating. But in 35-subjects with HR >65 bpm, the percentage of unevaluable-segments were significantly-higher in virtual prospective-ECG-gating without padding (13.6 +/- 27.9%) than in virtual prospective-ECG-gating with padding (0.7 +/- 3.1%), and retrospective-ECG-gating (0.7 +/- 3.1%) (both P = 0.012). Using only evaluable-lesions, in 35-subjects with HR >65 bpm, sensitivity, specificity, positive-predictive-value and negative-predictive-value of CT for detecting >50% luminal-stenosis compared with CCAG were 82%, 94%, 60%, and 98%, respectively, for virtual prospective-ECG-gating without padding, 97%, 96%, 73%, and 100%, respectively, for virtual prospective-ECG-gating with padding, and 97%, 96%, 73%, and 100%, respectively, for retrospective-ECG-gating (all P = not-significant). Conclusion: Virtual prospective-ECG gating at 75% of RR-interval without padding had significantly-more unevaluable-segments than virtual prospective-ECG-gating with padding and retrospective-ECG-gating only in subjects with HR >65 bpm. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

Purpose: Adrenal vein (AV) sampling (AVS) is the diagnostic gold standard for primary aldosteronism (PA), but right-sided AVS is difficult. We compared detection of AVs by selective retrograde CT adrenal venography (SRCTAV) with digital subtraction angiography (DSA). Materials and methods: Data on 29 subjects (11 males, mean age 55 y) with increased serum aldosterone concentrations (SAC) and a diagnosed right or left aldosterone-producing tumor (APT) by AVS who underwent laparoscopic adrenalectomy were retrospectively analyzed. Before AVS, visualizing AVs was attempted by DSA and SRCTAV (Aquilion). If after the adrenocorticotropic hormone loading test serum cortisol concentration (SCC) from either AV was > 200 mu g/dl, AVS was considered successful. If the SAC/SCC ratio for one side was >= 4 times higher than the other side, we diagnosed a one-sided APT. Results: Left and right AV, respectively, were visualized in 29 (100%) and 22 subjects (76%) by DSA and 29 (100%) and 28 subjects (97%) by SRCTAV, with right-AV detection significantly higher by SRCTAV (p < 0.05). Cannulations were regarded successful in 28 subjects having both AVs observed on SRCTAV but not in the remaining subject whose adrenocortical scintigram was positive, however. Adrenalectomy was performed with a diagnosis of adenoma. Among 28 subjects with successful AVS, histopathological diagnoses included adenoma (25), nodular hyperplasia (2) and normal (1). After adrenalectomy, antihypertensive drug usage in 28 patients was reduced or stopped with decreases in SAC (97%). Conclusions: Detection of AV was significantly higher by SRCTAV than DSA, especially on the right side, in 29 subjects diagnosed with one-sided APT. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

Notch signaling is involved in an intercellular communication mechanism that is essential for coordinated cell fate determination and tissue morphogenesis. The biological effects of Notch signaling are context-dependent. We investigated the functional and hierarchical relationship between angiotensin (Ang) II receptor signaling and Notch signaling in vascular smooth muscle cells (VSMCs). A fluorogenic substrate assay revealed directly that the enzymatic activity of gamma-secretase was enhanced after 10 min of Ang II stimulation in HEK293 cells expressing Ang II type 1 receptor. Notch cleavage by gamma-secretase was consistently induced and peaked at 10 min after Ang II stimulation, and the Ang II-stimulated increase in Notch intracellular domain production was significantly suppressed by treatment with the gamma-secretase inhibitor DAPT. Treatment with DAPT also significantly reduced the Ang II-stimulated proliferation and migration of human aortic VSMCs, as revealed by BrdU incorporation and the Boyden chamber assay, respectively. Systemic administration of the gamma-secretase inhibitor dibenzazepine reduced Ang II-induced medial thickening and perivascular fibrosis in the aortas of wild-type mice. These findings suggest that the hierarchical Ang II receptor-Notch signaling pathway promotes the proliferation and migration of VSMCs, and thereby contributes to the progression of vascular remodeling.

Purpose: We evaluated anatomical relationships between the coronary sinus and great cardiac vein (CS/GCV) and left circumflex coronary artery (LCX) along the mitral annulus (MA) in patients with atrial fibrillation (AF) using 320-slice CT. Methods: Fifty-three patients with AF (44 males; mean 63 +/- 11 years; 28 paroxysmal, 10 persistent, and 15 permanent AF) underwent 320-slice CT. Double-oblique CT images perpendicular to the MA short axis were created every 10 degrees for 36 circumferential sections. The angle of 0 degrees corresponded to the 12 o'clock position. Results: CS/GCV-MA distance was greatest in the posterolateral MA. CS/GCV diverged from the LCX more widely in the lateral through posterolateral MA than the anterior through anterolateral MA. CS/GCV crossed the LCX in 51 patients (96.2%) and left main coronary artery in 2 patients (3.8%). Median angle of the CS/GCV-LCX crossing point was at 40 degrees but ranged widely (0 degrees to 150 degrees) and was more frequent in the anterior and anterolateral MA than in the lateral, posterolateral, and posterior MA (31.4%, 45.1%, 11.8%, 11.8%, and 0%, respectively; P < 0.01). CS/GCV crossed over the LCX in 39 patients and under the LCX in 12 patients. Range of the CS/GCV-LCX overlapping course increased significantly as the CS/GCV-LCX crossing point neared the CS ostium. Correlation coefficient between the range of the overlapping course and crossing point angle was 0.78. Conclusions: Anatomical relationships between CS/GCV and LCX greatly varied in location and proximity among AF patients. Interventional electrophysiologists should know the potential risk for LCX injury when radiofrequency energy is delivered within the CS/GCV. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

Purpose: To identify predictors of chronic pulmonary vein (PV) reconnection (CPVR) after successful circumferential PV isolation (CPVI) for atrial fibrillation (AF). Materials and methods: A total of 718 PVs from 181 consecutive AF patients (141 males, median age 61 years, 92 paroxysmal AF) who underwent a second ablation procedure for recurrent AF were retrospectively analyzed. Results: During the second procedure, a CPVRwas observed in 477 PVs (66.4%) among 169 patients. In a multiple logistic regression analysis, the observation time after the final completion of the PVI (OT-final) was a significant negative predictor (odds ratio 0.980; P < 0.001). A receiver operating characteristic analysis demonstrated that the greatest area under the curve was for the OT-final (0.670). At an optimal cutoff of 35 min, the sensitivity and specificity for predicting a CPVR were 66.9% and 60.6%, respectively. By Kaplan Meier analysis, CPVR was more frequent in PVs with an OT-final of b35 min than = 35 min (log-rank test, P = 0.018). In a vessel-by-vessel analysis, the OT-final at all PV sites was a significant negative predictor, while male gender in the right PVs and left-inferior PV, number of RF applications for the ipsilateral CPVI in the right PVs and left-superior PV, and major PV diameter in the left-superior PV were significant positive predictors of a CPVR (all P < 0.05). Conclusions: An optimal observation time (>= 35 min in this study) to determinewhether PVI is successfully completed during the initial CPVI for AFmay be needed to prevent a CPVR and subsequent AF recurrence thereafter. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

Semaphorins and their receptors (plexins) are axon-guiding molecules that regulate the development of the nervous system during embryogenesis. Here we describe a previously unknown role of class 3 semaphorin E (Sema3E) in adipose tissue inflammation and insulin resistance. Expression of Sema3E and its receptor plexinD1 was upregulated in the adipose tissue of a mouse model of dietary obesity. Inhibition of the Sema3E-plexinD1 axis markedly reduced adipose tissue inflammation and improved insulin resistance in this model. Conversely, overexpression of Sema3E in adipose tissue provoked inflammation and insulin resistance. Sema3E promoted infiltration of macrophages, and this effect was inhibited by disrupting plexinD1 expression in macrophages. Disruption of adipose tissue p53 expression led to downregulation of Sema3E expression and improved adipose tissue inflammation. These results indicate that Sema3E acts as a chemoattractant for macrophages, with p53-induced upregulation of Sema3E expression provoking adipose tissue inflammation and systemic insulin resistance in association with dietary obesity.