Toll-like receptor 4 (TLR4) and angiotensin II (AngII) induce vascular remodeling through the production of reactive oxygen species (ROS). AngII has also been shown to increase antioxidant enzyme extracellular superoxide dismutase (ecSOD). However, the roles of TLR4 in Ang II-induced ROS production, vascular remodeling and hypertension remain unknown. Mice lacking TLR4 function showed significant inhibition of vascular remodeling in response to chronic AngII infusion, with no impact on blood pressure. The increases in ROS level and NADPH oxidase activity in response to AngII infusion were markedly blunted in TLR4-deficient mice. Similar effects were observed in wild-type (WT) mice treated with a sub-depressor dose of the AT1 receptor antagonist irbesartan, which had no effects on TLR4-deficient mice. Intriguingly, the AngII infusion-induced increases in ecSOD activity and expression were rather enhanced in TLR4-deficient mice compared with WT mice, whereas the expression of the proinflammatory chemokine MCP-1 was decreased. Importantly, AngII-induced vascular remodeling was positively correlated with NADPH oxidase activity, ROS levels and MCP-1 expression levels. Notably, chronic norepinephrine infusion, which elevates blood pressure without increasing ROS production, did not induce significant vascular remodeling in WT mice. Taken together, these findings suggest that ROS elevation is required for accelerating vascular remodeling but not for hypertensive effects in this model. We demonstrated that TLR4 plays a pivotal role in regulating AngII-induced vascular ROS levels by inhibiting the expression and activity of the antioxidant enzyme ecSOD, as well as by activating NADPH oxidase, which enhances inflammation to facilitate the progression of vascular remodeling.

We report a case of torsades de pointes (TdP) induced by donepezil without QT prolongation. An 86year-old woman was admitted to our hospital because of a syncopal attack. She had been treated for Alzheimer's disease with donepezil. Initial 12-lead electrocardiogram showed atrial fibrillation and normal corrected QT interval. After admission, atrial fibrillation spontaneously recovered to normal sinus rhythm on electrocardiographic monitoring. On the second day, electrocardiographic monitoring documented TdP. We discontinued donepezil immediately. After washout of donepezil, TdP was not observed again. Corrected QT interval was normal throughout hospitalization. This case suggests that donepezil may cause life-threatening ventricular arrhythmias without QT prolongation. Even if corrected QT interval is normal in patients taking donepezil and experiencing symptoms associated with TdP, electrocardiographic monitoring is recommended.

A 72-year-old male visited the hospital with a complaint of dyspnea. Under the diagnosis of pulmonary hypertension (PH) due to chronic thrombotic and/or embolic disease, this patient received anti-coagulant therapy. Unfortunately, the respiratory state deteriorated and died 34 days after admission. At autopsy, noncaseating granulomas, which were diagnostic of sarcoidosis, were found in bilateral enlarged hilar lymph nodes, lungs, heart, liver, spleen, testis and epididymis. In pulmonary vasculature, the following three kinds of lesions were observed; (i) sarcoid granulomatous vasculitis at the peripheral arteries and veins, (ii) intimal fibrous lesions ubiquitously found in proximal and peripheral arteries which were thought to be organized thromboemboli, (iii) Takayasu-like large vessel vasculitis with a huge fresh mural thrombus narrowing the lumen of most proximal portion of right pulmonary artery. Autopsy findings indicate that chronic sustained PH state in this patient was attributable to thrombotic and/or thromboembolic disease, and Takayasu-like vasculitis with thrombus played a role in the final deterioration of respiratory state through exacerbation of PH. In sarcoidosis patients, vasculitic lesions which can be formed in both small and large pulmonary arteries must be raised as the differential diagnosis for the initial cause of PH as well as the accelerating factor of PH.

Hereditary antithrombin (AT) deficiency is an autosomal dominant thrombophilic disorder caused by SERPINC1 abnormality. In the present study, we analyzed SERPINC1 in a Japanese patient with AT deficiency and autoimmune disease-like symptoms. Direct sequencing and multiplex ligation-dependent probe amplification revealed that the patient was hemizygous for the entire SERPINC1 deletion. Single nucleotide polymorphism genotyping, gene dose measurement, and long-range polymerase chain reaction (PCR) followed by mapping PCR and direct sequencing of the long-range PCR products revealed that the patient had an approximately 111-kb gene deletion from exon 2 of ZBTB37 to intron 5 of RC3H1, including the entire SERPINC1 in chromosome 1. We also found a 7-bp insertion of an unknown origin in the breakpoint, which may be a combination of three parts with a few base-pair microhomologies, resulting from a replication-based process known as 'fork stalling and template switching'. Because RC3H1, which encodes the protein roquin is involved in the repression of self-immune responses, the autoimmune disease-like symptoms of the patient may have resulted from this gene defect. In conclusion, we identified an entire SERPINC1 deletion together with a large deletion of RC3H1 in an AT-deficient patient with autoimmune disease-like symptoms.

Serial IVUS of the distal RA revealed a significant increase in IMV and decreases in LV and VV. Diabetes was the most powerful independent predictor of the percentage change in IMV of the distal RA after TRI. The percentage change in IMV was significantly positively correlated with HbA1c.