Jung-Ju Sir

Activated Forkhead Transcription Factor Inhibits Neointimal Hyperplasia After Angioplasty Through Induction of p27

Objective—We examined the effects of FKHRL1 (forkhead transcription factor in rhabdomyosarcoma like-1) overexpression on vascular smooth muscle cell (VSMC) proliferation, apoptosis, and cell cycle, in vitro, and the role of FKHRL1 and p27 in the pathophysiology of neointimal growth after balloon angioplasty, in vivo. Furthermore, we tested whether FKHRL1 overexpression can inhibit neointimal hyperplasia in a rat carotid artery model. Methods and Results—Adenovirus expressing the constitutively active FKHRL1 (FKHRL1-TM; triple mutant) with 3 Akt phosphorylation sites mutated was transfected to subconfluent VSMCs. FKHRL1 overexpression in cultured VSMCs increased p27 expression, leading to G1 phase cell-cycle arrest and increased apoptosis. In vivo, the phosphorylation of FKHRL1 increased significantly 3 hours after balloon injury and decreased thereafter, with the subsequent downregulation of p27. Although the phosphorylation of FKHRL1 was greatest at 3 hours, the downregulation of p27 showed a temporal delay, only slightly starting to decrease after 3 hours and reaching a nadir at 72 hours after balloon injury. Gene transfer of FKHRL1-TM increased p27, decreased proliferation, and increased apoptosis of VSMCs, which resulted in a marked reduction in neointima formation (intima-to-media ratio: 0.31±0.13 versus 1.17±0.28, for FKHRL1-TM versus Adv-GFP; P<0.001). Conclusion—Balloon angioplasty leads to the phosphorylation of FKHRL1 and decreased expression of p27, thereby promoting a proliferative phenotype in VSMCs in vitro and in vivo. This study reveals the importance of FKHRL1 in proliferation and viability of VSMCs and suggests that it may serve as a molecular target for interventions to reduce neointima formation after angioplasty.

Sulfasalazine induces haem oxygenase-1 via ROS-dependent Nrf2 signalling, leading to control of neointimal hyperplasia

AIMS Inflammation, and the subsequent proliferative activity of vascular smooth muscle cells (VSMCs), is one of the major pathophysiological mechanisms associated with neointimal hyperplasia following vascular injury. Although sulfasalazine (SSZ) has been used as an anti-inflammatory and immune-modulatory agent in various inflammatory diseases, its primary targets and therapeutic effects on vascular disease have not yet been determined. We investigated whether SSZ could suppress VSMC growth and prevent neointimal hyperplasia. METHODS AND RESULTS SSZ was found to have pro-apoptotic and anti-proliferative activity in cultured VSMCs. Unexpectedly, these effects were not mediated by nuclear factor kappa B (NF-kappaB) inhibition, which has been suggested to be the anti-inflammatory mechanism associated with the effects of SSZ. Instead, cell-cycle arrest of the VSMCs was observed, which was mediated by induction of haem oxygenase-1 (HO-1) followed by an increased expression of p21(waf1/Cip1). The underlying mechanism for SSZ-induced HO-1 expression was by reactive oxygen species (ROS)-dependent nuclear translocation and activation of nuclear factor erythroid-2-related factor 2 (Nrf2). In a rat carotid artery balloon injury model, administration of SSZ significantly suppressed neointimal growth. In a series of reverse experiments, inhibition of HO-1 by shRNA, ROS by N-acetylcysteine (NAC) or Nrf2 by dominant-negative Nrf2 abrogated the beneficial effects of SSZ. CONCLUSION Our data demonstrate that SSZ inhibits VSMC proliferation in vitro and in vivo through a novel signalling pathway and may be a promising therapeutic option for the treatment of proliferative vascular disease.

Hypereosinophilia Presenting as Eosinophilic Vasculitis and Multiple Peripheral Artery Occlusions without Organ Involvement

We report here a case with hypereosinophilia and peripheral artery occlusion. A 32-yr-old Korean woman presented to us with lower extremity swelling and pain. Angiography revealed that multiple lower extremity arteries were occlusive. The biopsy specimen showed perivascular and periadnexal dense eosinophilic infiltration in dermis and subcutaneous adipose tissue. Laboratory investigations revealed a persistent hypereosinophilia. She was prescribed prednisolone 60 mg daily. Her skin lesion and pain were improved and the eosinophil count was dramatically decreased. After discharge, eosinophil count gradually increased again. Cyanosis and pain of her fingers recurred. She had been treated with cyclophosphamide pulse therapy. Her eosinophilia was decreased, but the cyanosis and tingling sense were progressive. The extremity arterial stenoses were slightly progressed. Skin biopsy showed perivascular eosinophilic infiltration in the dermis and CD40 ligand (CD40L) positive eosinophilic infiltration. The serum TNF-α was markedly increased. These results suggest that CD40L (a member of TNF-α superfamily) could play a role in the inflammatory processes when eosinophil infiltration and activation are observed. We prescribed prednisolone, cyclophosphamide, clopidogrel, cilostazol, beraprost and nifedipine, and she was discharged.

A Case of Leclercia adecarboxylata Endocarditis in a Woman With Endometrial Cancer

Leclercia adecarboxylata, a motile, gram-negative bacillus of the enterobacteriaceae family, is rarely recovered as a pathogen. We report an exceptionally rare case of L. adecarboxylata endocarditis complicated by embolization of the kidney and spleen in a 48-year-old woman with endometrial cancer. After 4 weeks of antimicrobial treatment, she recovered without sequelae.

A case of severe coronary spasm associated with 5-fluorouracil chemotherapy.

Cardiotoxicity associated with 5-fluorouracil (FU) is an uncommon, but potentially lethal, condition. The case of an 83-year-old man with colon cancer who developed chest pain during 5-FU infusion is presented. The electrocardiogram (ECG) showed pronounced ST elevation in the lateral leads, and the chest pain was resolved after infusion of nitroglycerin. A coronary angiogram (CAG) revealed that the patient had significant atherosclerosis in the proximal left circumflex artery. Coronary artery spasm with fixed stenosis was considered, and a drug-eluting stent was implanted. After 8 hours, the patient complained of recurring chest pain, paralleled by ST elevation on the ECG. The chest pain subsided after administration of intravenous nitroglycerin followed by sublingual nifedipine. Repeated CAG showed patency of the previous stent. This case supports the vasospastic hypothesis of 5-FU cardiac toxicity, indicating that a calcium channel blocker may be effective in the prevention or treatment of 5-FU cardiotoxicity.

Serious cardioembolic stroke resulting from an overlooked left ventricular noncompaction.

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Right-sided myxomas with extramedullary hematopoiesis and ossification in Carney complex

The authors report the case of multiple right-sided myxomas in a 42-year-old man with Carney complex. He had previously been diagnosed as Cushings syndrome and undergone resection of pituitary adenoma at the age of 21. After 10 years, bilateral adrenalectomy had been performed with recurrence of Cushings syndrome. Recently, he complained of palpitation and intracardiac masses were detected. On physical examination, he had nevi on the lips and in the oral cavity. A tiny eyelid nodule was noted and histopathological analysis confirmed the diagnosis of skin myxoma. Thyroid ultrasonography revealed multiple hypoechoic nodules, which were confirmed pathologically as follicular adenomas. Scrotal ultrasonography also revealed small multiple testicular tumors. Echocardiography demonstrated intracardiac masses in right atrium and right ventricle. Right atriotomy revealed a right atrial mass attached to the annulus of the tricuspid valve and another mass arising from the interatrial septum. In right ventricle, a polypoid mass arose from the anterior leaflet of the tricuspid valve. Also, there were multiple tiny to small masses on the interatrial septum. The masses were completely excised and the tricuspid valve was repaired with annuloplasty. Histopathological analysis confirmed myxomas with foci of extramedullary hematopoiesis and ossification.

Successful Resection of a Giant Left Ventricular Pseudoaneurysm Developed Later after Mitral Valve Replacement

We present a case of successful surgical resection of a giant left ventricular (LV) pseudoaneurysm that developed 5 yr after mitral valve replacement (MVR). A 59-yr-old female was admitted with exertional chest pain radiating to left arm and back. 64-slice multidetector computed tomography (MDCT) revealed significant stenosis on the ostium of the first diagonal branch of the left anterior descending coronary artery and also a huge pseudoaneurysm compressing the right atrium and the inferior vena cava. She underwent resection of the pseudoaneurysm, and the pseudoaneurysm tunnel was repaired from the inside of LV cavity by removing the previously inserted prosthetic valve, followed by redo MVR together with coronary arterial bypass grafting (CABG) for a single-vessel disease. At the 6-month follow-up, the patient continued to do well without any complications.

Atypical takostubo cardiomyopathy associated with nasal packing for paranasal sinus surgery

Takotsubo cardiomyopathy (TC) is characterized by reversible left ventricular (LV) apical ballooning and no significant coronary artery stenosis. New variants of TC with localized wall motion abnormality or inversed pattern with hyperdynamic apex have been reported. We present the case of a 24-year-old female with atypical presentation of TC occurring in the setting of paranasal sinus surgery under local anaesthesia with post-surgical nasal packing. She did not demonstrate ST-segment elevation on electrocardiogram, but transient moderate LV systolic dysfunction and localized wall motion abnormality affecting basal to mid-ventricular anterior and anteroseptal wall. She rapidly and completely recovered without sequelae.

Additive Value of B-Type Natriuretic Peptide on Rest Tl-Dipyridamole Stress Tc-Sestamibi Gated Myocardial SPECT in Patients with Normal Left Ventricular Systolic Function.

We evaluated whether BNP has additive value to SPECT in patients with normal left ventricular (LV) systolic function. Data from 224 consecutive patients who underwent rest 201Tl-dipyridamole stress 99mTc-sestamibi gated SPECT and coronary angiography due to chest pain were analyzed. Patients with true positive SPECT showed significant higher BNP level than those with false positive defect (38.5 (19.0–79.8) versus 19.0 (9.3–35.8), P = .01). Patients with true negative SPECT also showed significantly lower BNP level than those with false negative SPECT (39.0 (23.0–77.0) versus 22.0 (15.0–43.0), P = .002). In multivariate analyses, elevated BNP level (using a cut-off value of 23.0 pg/mL) was the strongest and independent predictor of CAD in overall patients (OR 2.75, 95% CI: 1.50–5.023, P = .001) and patients with positive SPECT (OR 3.34, 95% CI: 1.51–7.37, P = .003). The area under the receiver-operating characteristic curve for CAD in overall patients and patients with positive SPECT was 0.673 (95% CI: 0.603–0.743, P < .001) and 0.694 (95% CI: 0.602–0.786, P < .001), respectively. This study suggests that BNP level has additive diagnostic value to SPECT findings in predicting CAD in patients with normal LV systolic function.