Akiho Minoshima

Immortalized multipotent pericytes derived from the vasa vasorum in the injured vasculature. A cellular tool for studies of vascular remodeling and regeneration.

Adventitial microvessels, vasa vasorum in the vessel walls, have an active role in the vascular remodeling, although its mechanisms are still unclear. It has been reported that microvascular pericytes (PCs) possess mesenchymal plasticity. Therefore, microvessels would serve as a systemic reservoir of stem cells and contribute to the tissues remodeling. However, most aspects of the biology of multipotent PCs (mPCs), in particular of pathological microvessels are still obscure because of the lack of appropriate methods to detect and isolate these cells. In order to examine the characteristics of mPCs, we established immortalized cells residing in adventitial capillary growing at the injured vascular walls. We recently developed in vivo angiogenesis to observe adventitial microvessels using collagen-coated tube (CCT), which also can be used as an adventitial microvessel-rich tissue. By using the CCT, CD146- or NG2-positive cells were isolated from the adventitial microvessels in the injured arteries of mice harboring a temperature-sensitive SV40 T-antigen gene. Several capillary-derived endothelial cells (cECs) and PCs (cPCs) cell lines were established. cECs and cPCs maintain a number of key endothelial and PC features. Co-incubation of cPCs with cECs formed capillary-like structure in Matrigel. Three out of six cPC lines, termed capillary mPCs demonstrated both mesenchymal stem cell- and neuronal stem cell-like phenotypes, differentiating effectively into adipocytes, osteoblasts, as well as schwann cells. mPCs differentiated to ECs and PCs, and formed capillary-like structure on their own. Transplanted DsRed-expressing mPCs were resident in the capillary and muscle fibers and promoted angiogenesis and myogenesis in damaged skeletal muscle. Adventitial mPCs possess transdifferentiation potential with unique phenotypes, including the reconstitution of capillary-like structures. Their phenotype would contribute to the pathological angiogenesis associated with vascular remodeling. These cell lines also provide a reproducible cellular tool for high-throughput studies on angiogenesis, vascular remodeling, and regeneration as well.

Ninjurin1 Is a Novel Factor to Regulate Angiogenesis Through the Function of Pericytes

BACKGROUND Capillary pericytes (cPCs), the mural cells of microvessels, play an important role in the formation and maintenance of microvessels; however, little is known about the mechanisms of how cPCs regulate angiogenesis. To identify factors that modulate cPC function, genes whose levels were altered in cPCs during neovessel formation were identified through a microarray screen. METHODS AND RESULTS Ninjurin1 (nerve injury-induced protein, Ninj1) was selected as a candidate factor for angiogenesis regulation. Ninj1 was expressed in capillary cells including endothelial cells (cECs) and was expressed at a higher level in cPCs. Hypoxia induced the gene expression of Ninj1 in addition of vascular endothelial growth factor (VEGF) in cPCs. When cPCs were co-incubated with a thoracic aorta in a three-dimensional Matrigel system, the length of the EC-tubes sprouting from the aorta was increased. Small interfering RNA-mediated downregulation of Ninj1 in cPCs enhanced these cPCs-mediated angiogenic effects, whereas overexpression of Ninj1 attenuated their effects. The production of angiogenic growth factors, such as VEGF and angiopoietin 1, by cPCs was enhanced by the downregulation of Ninj1, and reduced by the overexpression of Ninj1. CONCLUSIONS Ninj1 is a novel regulator for the angiogenic effect of PCs. Specifically, Ninj1 negatively regulates the formation of neovessels, that is, the EC-tube, by reducing the trophic effects of cPCs.

False Tendon‐Related Polymorphic Ventricular Tachycardia

A 39‐year‐old woman showed nonsustained polymorphic ventricular tachycardia (PVT) during light physical activity. Cardiac multidetector row computed tomography demonstrated false tendons, one of which proved to be the focus triggering premature ventricular contraction (PVC) in electrophysiological studies. The triggered PVC arose during the diastolic period, which might have caused tension in the false tendon. Radiofrequency catheter ablation targeting the triggered PVC by pace mapping was performed and proved partially effective against PVT. (PACE 2012;35:e341–e344)

Late gadolinium enhancement of cardiac magnetic resonance imaging indicates abnormalities of time-domain T-wave alternans in hypertrophic cardiomyopathy with ventricular tachycardia

BACKGROUND The presence of myocardial scar detected by late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging has been described as a good independent predictor of mortality in patients with hypertrophic cardiomyopathy (HCM). Time-domain T-wave alternans (TWA) is also a potential predictor of cardiac mortality in patients with left ventricular dysfunction. OBJECTIVE The purpose of this study was to elucidate the relationship between LGE distribution and TWA in patients with HCM. METHODS CMR and TWA analyses using Holter monitoring were performed in 42 patients with HCM. The average transmural extent of LGE was scored as 1-4 in each segment, and the sum of the LGE scores (total LGE score) was calculated for each patient. The correlation between the maximal time-domain TWA voltage and LGE findings was analyzed, and the differences in time-domain TWA voltage, total LGE score, and cardiac function assessed by CMR imaging in the presence or absence of ventricular tachycardia (VT) were also compared. RESULTS The total LGE score was significantly and positively correlated with the maximal time-domain TWA voltage (r = 0.59; P < .001). Furthermore, the total LGE score and maximal time-domain TWA voltage were significantly greater in patients who had episodes of VT (n = 21) than in those without VT (23 ± 7 vs. 10 ± 8; P < .001 and 87 ± 26 μV vs. 62 ± 12 μV; P < .001, respectively). However, the left ventricular ejection fraction did not statistically differ between patients with VT and those without VT (56% ± 14% vs. 61% ± 7%; P = .102). CONCLUSION The magnitude of the localized LGE was significantly correlated with abnormalities in ventricular repolarization as assessed by TWA and QT dispersion.

Three cases of corticosteroid therapy triggering ventricular fibrillation in J-wave syndromes

We describe three cases of J-wave syndrome in which ventricular fibrillation (VF) was probably induced by corticosteroid therapy. The patients involved were being treated with prednisolone for concomitant bronchial asthma. One of the three patients had only one episode of VF during her long follow-up period (14 years). Two patients had hypokalemia during their VF episodes. Corticosteroids have been shown to induce various types of arrhythmia and to modify cardiac potassium channels. We discuss the possible association between corticosteroid therapy and VF in J-wave syndrome based on the cases we have encountered.

A Case of Loss of Consciousness due to Epilepsy Diagnosed Using an Implantable Loop Recorder

We report a case of clonic‐tonic seizures diagnosed using an implantable loop recorder, a device for detecting cardiac arrhythmias. A 65‐year‐old man was referred to our hospital for loss of consciousness with myotonic jerks during sleep. He had experienced several similar episodes. No family history of sudden death was evident, and no structural heart disease was present. Coronary angiography with intracoronary acetylcholine (ACh) showed neither organic stenosis nor vasospastic angina. Ventricular tachyarrhythmias were not induced by programmed electrical stimuli. Sleep electroencephalography, brain magnetic resonance imaging and magnetic resonance angiography revealed no specific findings. We implanted a loop recorder to monitor rhythm abnormalities. One month later, an attack occurred at night. His wife recognized the episode and activated the implantable loop recorder. No arrhythmia was recorded, but myopotentials characteristic of tonic‐clonic seizures were detected.

Conifer-Derived Monoterpenes and Forest Walking.

Conifer and broadleaf trees emit volatile organic compounds in the summer. The major components of these emissions are volatile monoterpenes. Using solid phase microextraction fiber as the adsorbant, monoterpenes were successfully detected and identified in forest air samples. Gas chromatography/mass chromatogram of monoterpenes in the atmosphere of a conifer forest and that of serum from subjects who were walking in a forest were found to be similar each other. The amounts of α-pinene in the subjects became several folds higher after forest walking. The results indicate that monoterpenes in the atmosphere of conifer forests are transferred to and accumulate in subjects by inhalation while they are exposed to this type of environment.

[PS 01-25] NINJURIN1 IS A NOVEL FACTOR TO MEDIATE VESSEL MATURATION THROUGH ENDOTHELIAL-PERICYTES INTERACTIONS

Objective : It is known that abnormality of adventitial microvessel (vasa vasorum) is involved in vascular remodeling and progression of atherosclerosis. Although the normalization/maturation of micorvessels is attractive approach for anti-atherosclerosis, the knowledge about the mechanisms for microvascular normalization is limited. Interaction of vascular endothelial cells (ECs) and pericytes (PCs) is crucial to vascular maturation. Recently, we have reported that Ninjrin1(Ninj1) in PCs inhibit ECs growth. However, the role of Ninj1 in patho-physiological angiogenesis is still unclear . Accordingly, we examined the effects of Ninj1on the formation of neovessels using mouse hind limb ischemia (HLI) model. Design and Method: Capillary ECs and PCs were prepared from adventitia of mouse femoral artery . Cell cluster or 3D-gel assay was performed by mixture of ECs and PCs in non-adherent or Matri-gel-coated wells. Knock down of Ninj1 in cells or tissues were induced by transfection of Ninj1-SiRNA or biodegradable microspheres releasing Ninj1-siRNA. Blood flow recovery and formation of microvessels in limbs were measured by Doppler flow meter and staining with anti-CD31 or lectin-FITC. Results: Ninj1 was expressed in microvessels, both dominantly PCs and ECs. Cell cluster assay demonstrated that down-regulation of Ninj1 in PCs or ECs reduced the PC-EC interaction. When ECs were co-incubated with PCs in 3D-gel, they made matured mirovessel structure, i.e. EC-tube wrapped with PCs. Down-regulation of Ninj1 in PCs or ECs reduced inhibited the formation of this matured vessel structure. Ninj1 was expressed in microvessels within skeletal muscle tissues, and their expression was enhanced after HLI operation. When the expression of Ninj1 was inhibited by intra-muscular injection of Ninj1-siRNA leads the formation of lectin/CD31-positive functional matured microvessels and the blood flow recovery was decreased. Conclusions: Ninj1 is important for the association between PCs and ECs to form functional matured vessels. This finding would provide insights into the therapy for atherosclerosis in addition to ischemic diseases.

A COMBINATION OF 123I-BMIPP SPECT AND STRESS 201TL MYOCARDIAL PERFUSION SPECT AS A USEFUL PROGNOSTIC MARKER OF ASYMPTOMATIC PATIENTS WITH NON-OBSTRUCTIVE HYPERTROPHIC CARDIOMYOPATHY

Reduced coronary flow reserve (CFR) indicates adverse clinical outcome in hypertrophic cardiomyopathy (HCM). 123I-BMIPP (BMIPP) SPECT and stress 201Tl (TL) SPECT has been used to evaluate coronary microvascular dysfunction in HCM. We investigated the long-term prognostic value of BMIPP and stress TL

Eosinophilic myocarditis without hypereosinophilia accompanied by giant cell infiltration

A 53-year-old woman with a history of allergic disease was admitted to our hospital because of syncope induced by sustained ventricular tachycardia. The clinical course and the laboratory data did not correspond to those of acute myocarditis. Although eosinophils in the peripheral blood count were not increased, the diagnosis of eosinophilic myocarditis was made following a right ventricular endomyocardial biopsy that showed a remarkable infiltration of eosinophils. While giant cells were another histopathological feature of this case, they were considered to be an expression of the disease severity. This is a rare case of eosinophilic myocarditis, without peripheral eosinophilia. <Learning objective: Eosinophils in the peripheral blood usually increase in eosinophilic myocarditis. We describe a case of eosinophilic myocarditis without hypereosinophilia. Even in the absence of hypereosinophilia, endomyocardial biopsy should be performed during the investigation of unexplained myocardial disease.>.