Kensuke Tsushima

A common Ile 823 Met variant of ATP-binding cassette transporter A1 gene (ABCA1) alters high density lipoprotein cholesterol level in Japanese population

Recently, variants in ATP-binding cassette transporter A1 (ABCA1) were demonstrated to be associated with increased level of high density lipoprotein cholesterol (HDL-C) and decreased risk of coronary artery disease (CAD) in Caucasians. However, this is not universally applicable due to the ethnic or environmental differences. In this context, to clarify the effect of ABCA1 in Japanese, we evaluated the phenotypic effects of I/M 823 and R/K 219 variants on the plasma level of HDL-C in 410 patients recruited in our hospital. Subjects with M 823 allele had significantly higher level of HDL-C than those without M823 allele (49.0+/-15.1 vs. 44.9+/-11.5 mg/dl, respectively, P<0.05). This statistical significance did not change even after multiple regression analysis. In contrast, there was no difference in HDL-C level among the genotypes in R/K 219 polymorphism. Further, in our study population an inverse relationship was shown to exist between HDL-C level and incidence of CAD. However, no positive association was observed between those variants and susceptibility to CAD. In this study, we provide evidence that I/M 823 variant, not R/K 219 variant, in ABCA1 is one of the determinants of HDL-C level, suggesting the importance of this gene on lipid metabolism in Japanese.

Kruppel-like factor 5 causes cartilage degradation through transactivation of matrix metalloproteinase 9.

Although degradation of cartilage matrix has been suggested to be a rate-limiting step for endochondral ossification during skeletal development, little is known about the transcriptional regulation. This study investigated the involvement of KLF5 (Krüppel-like factor 5), an Sp/KLF family member, in the skeletal development. KLF5 was expressed in chondrocytes and osteoblasts but not in osteoclasts. The heterozygous deficient (KLF5+/-) mice exhibited skeletal growth retardation in the perinatal period. Although chondrocyte proliferation and differentiation were normal, cartilage matrix degradation was impaired in KLF5+/- mice, causing delay in replacement of cartilage with bone at the primary ossification center in the embryonic limbs and elongation of hypertrophic chondrocyte layer in the neonatal growth plates. Microarray analyses identified MMP9 (matrix metalloproteinase 9) as a transcriptional target, since it was strongly up-regulated by adenoviral transfection of KLF5 in chondrogenic cell line OUMS27. The KLF5 overexpression caused gelatin degradation by stimulating promoter activity of MMP9 without affecting chondrocyte differentiation or vascular endothelial growth factor expression in the culture of chondrogenic cells; however, in osteoclast precursors, it affected neither MMP9 expression nor osteoclastic differentiation. KLF5 dysfunction by genetic heterodeficiency or RNA interference was confirmed to cause reduction of MMP9 expression in cultured chondrogenic cells. MMP9 expression was decreased in the limbs of KLF5+/- embryos, which was correlated with suppression of matrix degradation, calcification, and vascularization. We conclude that KLF5 causes cartilage matrix degradation through transcriptional induction of MMP9, providing the first evidence that transcriptional regulation of a proteinase contributes to endochondral ossification and skeletal development.

IRF3 regulates cardiac fibrosis but not hypertrophy in mice during angiotensin II-induced hypertension

Hypertension is a typical modern lifestyle‐related disease that is closely associated with the development of cardiovascular disorders. Elevation of angiotensin II (ANG II) is one of several critical factors for hypertension and heart failure; however, the mechanisms underlying the ANG II‐mediated pathogenesis are still poorly understood. Here, we show that ANG II‐mediated cardiac fibrosis, but not hypertrophy, is regulated by interferon regulatory factor 3 (IRF3), which until now has been exclusively studied in the innate immune system. In a ANG II‐infusion mouse model (3.0 mg/kg/d), we compared IRF3‐deficient mice (Irf3−/−/Bcl2l12−/−) with matched wild‐type (WT) controls. The development of cardiac fibrosis [3.95±0.62% (WT) vs. 1.41±0.46% (Irj3−/−/Bcl2l12−/−); P<0.01] and accompanied reduction in left ventricle end‐diastolic dimension [2.89 ±0.10 mm (WT) vs. 3.51±0.15 mm (Irf3−/−/Bcl2l12−/−); P=0.012] are strongly suppressed in Irf3−/−/Bcl2l12−/− mice, whereas hypertrophy still develops. Further, we provide evidence for the activation of IRF3 by ANG II signaling in mouse cardiac fibroblasts. Unlike the activation of IRF3 by innate immune receptors, IRF3 activation by ANG II is unique in that it is activated through the canonical ERK signaling pathway. Thus, our present study reveals a hitherto unrecognized function of IRF3 in cardiac remodeling, providing new insight into the progression of hypertension‐induced cardiac pathogenesis.—Tsushima, K., Osawa, T., Yanai, H., Nakajima, A., Takaoka, A., Manabe, I., Ohba, Y., Imai, Y., Taniguchi, T., Nagai, R. IRF3 regulates cardiac fibrosis but not hypertrophy in mice during angiotensin II‐induced hypertension. FASEB J. 25, 1531–1543 (2011). www.fasebj.org

Autopsy report on central pontine myelinolysis triggered by vomiting associated with digoxin intoxication.

An 87-year-old male, prescribed digoxin and furosemide for congestive heart failure and Alzheimer disease, had dehydration and anemia due to poor food intake and hemorrhagic cystitis. Repeated vomiting due to an upper respiratory infection caused disturbance of consciousness and hypotension. The patient was admitted to hospital and diagnosed with digoxin intoxication and hypernatremia. The serum sodium (Na(+)) level was corrected, but the patient died 4 days after admission following uncontrollable seizure. A histologic examination after an autopsy revealed characteristic findings of central pontine myelinolysis (CPM). This is the first autopsy report on CPM triggered by vomiting in association with digoxin administration.

Temporary Dual-Chamber Pacing Can Stabilize Hemodynamics During Noncardiac Surgery in a Patient With Left Ventricular Hypertrophy and Outflow Obstruction

YPERTROPHIC CARDIOMYOPATHY (HCM) often includes asymmetric (or nonphysiologic) massive left ventricular hypertrophy, which can be diagnosed by electrocardiography and echocardiography. In patients with HCM, hypertrophy is more common in the ventricular septum below the aortic valve, leading to left ventricular outflow tract (LVOT) obstruction. 1-3 There have been many reports of anesthetic management for noncardiac surgery of patients with ischemic heart disease. However, there have been only a few reports concerning the anesthetic management of patients with HCM undergoing noncardiac surgery. 4-7 Hreybe et al reported that the presence of HCM significantly increased the risk of death and myocardial infarction associated with noncardiac surgery. 8 Patients with HCM undergoing elective procedures may require more careful preoperative assessment and perioperative monitoring. However, it is not known exactly what factors associated with HCM have harmful effects on the perioperative condition of a patient. Left ventricular hypertrophy and LVOT, which induce left ventricular diastolic dysfunction and a pressure gradient, may be involved. In addition, better ways for decreasing the risks have not yet been established. Permanent dual-chamber pacing has been proposed as an adjunct treatment to lessen symptoms in markedly symptomatic patients with obstructive HCM refractory to drugs. 9 This approach is based on the concept that pre-excitation of the interventricular septum by right ventricular pacing would cause the septum to move away from the left ventricular wall during systole and artificially make dyssynchrony, resulting in an increase in LVOT dimensions and, hence, a decrease in LVOT blood velocities. This would, in turn, decrease the systolic anterior motion of the mitral valve, resulting in further relief of the LVOT obstruction and less severe mitral regurgitation. However, the application of this procedure in perioperative management has been rare. Here, the authors describe a case of noncardiac surgery with left ventricular hypertrophy and LVOT obstruction. The surgery included resection of a catecholamine-secreting endocrine tumor that was having a harmful effect on the patient’s hypertrophic heart. After assessing the effect with temporary pacing, the authors performed temporary dual-chamber pacing to decrease the perioperative risks. Noncardiac surgery then was performed successfully without any adverse cardiac events. The clinical course of left ventricular hypertrophy and LVOT obstruction complicated with a catecholamine-secreting tumor involves significant implications in clinical practice.