永井 良三

Swallow syncope is a relatively rare disorder caused by a hypersensitive vagotonic reflex in response to deglutition, and is treatable when diagnosed. Here, we describe two documented cases of recurrent syncopal attacks associated with swallowing, and also discuss about some difficulties in the precise diagnosis and treatment of swallow syncope.

T wave oversensing represents one of the common inappropriate shocks in patients with cardiac defibrillators. This case report demonstrates a non-invasive clue to eliminate the aforementioned problem. We experienced an 82-year-old male with non-ischemic dilated cardiomyopathy who underwent CRT-D implantation. Seven months after the implantation surgery, he experienced abrupt shocks without any symptom and we interrogated his CRT-D device, which demonstrated the status of the three leads was acceptable and such inappropriate shocks had been delivered by misdiagnosing as ventricular fibrillation due to double or triple counts of high T waves and frequent premature ventricular contractions. His iplilateral subclavian vein was chronically occluded and the patient rejected further invasive strategies such as another lead insertion or device exchange. In this situation we evaluated whether change of VV timing may alter ventricular intracardiac electrogram. By sequential biventricular pacing in which LV pacing remarkably preceded RV pacing, we could successfully increase V wave amplitude with significant reduction of accompanying T wave, finally eliminating inappropriate diagnosis. This setting did not worsen cardiac performance and ventricular sensing to detect true tachyarrhythmia. In the oversensing of T wave, alteration of VV delay timing is a choice of the recommendable strategies to prevent inappropriate shock.

Obesity and insulin resistance, the key features of metabolic syndrome, are closely associated with a state of chronic, low-grade inflammation characterized by abnormal macrophage infiltration into adipose tissues. Although it has been reported that chemokines promote leukocyte migration by activating class IB phosphoinositide-3 kinase (PI3Kγ) in inflammatory states, little is known about the role of PI3Kγ in obesity-induced macrophage infiltration into tissues, systemic inflammation, and the development of insulin resistance. In the present study, we used murine models of both diet-induced and genetically induced obesity to examine the role of PI3Kγ in the accumulation of tissue macrophages and the development of obesity-induced insulin resistance. Mice lacking p110γ (Pik3cg(-/-)), the catalytic subunit of PI3Kγ, exhibited improved systemic insulin sensitivity with enhanced insulin signaling in the tissues of obese animals. In adipose tissues and livers of obese Pik3cg(-/-) mice, the numbers of infiltrated proinflammatory macrophages were markedly reduced, leading to suppression of inflammatory reactions in these tissues. Furthermore, bone marrow-specific deletion and pharmacological blockade of PI3Kγ also ameliorated obesity-induced macrophage infiltration and insulin resistance. These data suggest that PI3Kγ plays a crucial role in the development of both obesity-induced inflammation and systemic insulin resistance and that PI3Kγ can be a therapeutic target for type 2 diabetes.

82歳男性。患者は拡張型心筋症にて心不全悪化のためCRT-D植え込み術が施行された。だが、植え込みから約7ヵ月経過で左前胸部への突然の衝撃を自覚し、緊急で外来受診となった。心内心電図の解析を行ったところ、両室ペーシング時のT波オーバーセンシングによるICD不適切作動が判明した。このことから、本症例では時間の経過とともに右室ペーシングによる局所心内心電図波形のT波増高と関連して不適切なショック治療を生じたものと考えられ、VV delayのプログラミング変更を行った結果、右室ペーシングの寄与が最小限となり、T波の増高を回避することができ、7ヵ月間、ICD不適切作動および心不全増悪は認められていない。

OBJECTIVE: Accumulating evidence suggests that exaggerated formation of vasa vasorum (VV) plays an important role in the pathogenesis of atherosclerosis. However, it remains unclear whether augmented angiogenesis in the adventitia could promote hyperlipidemia-induced atherosclerotic lesion formation. METHODS AND RESULTS: First, we analyzed the time course of VV development in apolipoprotein E-deficient (ApoE-/-) mice. VV proliferation was observed only after atherosclerotic lesion formation. Next, we investigated whether forced perivascular angiogenesis could promote plaque progression. Basic fibroblast growth factor (bFGF) (100 μg/body) incorporated in acid gelatin hydrogel microspheres (AGHM) (bFGF+AGHM group, n=10), AGHM alone (AGHM group, n=7), or PBS (control group, n=8) was administered into the periaortic area of the retroperitoneal space in 10- to 11-week-old male ApoE-/- mice. At 13 weeks after the operation, lesions were significantly larger in the bFGF+AGHM group than in others (bFGF+AGHM: 3.4 ± 0.7 × 10(4)μm(2); AGHM: 0.1 ± 0.1 × 10(4)μm(2); control: 0 μm(2); p<0.0001), which was associated with increased neovascularization in the adventitia. The number of adventitial capillaries correlated with plaque size (r=0.69, p<0.0001). In the bFGF+AGHM group, an increase in the number of VV and accumulation of Mac3-positive macrophages were observed prior to atherosclerotic lesion formation. CONCLUSIONS: Our findings demonstrated that local administration of bFGF in the adventitia induced development of VV and accelerated plaque progression in ApoE-/- mice, supporting the notion that VV formation plays a crucial role in the pathogenesis of atherosclerosis.

In obese patients with type 2 diabetes, insulin delivery to and insulin-dependent glucose uptake by skeletal muscle are delayed and impaired. The mechanisms underlying the delay and impairment are unclear. We demonstrate that impaired insulin signaling in endothelial cells, due to reduced Irs2 expression and insulin-induced eNOS phosphorylation, causes attenuation of insulin-induced capillary recruitment and insulin delivery, which in turn reduces glucose uptake by skeletal muscle. Moreover, restoration of insulin-induced eNOS phosphorylation in endothelial cells completely reverses the reduction in capillary recruitment and insulin delivery in tissue-specific knockout mice lacking Irs2 in endothelial cells and fed a high-fat diet. As a result, glucose uptake by skeletal muscle is restored in these mice. Taken together, our results show that insulin signaling in endothelial cells plays a pivotal role in the regulation of glucose uptake by skeletal muscle. Furthermore, improving endothelial insulin signaling may serve as a therapeutic strategy for ameliorating skeletal muscle insulin resistance.

OBJECTIVE: Approximately 25% of children and adolescents with type 1 diabetes will develop diastolic dysfunction. This defect, which is characterized by an increase in time to cardiac relaxation, results in part from a reduction in the activity of the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a), the ATP-driven pump that translocates Ca(2+) from the cytoplasm to the lumen of the sarcoplasmic reticulum. To date, mechanisms responsible for SERCA2a activity loss remain incompletely characterized. RESEARCH DESIGN AND METHODS: The streptozotocin (STZ)-induced murine model of type 1 diabetes, in combination with echocardiography, high-speed video detection, confocal microscopy, ATPase and Ca(2+) uptake assays, Western blots, mass spectrometry, and site-directed mutagenesis, were used to assess whether modification by reactive carbonyl species (RCS) contributes to SERCA2a activity loss. RESULTS: After 6-7 weeks of diabetes, cardiac and myocyte relaxation times were prolonged. Total ventricular SERCA2a protein remained unchanged, but its ability to hydrolyze ATP and transport Ca(2+) was significantly reduced. Western blots and mass spectroscopic analyses revealed carbonyl adducts on select basic residues of SERCA2a. Mutating affected residues to mimic physio-chemical changes induced on them by RCS reduced SERCA2a activity. Preincubating with the RCS, methylglyoxal (MGO) likewise reduced SERCA2a activity. Mutating an impacted residue to chemically inert glutamine did not alter SERCA2a activity, but it blunted MGO's effect. Treating STZ-induced diabetic animals with the RCS scavenger, pyridoxamine, blunted SERCA2a activity loss and minimized diastolic dysfunction. CONCLUSIONS: These data identify carbonylation as a novel mechanism that contributes to SERCA2a activity loss and diastolic dysfunction during type 1 diabetes.

INTRODUCTION: NF-kB is a key regulator of inflammation and immunity in cancer development. The IkB kinase (IKK) is a multisubunit complex containing catalytic subunits termed IKK-α, -β and -γ. It is well known that many pro-inflammatory stimuli require the IKK-β subunit for NF-kB activation. AREAS COVERED: NF-kB affects the progression of inflammation-related diseases,such as myocardial ischemia, bronchial asthma, arthritis, cancer and other diseases. We review the characteristics and effects of these inhibitors on inflammatory and other diseases. EXPERT OPINION: Various synthesized IKK inhibitors have been developed and they will be used clinically in the near future.

Prostaglandins (PG) and their specific receptors for E type PG (EP) play an important role in inflammatory diseases. Although myocarditis results in inflammation of the heart, roles of PG and EP in its pathophysiology is still controversial. To clarify the role of PG and EP on the progression of myocarditis, we used an experimental autoimmune myocarditis model. A selective EP4 (EP4RAG) agonist was administered into both early (Day 0 to 21) and late (Day 14 to 21) -treated groups and the animals were killed on Day 21. We found that improved cardiac function was detected in the EP4RAG-treated groups in comparison to the untreated group. The infiltration area ratio in the early-treated (16.6% ± 4.6%) group was lower than those in the untreated group (32.1% ± 3.5%) (P < 0.05). The fibrosis area ratios in the early-treated (19.2% ± 6.3%) and the late-treated groups (24.4% ± 5.1%) were lower than those in the untreated group (37.4% ± 2.6%), respectively (P < 0.05). Moreover, we found that EP4RAG decreased T-cell proliferation and monocyte chemoattractant protein-1 production in vitro. We concluded that a selective EP4 agonist inactivates T-cells, which turns out to moderate the progression of experimental autoimmune myocarditis. Therefore, EP4 can be an effective target for myocarditis treatment.

INTRODUCTION: plasminogen activator inhibitor-1 (PAI-1) is critical in thrombus formation and inflammation. Although these are essential pathological features of cardiovascular diseases, the effects of PAI-1 inhibition against the development of cardiovascular remodeling have not been well studied. AREAS COVERED: the review explores the therapeutic value of PAI-1 in the progression of various cardiovascular diseases. To date, the authors have reported that a novel PAI-1 inhibitor suppressed the development of experimental autoimmune myocarditis, vascular remodeling after arterial injury, and heart transplant rejection using rodent models. Pathologically, the PAI-1 inhibitor improved histological remodeling of myocardium and arteries with suppression of inflammation and thrombus formation. EXPERT OPINION: PAI-1 inhibitors appear to exhibit potent effects on the prevention of adverse tissue remodeling. However, PAI-1 is a multifunctional protein and more research is needed to further elucidate the association between PAI-1 expression and cardiovascular disease.

Periarteritis, including periaortitis, is a systemic disorder characterized by an excessive fibroinflammatory reaction that can result in the compromise of great vessels and periarterial/periaortic structures. Recent studies have suggested that IgG4-related inflammation may play a role in chronic periaortitis. These pathologic conditions might represent a systemic disorder with fibrotic reaction rather than local inflammation. In this report, the authors describe a case of a 31-year-old man with marked periaortic fibrous thickening localized to the aortic arch, which was histologically and serologically proven to be IgG4 related. Positron emission tomography showed increased ¹⁸F-fluorodeoxyglucose uptake at this region. Histologic examination revealed infiltration of lymphoplasmacytes and marked fibrosis with numerous IgG4-positive plasma cells. The serum concentration of IgG4 was 263 mg/dL. The size of the periaortic mass and ¹⁸F-fluorodeoxyglucose uptake at this region markedly decreased under corticosteroid therapy. This case suggests that IgG4-related periarteritis can also occur as a solitary focus in the cardiovascular system.

BACKGROUND: Acute rejection and graft arterial disease (GAD) in cardiac transplantation limit the long-term survival of recipients; these processes are enhanced by inflammation and thrombus formation. Plasminogen activator inhibitor (PAI)-1 is critical in the inflammation and thrombus formation. However, little is known about the effect of PAI-1 in heart transplantation. Thus, the objective was to clarify the role of PAI-1 in the progression of cardiac rejection. METHODS: Murine hearts were heterotopically transplanted using major mismatch combinations for evaluation of acute rejection and class II mismatch combinations for the GAD. We administered the specific PAI-1 inhibitor (IMD-1622) into murine recipients after cardiac allografts. RESULTS: Nontreated allografts of the major mismatch group were acutely rejected, whereas the PAI-1 inhibitor prolonged their survival. Although severe cell infiltration and intimal thickening with enhancement of inflammatory factors were observed in untreated allografts of class II mismatch group on day 60, the PAI-1 inhibitor attenuated these changes. CONCLUSION: The PAI-1 inhibitor is potent for the suppression of both acute rejection and GAD.

Cardiac transplantation has been established in humans however, acute rejection and graft arterial disease (GAD) are still problems. Several cytokines and adhesion molecules enhance acute rejection the arteriopathy is characterized by intimal thickening comprised of proliferative smooth muscle cells. Strategies that target in the attenuation of acute rejection and GAD formation were not well studied in cardiac transplantation. Recent progress in the DNA technology, such as antisense oligodeoxynucleotides (ODNs) to regulate the transcription of disease-related genes, has important roles in therapeutic applications. We, for the first time, reported that antisense cdk2 kinase ODN transfection prevented the arteriopathy in murine cardiac allografts. Recently, transfection of cis-element double-stranded DNA, named as "decoy", has been reported to be a useful method for gene therapy. This decoy strategy has been not only a useful method for the experimental studies of endogenous gene regulation but also a novel clinical strategy for gene therapy. E2F plays a pivotal role in the coordinated transcription of cell cycle regulatory genes nuclear factor-kappa B (NF-kB) is critical in the transcription of multiple inflammatory genes. Therefore, we investigated the effects of E2F decoy and NF-kB decoy for prevention of cardiac acute allograft rejection and GAD. In this article, we reviewed the experimental results of NF-kB decoy, E2F decoy and other ODNs using the experimental heart transplant models. © 2009 by Nova Science Publishers, Inc. All rights reserved.

【背景】音声認識システムを用いた文字入力の有用性は，すでに放射線画像診断分野を中心に示されており，電子カルテなどにも応用されているが，循環器分野における意義は不明である．【目的】循環器検査の1例として，ホルター心電図の判読結果に基づくレポート作成における音声入力の有用性を検討する．【方法】ホルター心電図判読レポートを電子ファイルとして作成した278症例（年齢65±16歳，男性137例）で検討した．レポートは，キーボード入力（KB群，139例）または音声認識ソフトウェア（AmiVoice(R)）を用いた音声入力（AV群，139例）で作成し，両群間でその所要時間などを比較した．各レポートには有意所見数に応じたレベルを付帯し，レベル別での解析も行った．【結果】両群間で年齢・男女比やレポート文字数およびレベル分布に有意差は認められなかった．所要時間はKB群に比してAV群で有意に短く（883秒vs. 764秒，p<0.001），同傾向はレポートのレベルに関係なく認められた．【結語】ホルター心電図判読レポート作成において，時間効率の観点から音声認識システムは有用である．

Prostaglandin E2 (PGE(2)) is produced in inflammatory responses and regulates a variety of immunological reactions through 4 different receptor subtypes; EP1, 2, 3 and 4. However, the precise role of each receptor in cardiovascular disease has not yet been elucidated. Enhanced expression of some EPs has been observed in clinical and experimental cardiovascular diseases. EP agonists have been developed to clarify the role of each receptor. Recently, we developed a novel selective agonist to examine the effects of EP4 on cardiac transplantation, myocardial ischemia, and myocarditis. Of note, a selective EP4 agonist attenuated inflammatory cytokines and chemokines via attenuation of macrophage activation in inflammatory heart diseases. In this review article, we discuss the effects of PGE(2) receptor agonists on the development of cardiovascular diseases.

It is well known that disasters have great impact on the onset and frequency of arrhythmia in the patients with heart disease. On March 11 we experienced the unexpected the huge earthquake and tsunami waves. Moreover, the following Fukushima nuclear power plant accident caused severe anxiety to radiation exposure. These tremendous disasters caused strong mental as well as physical stress on the people living in not only the disaster area but also surrounding districts including Tokyo.To evaluate the impact of these disasters on the cardiovascular events, we compared arrhythmic events in the patients with pacemaker or ICD implanted in the University of Tokyo Hospital. Most of the patients had little events before and also after the earthquake, resulting in no significant difference. However, when we focused on the patients who had experienced relatively frequent arrhythmia before the earthquake, tachyarrhythmia events and AF burden were increased after the earthquake in the subset of our study population. Therefore, the strong stress has serious impact on arrhythmic events, which can at least partially contribute to the increase of major cardiovascular events. © 2011, Japanese Heart Rhythm Society. All rights reserved.

Serum amyloid A (SAA), an acute-phase protein, and lysophosphatidylcholine (LPC), an oxidized LDL component, contribute to the physiological processes of atherosclerosis and cardiovascular disease. However, the effects of SAA/LPC on human coronary artery smooth muscle cells (hCASMCs) have not been fully investigated. Therefore, we examined the effects of SAA/LPC on Ca(2+)/Mg(2+) mobilization and its underlying mechanisms in hCASMCs. Intracellular Ca(2+)/Mg(2+) concentration ([Ca(2+)](i) / [Mg(2+)](i)) was measured with fura-2 AM/mag-fura-2 AM. Conventional RT-PCR analysis was also performed. Both SAA and LPC increased [Ca(2+)](i) by Ca(2+) entry. The SAA-induced Ca(2+) entry was inhibited by Gd(3+), SKF96365, and 2-aminoethoxydiphenyl borate (2-APB), a nonselective transient receptor potential (TRP) channel blocker, but not nifedipine. The LPC-induced Ca(2+) entry was blocked by Gd(3+), but not nifedipine, SKF96365 and 2-APB. U-73122 and PTX prevented the activation of SAA-, but not LPC-induced Ca(2+) influx. LPC, but not SAA, increased [Mg(2+)](i) as well as [Ca(2+)](i). The RT-PCR analysis revealed the expression of TRPC1/4, TRPV1/2/4, and TRPM7/8 mRNA. These results suggest that SAA/LPC activate Ca(2+) influx in hCASMCs; SAA activates it via PTX-sensitive G-protein, PLC and TRPC pathways, while LPC activates it independently of these pathways, where TRPM7 may be partly involved. Thus, TRP protein appears to be a target molecule of Ca(2+) signaling in hCASMCs elicited by SAA/LPC, which may play roles in coronary muscle dysfunction under pathophysiological and inflammatory conditions such as atherosclerosis.

心筋を構成する細胞の中で,数が最も多いのは心臓線維芽細胞である.心臓線維芽細胞は単に線維化に寄与するだけでなく,心筋肥大や負荷への適応応答,また心臓の発生に必須の役割を果たす.心臓の適応応答や病態の発症において,心臓線維芽細胞と心筋細胞は,パラクライン因子等を介して密接に相互作用する.今後,心疾患の理解のために,心臓線維芽細胞を初めとする心筋間質に存在する細胞と,心筋細胞の相互作用の分子機構の解明が求められる.また,心筋細胞と間質細胞の相互作用は,新たな治療標的を与える可能性がある.(著者抄録)

Immunoglobulin G4 (IgG4)-related systemic disease was first recognized as a clinicopathological entity about 10 years ago, and since then, it has attracted growing attention. It is an autoimmune disease which affects multiple organs including the pancreas, bile duct, salivary glands and retroperitoneum. Further, it was recently reported that it can be manifested as periarteritis, often as inflammatory abdominal aortic aneurysm. We describe the case of a 75-year-old man with autoimmune pancreatitis and parotitis who presented with angina. The serum concentration of IgG4 was significantly increased at 2,510 mg/dl. Coronary angiography showed multiple stenotic lesions and pronounced dilatation of the right coronary artery. Cardiac computed tomography disclosed increased wall thickness of the coronary arteries and focal tumorous lesions surrounding the right coronary artery. Treatment with steroids proved only marginally effective and he underwent surgical resection of the aneurysm and coronary artery bypass grafting. The diagnosis of IgG4-related systemic disease was confirmed by histological examination of the resected mass, which showed a massive infiltration of IgG4-positive plasma cells. This case emphasizes the importance of considering the diagnosis in any patient with abnormally increased wall thickness or ectatic lesions in the coronary arteries.

BACKGROUND: In patients with diabetic retinopathy (DR), vitreous hemorrhage (VH) is a common complication that threatens visual acuity and hence, quality of life. A considerable number of DR patients at risk of VH require coronary revascularization, but little is known about the prevalence of VH after coronary revascularization. METHODS AND RESULTS: This study investigated 151 patients with DR who were followed up by ophthalmologists between April 2004 and September 2008, and underwent coronary revascularization (coronary artery bypass surgery n=36 or drug-eluting stent implantation n=115). At the time of coronary revascularization 56 had non-proliferative DR (NPDR) and 95 had proliferative DR (PDR). During an average follow-up of 531 days after revascularization, VH occurred in 24 (15.9%) patients, 18 (11.9%) of whom experienced VH within 6 months of the procedure. In VH patients, PDR rather than NPDR predominated as the background to VH (21 vs. 3, respectively). The 1-year prevalence of VH was higher in patients with PDR than in those with NPDR (22.0% vs. 1.9%, P=0.0055). CONCLUSIONS: VH is not a rare complication following coronary revascularization among patients with DR, especially in those with PDR. Thus, in terms of maintaining quality of life, VH after coronary revascularization needs further attention in these patients.

The chronic use of bosentan has been reported to reduce the plasma concentration of sildenafil. However, it remains unclear how sildenafil exerts the effect at reduced concentrations in pulmonary arterial hypertension (PAH) patients chronically treated with bosentan.We examined the hemodynamic effects of sildenafil (50 mg) in 8 Japanese patients with PAH, and simultaneously measured the plasma concentration of sildenafil ([Sil]) and its major metabolite, desmethylsildenafil ([Des]).The overall effects of sildenafil were 12.4% decrease in mean pulmonary arterial pressure, 19.9% increase in cardiac index (CI), and 25% reduction in derived pulmonary vascular resistance (PVR). When the patients were divided into two groups, a group with bosentan pretreatment [BOS (+), n = 4] and a group without bosentan pretreatment [BOS (-), n = 4], both [Sil] and [Des] were lower at the peak concentration (C(max)) and the area under the plasma concentration versus time curve (AUC(0-6h)), and the time to reach C(max) was longer in BOS (+), although only the difference in AUC(0-6h) of [Des] reached statistical significance (P = 0.02). In spite of lower concentration, the effect of sildenafil on CI was maintained in the BOS (+) group, while the decrease in PVR was less marked.Sildenafil acutely dilated the pulmonary artery and increased CI in the PAH patients. These effects were still observed or maintained in the PAH patients chronically treated with bosentan, even when [Sil] was reduced.

Downregulation of CD4+CD25+ regulatory T lymphocytes (Treg) has been found in local atherosclerotic lesions and in patients with myocardial infarction (MI). However, the roles of Treg in MI and the following inflammatory response have not yet been well elucidated. Therefore, we hypothesized that adoptive transfer of Treg could attenuate the postinfarction inflammatory response protecting from adverse remodeling, and we attempted to elucidate the mechanism of delayed heart failure after MI. To clarify the role of Treg in MI, we used a murine MI model and administered a single intravenous injection of Treg (1 × 10(5)) (treatment, n = 6) or saline (control, n = 7) and sacrificed the mice on day 14. Echocardiograms revealed that Treg improved LV contraction after MI. Histopathology also showed that Treg negated MI-induced LV remodeling. RT-PCR demonstrated that the mRNA levels of IFN-gamma in hearts were lower and Foxp3 in spleens were higher in the treatment group than in the control group. We observed that adoptive Treg transfer could attenuate MI-induced cardiac remodeling through the IFN-gamma and Foxp3 alteration.

Plasminogen activator inhibitor-1 (PAI-1) contributes to cardiac ventricular remodeling because migration of inflammatory cells and attenuation of extracellular matrix degradation are caused by plasmin and matrix metalloproteinase. However, the roles of PAI-1 in myocardial ischemia reperfusion (I/R) injury and the following inflammatory response have not yet been well elucidated. To clarify the role of PAI-1 in myocardial I/R injury, we used a specific PAI-1 inhibitor (IMD-1622) in a rat model. The left anterior descending coronary artery was ligated and reperfusion was performed by loosening the suture after 30 minutes of arterial occlusion. A single administration of IMD-1622 (20 mg/kg) or vehicle was given intraperitoneally and then the rats were sacrificed on day 1 or day 14 after I/R. Blood pressure, echocardiograms, histopathology, and molecular examination were performed. The examinations revealed that PAI-1 inhibitor showed limited effects on cardiac dysfunction and ventricular remodeling after I/R. We conclude that the pharmacological inhibition of PAI-1 may not affect ventricular remodeling after myocardial I/R injury.

Procedure-related coronary dissection is associated with an increased risk of major adverse cardiovascular events after percutaneous coronary intervention (PCI). In most patients with such an iatrogenic complication, further PCI or bypass surgery aimed at complete revascularization is performed. Moreover, conventional coronary angiography has been used as a standard modality in the follow-up of such patients. The present report describes a 70 year old female patient who was complicated by catheter-related extensive coronary dissection in the right coronary artery (RCA) when treated for an acute myocardial infarction. Although RCA flow was insufficient, we decided against revascularization and followed her medically without additional revascularization procedures. Her clinical course had been uneventful for 4 years. However, symptoms of effort angina developed and re-examinations were performed at approximately 5 years after the myocardial infarction. Although conventional coronary angiography failed to show the culprit lesion responsible for the angina symptoms, the superior spatial resolution of the coronary CT angiography clearly identified significant progression of the stenotic lesion in the true lumen of the dissected RCA. Thus, coronary CT angiography might be considered as a possible first-line follow-up modality in patients with procedure-related coronary dissection.

Interrupted inferior vena cava (IVC) with azygos continuation is a rare congenital anomaly, and is frequently associated with other cardiovascular malformations and situs anomalies, such as left isomerism. These patients usually develop deep vein thrombosis (DVT), and asymptomatic patients above 60 years of age are very rare. Here we report a case of interrupted IVC which we diagnosed in a 72-year-old woman. She was admitted to our hospital suffering from heart failure and supraventricular tachycardia. Echocardiography detected secundum atrial septal defect (ASD). An abnormal paravertebral pleural line on the chest X-rays indicated the existence of venous anomaly. Anatomical images obtained by Multidetector Computed Tomography (MDCT) helped us to successfully perform right heart catheterization procedures through azygos continuation including blood sampling from pulmonary veins. Even in elderly patients, a careful examination of chest X-rays can indicate undiagnosed venous anomalies; thus, it is critically important before planning surgical or interventional procedures.

BACKGROUND: Postoperative development of aortic insufficiency (AI) after implantation of left ventricular assist devices (LVADs) has recently been recognized, but the devices in the previous reports have been limited to the HeartMate I or II. The purposes of this study were to determine whether AI develops with other types of LVADs and to elucidate the factors associated with the development of AI. METHODS AND RESULTS: Thirty-seven patients receiving LVADs without evident abnormalities in native aortic valves were enrolled (pulsatile flow LVAD [TOYOBO]: 76%, continuous flow LVAD [EVAHEART, DuraHeart, Jarvik2000, HeartMate II]: 24%). Frequency of aortic valve opening and grade of AI were evaluated by the most recent echocardiography during LVAD support. None of the patients had more than trace AI preoperatively. During LVAD support AI >- grade 2 developed in 9 patients (24%) across all 5 types of devices. More severe grade of AI correlated with higher plasma B-type natriuretic peptide concentration (r = 0.53, P < 0.01) and with less frequent of the aortic valve (r = 0.45, P < 0.01). Multivariate analysis revealed that lower preoperative left ventricular ejection fraction and a continuous flow device type were independent risk factors for higher incidence of AI. CONCLUSIONS: AI, which is hemodynamically significant, develops after implantation of various types of LVADs. Physicians need to be more alert to the development of AI particularly with continuous flow devices.

BACKGROUND: In Japan, the TOYOBO left ventricular assist device (LVAD) has been commercially available for heart failure patients as of 2010, but clinical risk stratification before implantation has not been widely performed. METHODS AND RESULTS: In the present study data from 47 patients (age 38.6 ± 14.6 [SD] years, male 74.5%, non-ischemic 74.5%) implanted with a TOYOBO LVAD between November 2002 and February 2010 were analyzed. Kaplan-Meier survival analysis showed significantly higher mortality in the patients who had cardiogenic shock preoperatively (P = 0.031). Multivariate analysis revealed that the preoperative total bilirubin level (odds ratio [OR] 1.312, P < 0.001) and age (OR 1.076, P = 0.013) were independent risk factors for death. Perioperative necessity of a right ventricular assist device was also an independent risk factor for poor prognosis. CONCLUSIONS: LVAD implantation is preferable before the patient experiences hemodynamic collapse. The preoperative total bilirubin level can be used to predict prognosis after device implantation in end-stage heart failure patients.

BACKGROUND: Little is known about health-related quality of life (QOL) in Japanese patients with heart failure. The purpose of this study was to identify factors related to QOL using a disease-specific QOL instrument, and to clarify whether QOL independently predicts clinical outcomes among Japanese patients with heart failure. METHODS AND RESULTS: A total of 114 outpatients with heart failure were enrolled (mean age 64.7 ± 15.8 years; 73.7% males). The Minnesota Living with Heart Failure Questionnaire (MLHFQ) to assess patient's QOL was used. At baseline, depressive symptoms and chronic kidney disease were significantly associated with worse QOL in multiple regression analysis. During a 2-year follow up, patients with a MLHFQ score ≥ 26, indicating worse QOL, had a higher incidence of the combined endpoint of cardiac death or hospitalization for heart failure, and a higher all-cause mortality than those with a score < 26 (25.3% vs. 7.5%, P = 0.011; 18.5% vs. 6.4%, P = 0.018; respectively). Multivariate Cox proportional hazard models demonstrated that a higher MLHFQ score was significantly associated with increased risks of cardiac events (hazard ratio, 1.02, 95% confidential interval, 1.001-1.05, P = 0.038) and of all-cause death (hazard ratio, 1.04, 95% confidential interval, 1.02-1.07, P = 0.001). CONCLUSIONS: Depressive symptoms and chronic kidney disease are major determinants of impaired QOL, and the MLHFQ score is an independent predictor of both cardiac events and death among Japanese patients with heart failure.

Nicorandil has cardioprotective effects in the ischemic myocardium, mimicking ischemic preconditioning, and is thus expected to improve the prognosis of ischemic heart disease (IHD). As part of the Japanese Coronary Artery Disease (JCAD) Study, a multi-centre collaborative prospective observational study of a large cohort of coronary artery disease patients, the effect of nicorandil on outcome was examined. In total, 2,558 patients with nicorandil treatment and controls subjected to propensity score matching were eligible among 13,812 patients registered in the JCAD study. The mean follow-up interval was 2,7 years. The primary endpoint, death from all causes, was significantly lower, by 35% (hazard ratio 0,65, p=0,0008), in the nicorandil group than in the control group. There were also significant reductions in secondary endpoints, including cardiac death (56%), fatal myocardial infarction (56%), cerebral or vascular death (71%), and congestive heart failure (33%) in the nicorandil group, with no excess of deaths from other non-cardiovascular causes. Treatment with nicorandil reduced the number of deaths from all causes to a similar extent with or without treatment with sulfonylureas. The reduction in cardiovascular death with nicorandil was large in patients with IHD, which has important implications for treatment.

BACKGROUND: Despite mounting evidence of the benefit of intensive lowering of low-density lipoprotein-cholesterol (LDL-C) in coronary artery disease (CAD) patients, it has not been shown that intensive lowering of both LDL-C and blood pressure (BP) reduces cardiovascular events in these patients. METHODS AND RESULTS: 498 patients with hypertension and hypercholesterolemia with ≥ 75% stenosis in at least one major coronary artery, were recruited from 17 cardiovascular centers in eastern Japan. Patients were randomly assigned to conventional therapy (CT) or intensive therapy (IT). CT aimed to reduce BP to < 140/90 mm Hg and LDL-C to <100mg/dl, and IT aimed for < 120/80 mm Hg and < 80 mg/dl, respectively. The primary endpoint was a composite of all deaths, non-fatal myocardial infarction, unstable angina pectoris, coronary artery bypass graft surgery, non-fatal stroke, non-fatal major vascular disease, and peripheral artery disease. The mean follow-up period was 3.2 years. The achieved systolic BP was 126.8 mm Hg for the CT group, and 121.3 mm Hg for the IT group (P < 0.001). The achieved LDL-C was 92.1mg/dl for the CT group, and 79.6 mg/dl for the IT group (P < 0.001). We detected the primary endpoint in 18 (7.1%) patients in the CT group, and 26 (10.7%) in the IT group (hazard ratio 1.53, 95% confidence interval 0.84-2.80, P = 0.164). CONCLUSIONS: We could not show that intensively lowering both BP and LDL-C reduced cardiovascular risks in Japanese CAD patients with hypertension and hypercholesterolemia (UMIN-CTR UMIN000000571).

Human (h) induced pluripotent stem cells (iPSCs) are a potentially abundant source of blood cells, but how best to select iPSC clones suitable for this purpose from among the many clones that can be simultaneously established from an identical source is not clear. Using an in vitro culture system yielding a hematopoietic niche that concentrates hematopoietic progenitors, we show that the pattern of c-MYC reactivation after reprogramming influences platelet generation from hiPSCs. During differentiation, reduction of c-MYC expression after initial reactivation of c-MYC expression in selected hiPSC clones was associated with more efficient in vitro generation of CD41a(+)CD42b(+) platelets. This effect was recapitulated in virus integration-free hiPSCs using a doxycycline-controlled c-MYC expression vector. In vivo imaging revealed that these CD42b(+) platelets were present in thrombi after laser-induced vessel wall injury. In contrast, sustained and excessive c-MYC expression in megakaryocytes was accompanied by increased p14 (ARF) and p16 (INK4A) expression, decreased GATA1 expression, and impaired production of functional platelets. These findings suggest that the pattern of c-MYC expression, particularly its later decline, is key to producing functional platelets from selected iPSC clones.

The renin-angiotensin system (RAS) plays critical roles in the pathogenesis of atherosclerosis. Clinical studies demonstrate that pharmacological blockade of RAS with Angiotensin II type 1 receptor (AT1R) blockers (ARBs) is effective in the treatment of patients with cardiovascular diseases. Recent studies reported that telmisartan, an ARB, has a partial agonistic effect on peroxisome proliferator-activated receptor-gamma (PPAR-gamma). The role of PPAR-gamma-mediated signaling has been implicated in regulation of not only metabolic disorders but also atherosclerosis. Here, we investigated the effects of telmisartan, which is not related to AT1R blockade, using AT1aR and apolipoprotein E (ApoE) double-deficient (ApoE-/-AT1R-/-) mice in vivo. Both genetic ablation of AT1R in ApoE-deficient (ApoE-/-) mice and administration of telmisartan (10 mg/kg/day) to ApoE-/- mice for 20 weeks reduced the development of atherosclerosis (P &lt; 0.05, respectively). Telmisartan decreased lipid deposition (P &lt; 0.01) and increased collagen contents (P &lt; 0.05) in plaques in ApoE-/- mice. Administration of telmisartan to ApoE-/-AT1aR-/- mice also inhibited the progression of atherosclerosis in aorta (P &lt; 0.05) even in mice, which have no AT1aR genetically. Moreover, in these mice, telmisartan decreased macrophage accumulation and lipid deposition, and increased collagen contents in plaques in aortic root (P &lt; 0.05, respectively), indicating stabilization of plaques. Telmisartan-treated ApoE-/-AT1aR-/- mice showed lower body weight and higher plasma high-density lipoprotein levels compared with vehicle-treated mice (P &lt; 0.05, respectively). Telmisartan lowered systolic and diastolic blood pressure in ApoE-/-AT1aR-/- mice (P &lt; 0.01). These results suggest that telmisartan has protective effects on the development of atherosclerosis and metabolic disorders beyond AT1R blockade in ApoE-deficient mice. (C) 2010 Elsevier Masson SAS. All rights reserved.

RATIONALE: Hydrolysis of intracellular cholesterol ester (CE) is the key step in the reverse cholesterol transport in macrophage foam cells. We have recently shown that neutral cholesterol ester hydrolase (Nceh)1 and hormone-sensitive lipase (Lipe) are key regulators of this process in mouse macrophages. However, it remains unknown which enzyme is critical in human macrophages and atherosclerosis. OBJECTIVE: We aimed to identify the enzyme responsible for the CE hydrolysis in human macrophages and to determine its expression in human atherosclerosis. METHODS AND RESULTS: We compared the expression of NCEH1, LIPE, and cholesterol ester hydrolase (CES1) in human monocyte-derived macrophages (HMMs) and examined the effects of inhibition or overexpression of each enzyme in the cholesterol trafficking. The pattern of expression of NCEH1 was similar to that of neutral CE hydrolase activity during the differentiation of HMMs. Overexpression of human NCEH1 increased the hydrolysis of CE, thereby stimulating cholesterol mobilization from THP-1 macrophages. Knockdown of NCEH1 specifically reduced the neutral CE hydrolase activity. Pharmacological inhibition of NCEH1 also increased the cellular CE in HMMs. In contrast, LIPE was barely detectable in HMMs, and its inhibition did not decrease neutral CE hydrolase activity. Neither overexpression nor knockdown of CES1 affected the neutral CE hydrolase activity. NCEH1 was expressed in CD68-positive macrophage foam cells of human atherosclerotic lesions. CONCLUSIONS: NCEH1 is expressed in human atheromatous lesions, where it plays a critical role in the hydrolysis of CE in human macrophage foam cells, thereby contributing to the initial part of reverse cholesterol transport in human atherosclerosis.

BACKGROUND: It has been proposed that bone marrow-derived cells infiltrate the neointima, where they differentiate into smooth muscle (SM) cells; however, technical limitations have hindered clear identification of the lineages of bone marrow-derived "SM cell-like" cells. METHODS AND RESULTS: Using a specific antibody against the definitive SM cell lineage marker SM myosin heavy chain (SM-MHC) and mouse lines in which reporter genes were driven by regulatory programs for either SM-MHC or SM α-actin, we demonstrated that although some bone marrow-derived cells express SM α-actin in the wire injury-induced neointima, those cells did not express SM-MHC, even 30 weeks after injury. Likewise, no SM-MHC(+) bone marrow-derived cells were found in vascular lesions in apolipoprotein E(-/-)mice or in a heart transplantation vasculopathy model. Instead, the majority of bone marrow-derived SM α-actin(+) cells were also CD115(+)CD11b(+)F4/80(+)Ly-6C(+), which is the surface phenotype of inflammatory monocytes. Moreover, adoptively transferred CD11b(+)Ly-6C(+) bone marrow cells expressed SM α-actin in the injured artery. Expression of inflammation-related genes was significantly higher in neointimal subregions rich in bone marrow-derived SM α-actin(+) cells than in other regions. CONCLUSIONS: It appears that bone marrow-derived SM α-actin(+) cells are of monocyte/macrophage lineage and are involved in vascular remodeling. It is very unlikely that these cells acquire the definitive SM cell lineage.

Fluid retention is characteristic of veno-occlusive disease (VOD). We hypothesized that plasma brain natriuretic peptide (BNP), a neurohormone secreted in response to volume expansion, may be associated with VOD after hematopoietic stem cell transplantation (HSCT). BNP was measured before and weekly after HSCT in 46 recipients. Sixteen patients developed VOD. BNP concentrations were similar before and on day 0 in patients with and without VOD, but were significantly higher on day 7 and later in those with VOD. Patients with VOD had significantly higher peak BNP concentrations before engraftment than those without VOD (median, 634.4 versus 80.9 pg ml -1 P=0.01). Multivariate analysis showed that VOD was independently associated with BNP elevation (odds ratio, 50.1 95% CI: 5.2-478.4 P&lt 0.01). Landmark analysis at day 7 showed that patients with peak BNP concentration of ≥180 pg ml-1 had significantly worse 100-day survival than patients with peak BNP &lt 180 pg ml-1 (54 versus 91% P&lt 0.01). In multivariate analysis, BNP elevation before day 7 significantly predicted 100-day survival (hazard ratio 5.3 95% CI: 1.1-24.3 P=0.03). These findings suggest that plasma BNP may serve as a diagnostic and prognostic marker of VOD. © 2010 Macmillan Publishers Limited. All rights reserved.