Pulmonary Tumor Thrombotic Microangiopathy with Administration of Pulmonary Vasodilator Resulting in Clinical Improvement Prior to Final Diagnosis.

BACKGROUND The pathophysiology of pulmonary tumor thrombotic microangiopathy (PTTM) was recently revealed by autopsy. Considered rare, we suggest that this fatal disease is not rare, but has not been diagnosed pre-mortem. Some patients with pulmonary thromboembolism with unknown thrombus source or with sudden death have been treated for malignant carcinoma. We report a patient with PTTM who was successfully rescued acutely by treatment with soluble guanylate cyclase (sGC), resulting in appropriate palliative care. CASE REPORT An 80-year-old Japanese woman was transferred to our emergency room for severe dyspnea owing to type I respiratory failure. Her clinical findings indicated pulmonary thromboembolism, but we found no thrombus in either the pulmonary artery or inferior vena cava. However, we incidentally found gallbladder cancer with peritoneal metastases. These findings raised the suspicion of PTTM. We began concurrent sGC and direct oral anticoagulant (DOAC) on the assumption that PTTM had occurred, while performing peripheral pulmonary artery sampling for cytology, and pulmonary perfusion scintigraphy. Cytology revealed several aplastic cells; consequently, we finally diagnosed PTTM. Because she did not wish to undergo examination and active treatment for carcinoma, we initiated palliative care while continuing sGC. She was able to spend time with her family for more than 100 days, without dyspnea. CONCLUSIONS We must recognize PTTM, which is a lesser-known disease, and introduce diagnostic therapy with a pulmonary vasodilator, such as sGC, immediately, when we suspect PTTM, leading to appropriate clinical care.

Persistent Primitive Hypoglossal Artery with Ipsilateral Symptomatic Carotid Artery Stenosis and Cerebral Aneurysm.

OBJECTIVE: Persistent primitive hypoglossal artery (PPHA) is a rare type of persistent carotid-basilar anastomosis sometimes associated with other vascular lesions. We treated an extremely rare case of PPHA with concomitant ipsilateral symptomatic cervical internal carotid artery (ICA) stenosis and unruptured aneurysm. CASE PRESENTATION: A 67-year-old woman visited our institution with acute onset of diplopia. Magnetic resonance imaging revealed multiple acute infarctions in the right anterior and posterior circulations. Digital subtraction angiography demonstrated the right PPHA concomitant with ipsilateral cervical ICA stenosis and an unruptured ICA aneurysm with maximum diameter of 8 mm. The multiple infarctions were considered to result from artery-to-artery embolism due to microthrombi from the ICA plaque passed along the PPHA, so carotid endarterectomy was performed as the first step with preoperative modified Rankin Scale (mRS) grade 1. During the operation, the patient had impaired ICA perfusion due to internal shunt catheter migration into the PPHA followed by acute infarction in the right hemisphere causing mild left hemiparesis. The patient was transferred to the rehabilitation hospital with mRS grade 3. After 3 months of rehabilitation, the patient recovered to mRS grade 1 and clipping surgery for the unruptured right ICA aneurysm was performed as the second step with uneventful postoperative course. CONCLUSION: The treatment strategy should be carefully considered depending on the specific blood circulation for such cases of PPHA with unique vasculature.

Cerebrospinal fluid leak presented with the C1-C2 sign caused by spinal canal stenosis: a case report.

BACKGROUND: Intracranial hypotension is a disorder characterized by low cerebrospinal fluid (CSF) pressure typically caused by loss of CSF. Although some mechanisms account for the CSF leakage have been elucidated, spinal canal stenosis has never been reported as a pathological cause of intracranial hypotension. C1-C2 sign is a characteristic imaging feature, which indicates CSF collection between the spinous processes of C1 and C2, occasionally observed on magnetic resonance imaging (MRI) in patients with intracranial hypotension. CASE PRESENTATION: A 58-year-old man was presented to our institute with complaints of posterior cervical pain persisting for 3 months, along with numbness and muscle weakness of extremities. A fat suppression T2-weighted image of MRI illustrated fluid collection in the retrospinal region at C1-C2 level, and an 111In-DTPA cisternoscintigram clearly revealed the presence of CSF leakage into the same region. The MRI also showed stenosis in spinal canal at C3/4 level, and a computed tomography (CT) myelogram suggested a blockage at the same level. We gave a diagnosis as intracranial hypotension due to the CSF leakage, which might be caused by the spinal canal stenosis at C3/4 level. Despite 72 h of conservative therapy, a brain CT showed the development of bilateral subdural hematomas. We, therefore, performed burr-hole drainage of the subdural hematoma, blood-patch therapy at C1/2 level, and laminoplasty at C3-4 at the same time. Improvement of symptoms and imaging features which suggested the CSF leak and subdural hematoma were obtained post-operatively. CONCLUSION: The present case suggested the mechanism where the CSF leakage was revealed as fluid collection in the retrospinal region at C1-C2 level. Increased intradural pressure due to the spinal canal stenosis resulted in dural tear. CSF leaked into the epidural space and subsequently to the retrospinal region at C1-C2 level, due to the presence of spinal canal stenosis caudally as well as the vulnerability of the tissue structure in the retrospinal region at C1-C2 level. Thus, our theory supports the mechanisms of previously reported CSF dynamics associated to C1-C2 sign, and also, we suggest spinal canal stenosis as a novel etiology of intracranial hypotension.

Topological Boundary Modes from Translational Deformations.

Localized states universally appear when a periodic potential is perturbed by defects or terminated at its surface. In this Letter, we theoretically and experimentally demonstrate a mechanism that generates localized states through continuous translational deformations of periodic potentials. We provide a rigorous proof of the emergence of the localized states under the deformations. The mechanism is experimentally verified in microwave photonic crystals. We also demonstrate topological phase windings of reflected waves for translated photonic crystals.

Influence of cognitive impairment on cardiac mortality after percutaneous coronary intervention in very elderly patients: a retrospective observational study.

BACKGROUND: Cognitive impairment (CI) increases cardiac mortality among very elderly patients. Percutaneous coronary intervention (PCI) for ischemic heart disease (IHD) patients is considered a favorable strategy for decreasing cardiac mortality. Here, we investigated the influence of CI on cardiac mortality after PCI in very elderly patients. METHODS: We performed a retrospective observational analysis of patients who received PCI between 2012 and 2014 at the South Miyagi Medical Center, Japan. IHD patients over 80 years old who underwent the Mini-Mental State Examination for CI screening during hospitalization and/or who had been diagnosed with CI were included. Participants were divided into CI and non-CI groups, and cardiac mortality and incidence of adverse cardiac events in a 3-year follow-up period were compared between groups. Statistical analyses were performed using the t-test, χ2 test, and multivariable Cox regression analysis, with major comorbid illness and conventional cardiac risk factors as confounders. RESULTS: Of 565 patients, 95 were included (41 CI, 54 non-CI). Cardiac mortality during the follow-up period was significantly higher in the CI group (36%) compared with the non-CI group (13%) (OR = 4.3, 95% CI: 1.56-11.82, P < 0.05). CI was an independent cardiac prognostic factor after PCI and, for CI patients, living only with a CI partner was an independent predictor of cardiac death within three years. CONCLUSIONS: CI significantly affected cardiac prognosis after PCI in very elderly patients, particularly those living with a CI partner. To improve patients' prognoses, social background should be considered alongside conventional medical measures.

Influence of atrial fibrillation on cardiac prognosis in chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD), a known risk factor for the development of congestive heart failure (CHF), was recently shown to predict the prevalence of atrial fibrillation (AF). Here, we explore the influence of AF on cardiac prognosis in COPD patients. METHODS: A total of 339 consecutive patients who underwent spirometry from 2010 to 2013 for various reasons were retrospectively examined. Based on the diagnostic criteria, patients were stratified into COPD and non-COPD groups, which were both further divided into those with AF (chronic AF or paroxysmal AF) or sinus rhythm (SR) based on previous electrocardiography results. Significances of differences in cardiac events were assessed by the chi-square test. Multivariate logistic regression analyses and Cox proportional hazard models were applied to evaluate the influence of AF on cardiac events. RESULTS: Of the 339 patients, 190 were diagnosed with COPD, with 42 of these were having AF. During the mean follow-up period of 7.4 ± 0.8 years, CHF developed more frequently in COPD patients with AF than in COPD patients without AF [50% vs 7%; odds ratio (OR) 12.4, 95% confidence interval (CI): 5.25-29.49, p < 0.05]. AF was an independent predictor of CHF development (OR 20.4, 95% CI: 6.55-79.80, p < 0.05) and cardiac mortality (OR 2.8, 95% CI: 1.79-4.72, p < 0.05). Moreover, positive correlations were found between the severity of pulmonary obstruction with AF and CHF development (R = 0.69, p < 0.05), as well as cardiac mortality (R = 0.78.p < 0.05). CONCLUSIONS: These results suggest that AF may be strongly associated with cardiac mortality and CHF in COPD patients.

Multiple Metastasizing Pleomorphic Adenomas of the Lung.

A 40-year-old woman was referred to our hospital with abnormal findings on chest X-ray. Her medical history was remarkable in that she had presented with a pleomorphic adenoma in the right parotid gland treated by surgical removal approximately 12 years previously. Chest computed tomography showed well-defined non-calcified nodules of the bilateral lobes, so she underwent segmentectomy of the right upper lobe and middle lobe. The histopathological diagnosis was metastasizing pleomorphic adenoma of the lung, a rare entity.

Recurrent Acute Myocardial Infarction in a Patient with Severe Coronary Artery Ectasia: Implication of Antithrombotic Therapy.

BACKGROUND Acute myocardial infarction (AMI) can be caused not only by plaque rupture/erosion, but also by many other mechanisms. Thromboembolism due to atrial fibrillation and coronary thrombosis due to coronary artery ectasia are among the causes. Here we report on a case of recurrent myocardial infarction with coronary artery ectasia. CASE REPORT Our case was a 78-year-old woman with hypertension. Within a one-month interval, she developed AMI twice at the distal portion of her right coronary artery along with coronary artery ectasia. On both events, emergent coronary angiography showed no obvious organic stenosis or trace of plaque rupture at the culprit segment after thrombus aspiration. After the second acute event, we started anticoagulation therapy with warfarin to prevent thrombus formation. In the chronic phase, we confirmed, by using coronary angiography, optimal coherence tomography and intravascular ultrasound, that there was no plaque rupture and no obvious thrombus formation along the coronary artery ectasia segment of the distal right coronary artery, which suggested effectiveness of anticoagulant. Furthermore, by Doppler velocimetry we found sluggish blood flow only in the coronary artery ectasia lesion but not in the left atrium which is generally the main site of systemic thromboembolism revealed by transesophageal echocardiography. CONCLUSIONS These results suggest that the two AMI events at the same coronary artery ectasia segment were caused by local thrombus formation due to local stagnant blood flow. Although it has not yet been generally established, anticoagulation therapy may be effective to prevent thrombus formation in patients with coronary artery ectasia regardless of the prevalence of atrial fibrillation.

Application of water-insoluble polymers to orally disintegrating tablets treated by high-pressure carbon dioxide gas.

The phase transition of pharmaceutical excipients that can be induced by humidifying or heating is well-known to increase the hardness of orally disintegrating tablets (ODTs). However, these conditions are not applicable to drug substances that are chemically unstable against such stressors. Here, we describe a system which enhances the hardness of tablets containing water-insoluble polymers by using high-pressure carbon dioxide (CO2). On screening of 26 polymeric excipients, aminoalkyl methacrylate copolymer E (AMCE) markedly increased tablet hardness (+155N) when maintained in a high-pressure CO2 environment. ODTs containing 10% AMCE were prepared and treatment with 4.0MPa CO2 gas at 25°C for 10min increased the hardness to +30N, whose level corresponded to heating at 70°C for 720min. In addition, we confirmed the effects of CO2 pressure, temperature, treatment time, and AMCE content on the physical properties of ODTs. Optimal pressure of CO2 gas was considered to be approximately 3.5MPa for an AMCE formula, as excessive pressure delayed the disintegration of ODTs. Combination of high-pressure CO2 gas and AMCE is a prospective approach for increasing the tablet hardness for ODTs, and can be conducted without additional heat or moisture stress using a simple apparatus.

Aberrant differentiation of Tsc2-deficient teratomas associated with activation of the mTORC1-TFE3 pathway.

The model animal of renal cell carcinoma (RCC), the Eker rat, has a germline mutation in the tuberous sclerosis 2 (Tsc2) gene. Heterozygous mutants develop RCCs by second hit in the wild-type Tsc2 allele, whereas homozygous mutants are embryonic lethal. In the present study, a new cell differentiation model was developed to study the mechanism of Tsc2 mutation-associated pathogenesis by generating Tsc2-deficient embryonic stem cells (ESCs) from Eker rats. Tsc2+/+, Tsc2+/- and Tsc2-/- ESCs were all capable of generating three germ layers: mesoderm, ectoderm, and endoderm. Interestingly, epithelial tumor-like abnormal ductal structures were reproducibly observed in Tsc2-/- teratomas from different ESC lines. Immunohistochemical analysis revealed that mammalian target of rapamycin complex 1 (mTORC1) signaling was activated in abnormal ducts of Tsc2-/- teratomas, on the basis of positive staining for p-S6 and p-4EBP1. In these abnormal ducts, expression levels of epithelial markers (i.e., megalin and cubilin) and the cytoplasmic localization of E-cadherin and ß-catenin were similar to those in Eker rat RCCs. Moreover, a transcription factor regulated by mTORC1, named TFE3, was located in the nuclei of abnormal ducts and Eker rat RCCs. As a negative regulator of ESC differentiation, TFE3 may result in tissue-specific differentiation defects related to tumorigenesis in Eker rats and Tsc2-/- teratomas. The present study suggests that ESCs derived from Eker rats constitute a novel experimental tool with which to analyze differentiation defects and cell-type specific pathogenesis associated with Tsc2 deficiency.

Mechanical characterization and modelling of the temperature-dependent impact behaviour of a biocompatible poly(L-lactide)/poly(ε-caprolactone) polymer blend.

Poly(ε-caprolactone) (PCL) is a ductile, bioabsorbable polymer that has been employed as a blend partner for poly(L-lactic acid) (PLLA). An improvement of the material strength and impact resistance of PLLA/PCL polymer blends compared to pure PLLA has been shown previously. To use numerical simulations in the design process of new components composed of the PLLA/PCL blend, a constitutive model for the material has to be established. In this work, a constitutive model for a PLLA/PCL polymer blend is established from the results of compressive tests at high and low strain rates at three different temperatures, including the body temperature. Finite element simulations of the split Hopkinson pressure bar test using the established constitutive model are carried out under the same condition as the experiments. During the experiments, the changes in the diameter and thickness of the specimens are captured by a high-speed video camera. The accuracy of the numerical model is tested by comparing the simulation results, such as the stress, strain, thickness and diameter histories of the specimens, with those measured in the experiments. The numerical model is also validated against an impact test of non-homogenous strains and strain rates. The results of this study provide a validated numerical model for a PLLA/PCL polymer blend at strain rates of up to 1800 s(-1) in the temperature range between 22°C and 50°C.

Middle Cerebral Artery Occlusion Presenting as Upper Limb Monochorea.

BACKGROUND: Hemichorea is usually caused by a structural lesion in the contralateral basal ganglia or subthalamic nuclei or it develops as a form of a neurologic complication including hyperglycemia. We report a rare case of a patient who developed choreic movement in the right upper extremity associated with a contralateral middle cerebral artery (MCA) occlusion. METHODS: A 76-year-old man presented with chorea in the right upper limb, known as monochorea, which occurred after recovery from losing consciousness while standing. He was found to have idiopathic orthostatic hypotension. His diffusion-weighted magnetic resonance imaging did not show signal changes indicative of acute ischemic lesions. A left carotid artery angiogram showed occlusion of the left MCA. (123)I-N-isopropyl-4-iodoamphetamine single-photon emission computed tomography of the brain showed marked hypoperfusion in the left MCA territory. His cerebrovascular reserve capacity determined using acetazolamide was relatively decreased in this territory. This decrease in cerebrovascular reserve capacity, however, did not require surgical treatment, such as extracranial-intracranial bypass surgery. RESULTS: The recurrence of chorea was not observed after antiplatelet therapy and instruction on how to cope with orthostatic hypotension. CONCLUSIONS: It is considered that transient hemodynamic ischemia in the right basal ganglia-thalamocortical circuits because of the combination of MCA occlusion and hypotension was the underlying cause of the monochorea in this patient.Vascular imaging studies for early identification of occlusion or severe stenosis of cerebral major arteries should be carried out in patients acutely presenting with chorea, even in the absence of other clinical signs.

Myocardial depression induced by severe sepsis: successful rescue using extracorporeal cardiopulmonary resuscitation from initial phase of severe sepsis.

A 60-year-old man was diagnosed with severe sepsis caused by pyelonephritis. During transfer to the hospital room, he suddenly developed ventricular fibrillation and the patient recovered after electrical defibrillation. After this cardiac event, his haemodynamics collapsed despite administration of crystalloid fluid. Transthoracic echocardiography was immediately performed showing the oedema and reduced left ventricular wall motion. Since the haemodynamic collapse was too severe to maintain with conventional septic shock therapy, we introduced extracorporeal cardiopulmonary resuscitation, bridging to administration of antibiotics. As a result of these combined therapies, the patient was successfully resuscitated. From this clinical course, we finally diagnosed that the severe sepsis was concomitant with myocardial depression. Introduction of mechanical support, including extracorporeal cardiopulmonary resuscitation may be recommendable in cases of severe sepsis with myocardial depression resulting in haemodynamic collapse, however, the option of introduction of an invasive approach needs further examination.

Establishment of Tsc2­deficient rat embryonic stem cells.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by TSC1 or TSC2 mutations. TSC causes the development of tumors in various organs such as the brain, skin, kidney, lung, and heart. The protein complex TSC1/2 has been reported to have an inhibitory function on mammalian target of rapamycin complex 1 (mTORC1). Treatment with mammalian target of rapamycin (mTOR) inhibitors has demonstrated tumor­reducing effects in patients with TSC but is also associated with various adverse effects. In recent years, experiments involving in vivo differentiation of pluripotent stem cells have been reported as useful in elucidating mechanisms of pathogenesis and discovering new therapeutic targets for several diseases. To reveal the molecular basis of the pathogenesis caused by the Tsc2 mutation, we derived embryonic stem cells (ESCs) from Eker rats, which have the Tsc2 mutation and develop brain lesions and renal tumors. Although several studies have reported the necessity of Tsc1 and Tsc2 regulation to maintain ESCs and hematopoietic stem cells, we successfully established not only Tsc2+/+ and Tsc2+/- ESCs but also Tsc2-/- ESCs. We confirmed that these cells express pluripotency markers and retain the ability to differentiate into all three germ layers. Comprehensive gene expression analysis of Tsc2+/+ and Tsc2+/- ESCs revealed similar profiles, whereas the profile of Tsc2-/- ESCs was distinct from these two. In vitro differentiation experiments using these ESCs combined with in vivo experiments may reveal the mechanism of the tissue­specific pathogenesis caused by the Tsc2 mutation and identify specific new therapeutic targets.

Impact of cigarette smoking on coronary plaque composition.

OBJECTIVES: Cigarette smoking is associated with atherosclerosis and is an important risk factor for cardiovascular disease. We evaluated the impact of cigarette smoking on coronary plaque composition using integrated backscatter intravascular ultrasound (IB-IVUS). METHODS: A total of 143 consecutive patients undergoing percutaneous coronary intervention were enrolled. A history of illness, as well as smoking habits, was obtained by interview. Participants were asked to report whether they were current smokers, had quit smoking, or had never smoked. According to interview results, patients were divided into the following three groups: current, former, and never smokers. Conventional and IB-IVUS tissue characterization analyses were carried out. Three-dimensional analyses were carried out to determine plaque volume and the volume of each plaque component (lipid, fibrous, and calcified). RESULTS: IB-IVUS analysis indicated that the patients in the current smoker group had significantly increased percent lipid volume and significantly decreased percent fibrous volume (P=0.01 and 0.03). Logistic regression analysis showed that the current smoking state (odds ratio 3.51, 95% confidence interval 1.02-12.10, P=0.04) was independently associated with the presence of lipid-rich plaques, which was defined as the upper 75th percentile of the study population. CONCLUSION: Smoking is independently associated with lipid-rich plaques, contributing to the increasing risk for plaque vulnerability.

Circadian variation of Rho-kinase activity in circulating leukocytes of patients with vasospastic angina.

BACKGROUND: Vasospastic angina (VSA) is known to exhibit circadian variation with an early morning peak. We examined whether Rho-kinase activity in circulating leukocytes, which is a useful biomarker for disease activity assessment of VSA, exhibits circadian variation in patients with VSA. METHODS AND RESULTS: In consecutive 31 VSA patients (M/F 23/8, 57±13 [SD] years) and 18 non-VSA patients (M/F 8/10, 57±14 years), we measured Rho-kinase activity in circulating leukocytes at 6:00, 12:00 and 21:00. We also examined the relationship between the Rho-kinase activity and coronary vasomotor responses during provocation test. Rho-kinase activity was significantly higher in VSA patients than in non-VSA patients at 6:00 (1.17±0.17 vs. 0.92±0.22, P<0.001), and showed a significant circadian variation with a peak at 6:00 (1.00±0.15 at 21:00, 1.17±0.17 at 6:00 and 1.12±0.22 at 12:00, P<0.001) in VSA patients, whereas no such variation was noted in non-VSA patients. Importantly, Rho-kinase activity at spasm provocation test was significantly correlated with basal coronary tone defined by vasodilating responses to intracoronary nitrate (r=0.40, P<0.05) and coronary vasoconstricting responses to acetylcholine (r=0.44, P<0.05) in VSA patients. Furthermore, their Rho-kinase activity at 6:00 was positively correlated with nocturnal parasympathetic activity as evaluated by heart rate variability in Holter monitoring (r=0.48, P<0.05). CONCLUSIONS: Rho-kinase activity exhibits distinct circadian variation associated with alterations in coronary vasomotor responses and autonomic activity in VSA patients.

Emergency care of acute myocardial infarction and the great East Japan earthquake disaster.

BACKGROUND: Although emergency care of acute myocardial infarction (AMI) could theoretically be improved through improved patient delay, this notion remains to be confirmed. Additionally, the influence of large earthquakes on the emergency care of AMI cases remains to be elucidated. The Great East Japan Earthquake (March 11, 2011) has enabled us to address these issues. METHODS AND RESULTS: We analyzed the data from 2008 to 2011 (n=3,937) in the Miyagi AMI Registry Study. In-hospital mortality was significantly lower in 2011 as compared with the previous 3 years (7.3% vs. 10.5%, P<0.05). This improvement was noted especially during the first 2 months after the Earthquake, associated with shorter elapsing time from onset to admission (120 vs. 240min, P<0.001) and higher performance rate of primary percutaneous coronary intervention (PCI) (86.8% vs. 76.2%, P<0.01). Importantly, after the Earthquake, patients with early admission (≤3h from onset) was significantly increased (59.1% vs. 47.0%, P<0.05) and their prognosis became better (7.9% vs. 11.4%, P=0.02), associated with a lower prevalence of heart failure on admission (6.9% vs. 16.2%, P=0.02) and higher performance rate of primary PCI (89.1% vs. 76.4%, P<0.01). CONCLUSIONS: Emergency care of AMI improved soon after the Great East Japan Earthquake compared with ordinary times by the contribution of earlier admission from onset and higher performance rate of primary PCI. (Circ J 2014; 78: 634-643).

Plasma cyclophilin A is a novel biomarker for coronary artery disease.

BACKGROUND: Oxidative stress induces secretion of cyclophilin A (CyPA) from vascular smooth muscle cells and it plays a crucial role in the pathogenesis of atherosclerosis in mice. Therefore, we tested our hypothesis that plasma CyPA levels are increased in patients with coronary artery diseases (CAD). METHODS AND RESULTS: In 320 consecutive patients undergoing coronary angiography, we examined the relationship between plasma CyPA levels and the severity of CAD. We measured plasma CyPA by an immunoassay based on the sandwich technique. Plasma CyPA levels were significantly higher in patients with significant coronary stenosis compared to those without it (P<0.001). A positive correlation was noted between plasma CyPA levels and significant coronary stenosis. The average number of stenotic coronary arteries and the need for coronary intervention were significantly increased in the quartiles of higher CyPA levels (both P<0.001). Indeed, the plasma CyPA level significantly correlated with the presence of CAD (adjusted odds ratio for CAD, 6.20; 95% confidence interval, 3.14-12.27; P<0.001). Interestingly, plasma levels of CyPA increased according to the number of atherosclerotic risk factors, all of which induce oxidative stress. Furthermore, plasma levels of CyPA significantly reduced after medical treatment of risk factors. Finally, CyPA was strongly expressed in coronary atherosclerotic plaque in patients with myocardial infarction. CONCLUSIONS: Plasma CyPA level is a novel biomarker for oxidative stress and CAD in humans.

Enhanced Rho-kinase activity in patients with vasospastic angina after the Great East Japan Earthquake.

BACKGROUND: It remains unclear whether disease activity of vasospastic angina (VSA) is altered during a disaster. METHODS AND RESULTS: Before and after the Great East Japan Earthquake, we examined Rho-kinase activity in circulating neutrophils of 11 VSA patients and their mental stress with the post-traumatic stress disorder (PTSD) questionnaire. Rho-kinase activity was significantly increased at 6 months after the Earthquake, and was returned to baseline level at 12 months. Importantly, percent change in Rho-kinase activity was significantly correlated with the PTSD score. CONCLUSIONS: These results indicate that the Rho-kinase activity of VSA patients was transiently enhanced associated with disaster-related mental stress.

Involvement of rho-kinase activation in the pathogenesis of coronary hyperconstricting responses induced by drug-eluting stents in patients with coronary artery disease.

BACKGROUND: Activation of Rho-kinase plays a central role in the pathogenesis of drug-eluting stents (DES)-induced coronary hyperconstricting responses in pigs in vivo has been previously demonstrated. In the present study, Rho-kinase activation involved in those responses in patients with coronary artery disease (CAD) is examined. METHODS AND RESULTS: In 24 patients with CAD who underwent coronary intervention with either DES or bare-metal stents (BMS), coronary vasomotor responses to intracoronary acetylcholine (ACh) before and after intracoronary pre-treatment with a Rho-kinase inhibitor, fasudil was examined. Coronary vasomotor responses by quantitative coronary angiography (QCA) and coronary vascular structure by optical coherence tomography (OCT) was evaluated. QCA showed that the coronary vasoconstricting responses to ACh were significantly enhanced in the DES group compared with the BMS group both at the proximal and the distal segments adjacent to the stents (proximal: BMS -13.0±10.7% vs. DES -25.4±14.3%, P=0.036; distal: BMS -24.4±12.2% vs. DES -43.8±14.7%, P=0.003). Importantly, fasudil markedly attenuated the enhanced vasoconstricting responses to ACh in the DES group (proximal 10.2±11.7%, distal 14.4±10.5% vs. before fasudil, both P<0.01). In the OCT imaging analysis, there was no significant correlation between intimal thickness and coronary vasoconstriction to ACh. CONCLUSIONS: These results indicate that Rho-kinase activation is substantially involved in the pathogenesis of the DES-induced coronary hyperconstricting responses in patients with CAD, suggesting the therapeutic importance of Rho-kinase pathway.