Aiko Sakamoto

Idiopathic retroperitoneal fibrosis, inflammatory aortic aneurysm, and inflammatory pericarditis—-Retrospective analysis of 11 case histories

Retroperitoneal fibrosis, inflammatory aortic aneurysm, and pericardial and mediastinal fibrosis are characterized by infiltration of immuno-inflammatory cells and deposition of thickened fibrous tissues. Several recent studies suggested that an immunoglobulin-G4 (IgG4)-related immunological mechanism may play a role in these diseases. By searching the clinical database of patients admitted to our department between 2000 and 2010, we summarized the clinical data of 11 patients who were diagnosed to have these disorders. The diagnoses were idiopathic retroperitoneal fibrosis (8 cases), mediastinal and/or pericardial fibrosis (4 cases), inflammatory abdominal aneurysm (2 cases), and inflammatory coronary periarteritis (1 case). Hypertension, diabetes, and dyslipidemia were found in 45%, 36%, and 55%, respectively, in these patients, and they were all either current or former smokers. Two patients with pericardial involvement showed a rushed clinical course, resulting in in-hospital death. Serum levels of IgG were elevated in 67%, and soluble interleukin-2 receptor was elevated in 75%, when measured. Immunohistochemical analysis showed marked infiltration of IgG4-positive plasma cells in the pericardium in patients who died of constrictive pericarditis. Our data support the notion that immune-inflammatory mechanism, which might be IgG4-related sometimes, may play a role in idiopathic retroperitoneal fibrosis, inflammatory aortic aneurysm, and mediastinal/pericardial fibrosis, although clinical course may differ substantially.

Serum levels of IgG4 and soluble interleukin-2 receptor in patients with coronary artery disease.

BACKGROUND Immunoglobulin G4 (IgG4)-related immuno-inflammation has been suggested to play a role in the development of remodeling of arterial wall. We investigated the association between serum concentrations of IgG4 or soluble interleukin-2 receptor (sIL-2R) and coronary artery disease (CAD). METHODS Serum concentrations of IgG4 and sIL-2R were measured in 286 patients who underwent coronary angiography. RESULTS In patients with CAD, the medians of serum concentrations of IgG4 (39.3 mg/dl) and sIL-2R (388 U/ml) were significantly higher than corresponding values in patients without CAD (IgG4 27.0 mg/dl, sIL-2R 312 U/ml). In receiver-operating characteristic curve analysis, the area under the curve of sIL-2R and IgG4 for the presence of CAD was 0.634 and 0.632, respectively. Age- and gender-adjusted logistic regression analysis showed that both of the fourth quartile of sIL-2R concentrations (≥509 U/ml) and that of IgG4 concentrations (≥57.7 mg/dl) were found to be associated with CAD with an odds ratio of 2.82 and 4.08, respectively, compared with the corresponding lowest quartile. CONCLUSIONS Serum concentrations of IgG4 and sIL-2R were increased in patients with angiographically-proven CAD, suggesting that IgG4-related immuno-inflammation may also have a role in the development and/or progression of coronary artery atherosclerosis.

Pioglitazone ameliorates systolic and diastolic cardiac dysfunction in rat model of angiotensin II-induced hypertension

We previously showed that administration of angiotensin II to rats causes fibrosis and lipid accumulation in the heart. In the current study, we examined the effect of pioglitazone, an agonist of peroxisome proliferator activated receptor-γ, on angiotensin II-induced intracardiac lipid accumulation and cardiac dysfunction. Pioglitazone, given orally at a dose of 2.5mg/kg/d, reduced cardiac triglyceride content and suppressed lipid deposition in the heart of angiotensin II-induced hypertensive rats without affecting angiotensin II-induced upregulation of lipogenic gene expression. Histological examination showed that pioglitazone reduced the area of cardiac fibrosis and iron deposition in the heart of angiotensin II-treated rats. Expression of an antioxidative molecule, heme oxygenase-1, was increased by angiotensin II infusion, and pioglitazone treatment preserved expression of HO-1. Angiotensin II increased the superoxide signals detected by dihydroethidium staining in myocardial cells with lipid deposition, and this increase was suppressed by pioglitazone. Cardiac function was analyzed in an ex vivo isolated cardiac perfusion system. It was found that pioglitazone improved both the systolic and diastolic cardiac performance, which was weakened by angiotensin II infusion, after transient ischemia and reperfusion. These findings collectively suggest that pioglitazone treatment ameliorated the histological and functional cardiac damage induced by angiotensin II infusion, the mechanism of which may be related to the antioxidative action of pioglitazone.

Reduction of renal lipid content and proteinuria by a PPAR-γ agonist in a rat model of angiotensin II-induced hypertension

An excess of lipids may accumulate in the kidney in conditions such as diabetes and hypertension, and can potentially cause renal injury. We previously reported that an infusion of angiotensin II into a rat induced deposition of lipids in the renal tubular epithelial cells. Here we have examined the effect of pioglitazone, an agonist of the peroxisome proliferator-activated receptor-γ (PPAR-γ), on renal lipid accumulation and renal injury induced by angiotensin II infusion. Pioglitazone treatment (2.5mg/kg/day) reduced the amount of triglycerides in the kidney of the angiotensin II-induced hypertensive rat without significantly altering either blood pressure levels or mRNA expression of lipogenic genes in the kidney. In addition, pioglitazone, either alone or in conjunction with angiotensin II, increased the expression of phosphorylated, but not total, AMP-activated protein kinase (AMPK). Proteinuria and kidney weight in the angiotensin II-infused rat were significantly decreased by pioglitazone treatment. In addition, pioglitazone suppressed iron deposition and ferritin protein induction, but did not alter upregulated expression of the antioxidative molecule, heme oxygenase-1, in the kidney of the angiotensin II-infused rat. These findings suggested that pioglitazone suppressed the angiotensin II-induced increase in renal lipid content by inhibiting its proteinuric action, but not by direct alteration of the expression or activity of lipid metabolism-related genes. Reduction of lipotoxic renal damage may represent one of the renoprotective effects provided by pioglitazone in hypertension with activation of the renin-angiotensin system.

Reversible photochromism of a ferrocenylazobenzene monolayer controllable by a single green light source

A 3-ferrocenylazobenzene monolayer on an ITO electrode exhibits reversible azobenzene isomerization using a single green light source, assisted by electrochemical control of the ferrocene redox state.

Effects of the AT(1) receptor blocker losartan and the calcium channel blocker benidipine on the accumulation of lipids in the kidney of a rat model of metabolic syndrome.

Unfavorable lipid accumulation may occur in the kidneys in the presence of metabolic syndrome and diabetes. The aim of this study was to investigate whether excess lipids would accumulate in the kidneys of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of metabolic syndrome. From 34 weeks of age, OLETF rats were treated orally with a calcium channel blocker, benidipine (3 mg kg−1 per day), or an AT1 receptor blocker, losartan (25 mg kg−1 per day), for 8 weeks. Blood pressure was slightly but significantly higher in the untreated OLETF rats (149±4 mm Hg) than in Long-Evans Tokushima Otsuka (LETO) rats (136±2 mm Hg), and both losartan (135±3 mm Hg) and benidipine (138±3 mm Hg) reduced blood pressure in OLETF rats to a level comparable to that in LETO rats. Tissue content of triglycerides (TG) was greater in OLETF rats than in LETO rats (6.24±3.77 and 2.85±1.32 μg mg−1·tissue, respectively), and both losartan and benidipine reduced these values. Histological analysis showed lipid droplets in tubular cells in which increased dihydroethidium fluorescence was present. Expression of peroxisome proliferator-activated receptor-α, PGC-1α and uncoupling protein-2 was found to be higher in OLETF rats than in LETO rats; however, the expression of these genes was not altered by treatment with either antihypertensive drug. In contrast, both losartan and benidipine increased the amount of total and phosphorylated forms of AMP kinase and the expression of carnitine palmitoyltransferase-1 (CPT-1). In conclusion, treatment of OLETF rats with losartan and benidipine reduced the tissue content of TG, decreased the production of superoxide and regulated the expression of genes related to fatty acid oxidation such as AMP-activated protein kinase and CPT-1 in the kidneys.

Association of serum IgG4 and soluble interleukin-2 receptor levels with epicardial adipose tissue and coronary artery calcification.

BACKGROUND Immunoglobulin G4 (IgG4)-related immuno-inflammation may play a role in the development of coronary artery disease (CAD). We analyzed the association of serum IgG4 and soluble interleukin-2 receptor (sIL-2R) concentrations with epicardial fat volume (EFV) and coronary artery calcification (CAC). METHODS Serum IgG4 and sIL-2R concentrations were measured in 267 patients who underwent 320-slice cardiac computed tomography. RESULTS The median serum concentrations of IgG4 and sIL-2R were higher in patients with CAD than in those without. Serum IgG4 concentrations were significantly greater in patients with EFV within the second and fourth quartile (≥75ml) than in those with low EFV (<75ml) (33.5 vs. 22.5mg/dl). On the other hand, serum sIL-2R concentrations were significantly higher in patients with CAC than in those without (409 vs. 345 U/ml). In age- and gender-adjusted logistic regression analysis, the fourth quartile of IgG4 (≥56.7mg/dl) was associated with EFV within the second and fourth quartile (≥75ml) with an odds ratio of 3.13. CONCLUSION Serum IgG4 concentrations were greater in patients with EFV within the second and fourth quartile, whereas serum sIL-2R concentrations were increased in patients with CAC. These two biomarkers may reflect different mechanisms underlying development of cardiovascular remodeling.

Liver lipid content is reduced in rat given 7-day administration of angiotensin II

Activation of the renin–angiotensin system may be involved in the development of hepatic steatosis, a condition that is associated with insulin resistance. We showed that in rats, angiotensin II induced accumulation of triglycerides in the renal tubular and cardiac cells, although it significantly reduced the weight of the rats. Here we investigated the liver lipid content of rats given long-term angiotensin II administration. Angiotensin II (0.7 mg/kg/day) was infused into the rats for 7 days via an osmotic minipump. Some rats also received hydralazine or losartan concomitantly. It was shown that angiotensin II reduced oil red O-stainable lipid droplets (6% of the control value) and liver triglyceride content (angiotensin II: 4.6 ± 0.8 µg/mg, control: 11.7 ± 1.1 µg/mg). Both of these phenomena were blocked by losartan, but not by hydralazine. Angiotensin II infusion reduced the expression and activity of AMP-activated protein kinase. In addition, angiotensin II decreased the mRNA expression of peroxisome proliferator-activated receptor-α and genes related to β-oxidation, although mRNA expression of genes related to lipogenesis were not affected. Angiotensin II reduced triglyceride content in the liver, unlike in the kidney or heart, via an AT1 receptor-dependent mechanism.

Association between serum IgG4 concentrations and the morphology of the aorta in patients who undergo cardiac computed tomography

BACKGROUND Immunoglobulin G4 (IgG4)-related disease has been suggested to be involved in cardiovascular disorders such as chronic periaortitis. However, it remains unclear whether IgG4-related immuno-inflammation affects the subclinical stages of aortic remodeling. Here, we analyzed the relationship between serum IgG4 concentrations and the morphology of the ascending aorta. METHODS Serum concentrations of IgG4 were measured in 322 patients who underwent 320-slice cardiac computed tomography (CT). We assessed the aortic wall area and intravascular area at the portion between the aortic valve and the bifurcation of the pulmonary artery. RESULTS In total, 174 patients (54.0%) were diagnosed to have coronary artery disease (CAD) by cardiac CT. The intravascular area was significantly larger in patients with CAD than in those without (893mm(2) vs. 811mm(2), p=0.001). The aortic wall area was slightly, but not significantly, larger in patients with CAD than in those without (183mm(2) vs. 176mm(2), p=0.051). Serum concentrations of IgG4 were significantly higher in patients with an aortic wall area of median or greater size (≥181mm(2)) than in those with a smaller area (<181mm(2)) (32.9mg/dL vs. 23.1mg/dL, p=0.026). In logistic regression analysis using age, gender, and CAD as covariates, the fourth quartile of IgG4 (≥55.4mg/dL) was significantly associated with an aortic wall area of median or greater size with an odds ratio of 2.09. CONCLUSIONS Serum concentrations of IgG4 were found to be significantly associated with the aortic wall area. These findings collectively suggest that immuno-inflammatory processes may play a role in the subclinical stages of aortic remodeling.

The prevalence of malignant neoplastic and non-malignant gastrointestinal lesions in cardiology inpatients

BACKGROUND Although gastrointestinal (GI) complications are receiving more attention in cardiovascular patients owing to the widespread use of antithrombotic drugs, information seems to be limited over the prevalence of GI malignancies in those patients. METHODS AND RESULTS The prevalence of malignant as well as non-malignant GI lesions diagnosed in cardiology inpatients was investigated. We retrospectively analyzed 274 cardiology inpatients who underwent upper and/or lower GI tract endoscopies. A total of 97 patients (35.4%) were taking multiple antithrombotic drugs and the mean number of antithrombotic drugs used was 1.19. Malignant neoplasm was found in 26 patients (9.5%), and non-malignant lesions (ulcers, adenomas, polyps) were found in 106 patients (38.7%). Multivariate analysis showed that antiplatelet drug usage was negatively (odds ratio [OR] 0.38, 95% confidence interval [CI] 0.16-0.91) whereas positive fecal occult blood test was positively (OR 4.44, 95% CI 1.44-13.66) associated with GI malignancies. On the other hand, for non-malignant GI lesions, both antiplatelet drug usage (OR 1.85, 95% CI 1.05-3.25) and positive fecal occult blood test (OR 1.99, 95% CI 1.14-3.47) were found to be positive predictors. CONCLUSIONS During the 59-month study period, 26 and 106 patients were diagnosed to have GI malignancies and non-malignant GI lesions, respectively, among cardiology inpatients. Cardiology physicians should not overlook the possibility of GI malignancies in an era of multiple antithrombotic drug usage.