Long-term safety and effectiveness of mycophenolate mofetil in adults with lupus nephritis: a real-world study in Japan.

OBJECTIVES: To assess the safety and effectiveness of mycophenolate mofetil (MMF) in Japanese adults with lupus nephritis (LN) in real-world clinical practice. METHODS: This multicentre, prospective, post-marketing surveillance study investigated the effectiveness and safety of MMF, as induction or maintenance therapy, in LN patients. Primary endpoints were adverse drug reactions (ADRs), changes in renal function from baseline, and relapse rate (RR) after 6 months in the maintenance group, estimated using the Kaplan-Meier method. Complete remission (CR) and partial remission (PR) were estimated by renal measurements. RESULTS: Overall, 112 patients were enrolled in the induction group and 340 in the maintenance group. Of these 452 patients, 418 were evaluable for safety and 396 for effectiveness. Eighty-three patients (19.85%) experienced ADRs, most commonly herpes zoster (3.34%) and diarrhoea (3.11%). Serious ADRs occurring in more than three patients were cytomegalovirus infections (1.43%), acute pyelonephritis (0.71%), and herpes zoster (0.71%). One patient died from herpes zoster disseminated. CR and PR were 19.54% and 44.82%, respectively, in the induction group, and 40.62% and 66.16%, respectively, in the maintenance group. RR in the maintenance group was 0.70%. CONCLUSIONS: The tolerability of MMF is in line with that reported in other studies. Since the average dose of MMF was <1.5 g/day, research into the optimal dose for achieving effectiveness is required.

Changes in physical activity and risk of all-cause mortality in patients on maintence hemodialysis: a retrospective cohort study.

BACKGROUND: A previous cohort study indicated a significant association of lower baseline level of physical activity in hemodialysis patients with elevated risks of mortality. However, there have been no reports regarding the association between changes in physical activity over time and mortality in hemodialysis patients. This study was performed to examine the prognostic significance of physical activity changes in hemodialysis patients. METHODS: This retrospective cohort study was performed in 192 hemodialysis patients with a 7-year follow-up. The average number of steps taken per non-dialysis day was used as a measure of physical activity. Forty (20.8%) patients had died during the follow-up period. The percentage change in physical activity between baseline and 12 months was determined, and patients were divided into three categories according to changes in physical activity. A decrease or increase in physical activity > 30% was defined as becoming less or more active, respectively, while decrease or increase in physical activity < 30% were classified as stable. RESULTS: Forty seven (24.5%), 51 (26.6%), and 94 (49.0%) patients were classified as becoming less active, becoming more active, and stable, respectively. The hazard ratio on multivariate analysis in patients with decreased physical activity was 3.68 (95% confidence interval, 1.55-8.78; P < 0.01) compared to those with increased physical activity. CONCLUSIONS: Reductions in physical activity were significantly associated with poor prognosis independent of not only patient characteristics but also baseline physical activity. Therefore, improved prognosis in hemodialysis patients requires means of preventing a decline in physical activity over time.

Upregulated expression of glucose transporter isoform 1 in invasive and metastatic extramammary Paget's disease.

Glucose transporter isoform 1 (GLUT1), which is upregulated in a variety of malignant tumors, facilitates cellular glucose uptake to boost rapid tumor growth and progression. In several types of cancer, inhibition of GLUT1 suppresses tumor proliferation and metastasis, indicating that GLUT1 is a potential target of anticancer therapy. The present study performed immunohistochemistry to analyze GLUT1 expression levels in 51 patients with extramammary Paget's disease (EMPD), including 23 with only intraepidermal lesions and 28 with dermal-invasive lesions. Of the 28 patients with dermal invasion, nine had available samples of lymph node metastasis. GLUT1 staining scores were significantly higher in dermal-invasive (P<0.0001) and metastatic lesions (P=0.0008) compared with in intraepidermal lesions. GLUT1 is upregulated during the transition from preinvasive to invasive or metastatic tumor in EMPD. Moreover, GLUT1 staining scores were statistically higher in intraepidermal tumor cells of dermal-invasive EMPD compared with tumor cells of only in situ EMPD (P=0.0338). GLUT1 is upregulated even during the preinvasive phase in patients with invasive EMPD, suggesting that GLUT1 immunostaining can predict the risk of dermal invasion. The present study provides novel evidence to pursue in vitro and in vivo studies to confirm that upregulated expression of GLUT1 enhances tumor aggressiveness in EMPD.

Iron restriction prevents diabetic nephropathy in Otsuka Long-Evans Tokushima fatty rat.

High body iron levels are found in type 2 diabetes mellitus (DM). Iron excess leads to tissue injury through free radical formation. We investigated the effect of iron restriction on renal damage in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type 2 DM. OLETF rats (n = 18) were divided into three groups at 10 weeks of age: high fat diet containing 8% NaCl (HFS, n = 6), HFS diet with iron restricted (HFS + IR, n = 6), and HFS with hydralazine (HFS + Hyd, n = 6). Long-Evans Tokushima (LETO) rats served as control. Iron restriction decreased hemoglobin levels, systolic blood pressure, and urinary excretion of protein and 8-hydroxy-2'-deoxyguanosine in the OLETF rats fed with HFS diet. Compared to the HFS group, the expression of desmin, renal glomerular injury marker and iron deposition in the renal tubules were attenuated in the HFS + IR group but not in the HFS + Hyd group at 26 weeks of age. Moreover, renal hypoxia (evaluated as pimonidazole adducts) was improved in the HFS + IR group compared to the HFS group in spite of anemia. Iron restriction prevented the production of reactive oxygen species and the development of early stage nephropathy in OLETF rats. Iron restriction may be beneficial in prevention of nephropathy in type 2 DM.

Distinct features of protein folding by the GroEL system from a psychrophilic bacterium, Colwellia psychrerythraea 34H.

We investigated the protein folding mechanism of the GroEL system of a psychrophilic bacterium, Colwellia psychrerythraea 34H. The amount of mRNA of the groESL operon of C. psychrerythraea was increased about 6-fold after a temperature upshift from 8 to 18 °C for 30 min, suggesting that this temperature causes heat stress in this bacterium. A σ(32)-type promoter was found upstream of the groESL, suggesting that the C. psychrerythraea groESL is regulated by the σ(32) system, like the groESL in E. coli. The maximum ATPase and CTPase activities of CpGroEL were observed at 45 and 35 °C, respectively, which are much higher than the growth temperatures of C. psychrerythraea. We found that the refolding activity of the CpGroEL system in the presence of ATP is lower than that in the presence of CTP. This suggests that ATP is not the optimum energy source of the CpGroEL system. Analyses for the interaction of CpGroEL-CpGroES revealed that CTP could weaken this interaction, resulting in effective refolding function of the CpGroEL system. From these findings, we consider that the CpGroEL system possesses an energy-saving mechanism for avoiding excess consumption of ATP to ensure growth in a low-temperature environment.

Evaluation of the degree of mixing of combinations of dry syrup, powder, and fine granule products in consideration of particle size distribution using near infrared spectrometry.

We used near infrared (NIR) spectroscopy to evaluate the degree of mixing of blended dry syrup (DS) products whose particle sizes are not specified in the Revised 16th Edition of the Japanese Pharmacopoeia, and also evaluated the degree of mixing when powder products or fine granule products were added to DS products. The data obtained were used to investigate the relationship between the particle size distributions of the products studied and the degree of mixing. We found that the particle size distribution characteristics of the 15 DS products studied can be broadly classified into 5 types. Combinations of frequently prescribed products were selected to represent 4 of the 5 particle size distribution types and were blended with a mortar and pestle. The coefficient of variation (CV) decreased as the percent mass of Asverin® Dry Syrup 2% (Asverin-DS) increased in blends of Periactin® Powder 1% (Periactin) and Asverin-DS, indicating an improved degree of mixing (uniformity). In contrast, in blends of Periactin and Mucodyne® DS 33.3%, mixing a combination at a 1:1 mass ratio 40 times resulted in a CV of 20%. Other mixing frequencies and mass ratios resulted in a CV by 50% to 70%, indicating a very poor degree of mixing (poor uniformity). These results suggest that when combining different DSs, or a DS with a powder or fine granule product, the blending obtained with a mortar and pestle improves as the particle size distributions of the components approach each other and as the ranges of the distributions narrow.

Intraleaflet haemorrhage is associated with rapid progression of degenerative aortic valve stenosis.

AIMS: The haemorrhage in the plaque (intraplaque haemorrhage) plays a critical role in the progression of atherosclerosis. The purpose of this study is to clarify whether the haemorrhage in the aortic valve leaflet (intraleaflet haemorrhage) accelerates the progression of aortic valve stenosis (AS). METHODS AND RESULTS: We examined specimens of aortic valve leaflets obtained from 36 patients who had undergone aortic valve replacement for degenerative AS and in whom echocardiographic data were available just before the operation and at least 180 days before the last study. The stenotic valves were examined by immunohistochemistry to detect intraleaflet haemorrhage with antibody against glycophorin A, an erythrocyte-specific protein. The progression of AS was assessed by annualized change in the aortic valve area (ΔAVA: cm(2)/year). The patients were divided into two groups, namely the rapid progression group (ΔAVA ≥ 0.1 cm(2)/year) and the slow progression group (ΔAVA < 0.1 cm(2)/year), according to the reported average progression rate of AS. Intraleaflet haemorrhage was observed in 78 % of the specimens. Intraleaflet haemorrhage was associated with neovascularization and macrophage infiltration. The areas of intraleaflet haemorrhage and macrophage infiltration were greater in the rapid progression group than in the slow progression group. Multivariate analysis has shown that the area of intraleaflet haemorrhage was the sole independent factor that positively correlated with ΔAVA. CONCLUSIONS: Intraleaflet haemorrhage was frequently observed in the valve leaflets of degenerative AS and associated with a rapid progression of AS.

Serum interleukin-6 and C-reactive protein are markedly elevated in acute decompensated heart failure patients with left ventricular systolic dysfunction.

Cytokines play important roles in heart failure (HF). We examined whether cytokine levels are different in acute decompensated heart failure (ADHF) patients between with left ventricular systolic dysfunction (LVSDF) and with preserved LV ejection function (PLVEF). We studied 81 HF patients who were admitted to our hospital with acute decompensation. They were divided into two groups: LVSDF (LVEF)<45% and PLVEF (LVEF45%). Serum interleukin-6 (IL-6), highly sensitive C-reactive protein (hsCRP), tumor necrosis factor alpha (TNF-alpha), and IL-18 and plasma brain natriuretic peptide (BNP) were measured on admission and at discharge. On admission, IL-6 and hsCRP were higher in LVSDF than in PLVEF. IL-6 and hsCRP decreased after treatment in LVSDF, but not in PLVEF, while plasma BNP levels decreased in both HF with treatment. There was no difference in TNF-alpha or in IL-18 level between LVSDF and PLVEF, and they did not change after treatment in either group. In conclusion, cytokine profiles were different in ADHF between those with LVSDF and PLVEF. Activation of IL-6-hsCRP pathway may play a specific role in ADHF with LVSDF.

Iron regulatory hormone hepcidin decreases in chronic heart failure patients with anemia.

BACKGROUND: The etiology of anemia is still unclear in patients with chronic heart failure (CHF). Hepcidin is an iron regulatory peptide that is synthesized in the liver to suppress iron absorption and utilization. Hepcidin synthesis is suppressed by anemia, hypoxia and erythropoiesis, and induced by inflammation. Inflammatory cytokines, such as interleukin-6 (IL-6), increase the synthesis of hepcidin, resulting in anemia of inflammation (AI). The serum hepcidin concentration in CHF patients with anemia was measured in order to better understand anemia in CHF. METHODS AND RESULTS: Serum hepcidin-25, erythropoietin (EPO), ferritin and IL-6 concentrations were measured in 61 CHF patients. Among these patients, 36 patients had anemia. A group of 16 patients without cardiac disease or anemia were recruited as controls. Serum IL-6 and EPO were higher and hepcidin-25 was lower in CHF patients with anemia than in controls. Hepcidin-25 correlated with EPO and ferritin but not with IL-6. Results of multivariable regression analysis showed that independent predictors of serum hepcidin-25 included EPO and ferritin but not IL-6. CONCLUSIONS: Serum hepcidin-25 concentrations were regulated by iron storage and erythropoiesis but not by IL-6 in CHF patients with anemia. These findings might indicate that AI is a minor cause of anemia in CHF.

Characterization of cardiac size and function in SHRSP.Z-Lepr(fa)/IzmDmcr rats, a new animal model of metabolic syndrome.

Cardiac structural and functional abnormalities are observed in metabolic syndrome. However, such changes have not been investigated in the SHRSP.Z-Lepr(fa)/IzmDmcr rat (SHRSP-fatty) model of metabolic syndrome. Here we compare cardiac size and hemodynamic function in these rats with their lean littermates (SHRSP) and normotensive control Wistar-Kyoto rats (WKY). In male 16-week-old SHRSP-fatty, we determined heart rate and systolic blood pressure (SBP) by tail-cuff, cardiac output (CO), subcutaneous peripheral blood flow (BF) and stroke volume (SV) by plethysmography, and systolic and diastolic functions by echocardiography. We also assessed weight and collagen type I expression by Western blot in isolated atrium and ventricle, and beat rate in isolated atrial preparation by myography. Heart rate was lower in conscious SHRSP-fatty than SHRSP, and the beat rate of isolated atria was lower in SHRSP-fatty and SHRSP than that of WKY. Atrial weight was larger in SHRSP-fatty than others. Ventricular weight of SHRSP-fatty and SHRSP was larger than WKY. There were significant inverse correlations between atrial weight and heart rate or beat rate in SHRSP-fatty. SBP, CO, BF and SV were increased in SHRSP-fatty similarly to SHRSP. Increased deceleration time and decreased E/A ratio, and preserved fractional shortening were observed in SHRSP-fatty. Expressions of collagen type I were increased in atria and ventricle of SHRSP-fatty. SHRSP-fatty with metabolic syndrome exhibit cardiac changes, including slowed heart rate, ventricular diastolic dysfunction, and fibrosis, and atrial enlargement. SHRSP-fatty may be a useful rat model to study on cardiac abnormalities in metabolic syndrome.

Value of assessment of left atrial volume and diameter in patients with heart failure but with normal left ventricular ejection fraction and mitral flow velocity pattern.

AIMS: We assessed the comparative value of measurements of tissue Doppler early diastolic mitral annular velocity (E'), left atrial diameter (LAD), and left atrial volume (LAV) in patients with possible heart failure (HF) but with normal left ventricular (LV) ejection fraction (EF) and mitral flow velocity pattern. METHODS AND RESULTS: We determined LAV and LAD indexes in addition to the ratio of peak early diastolic mitral flow velocity (E) to E' (E/E' ratio) in 91 patients with all three of the followings: HF, LVEF of greater than 55%, and normal mitral E/A ratio between 0.8 and 1.5. Twenty healthy subjects were used as controls. E/E' ratio was abnormal (>1.5) in 38 of the 91 patients (sensitivity=44%). LAV index was 32 mL/m(2) or greater in 71 of the 91 patients (sensitivity=78%), while LAD index was 27 mm/m(2) or greater in 81 of 91 patients (sensitivity=89%). The area under the curve by receiver-operator curve analyses was 0.995 for LA volume index, 0.998 for LAD index, and 0.885 for E/E' ratio. CONCLUSION: LAV and LAD indexes are more useful in detecting with HF and normal EF patients than E' related parameters.

Matrix metalloproteinase-1 and -2 levels are differently regulated in acute exacerbation of heart failure in patients with and without left ventricular systolic dysfunction.

Matrix metalloproteinases (MMPs) play important roles in progression of chronic heart failure (HF) by regulating cardiac extracellular matrix metabolism. However, there is no report to investigate the difference of circulating MMP-1 and MMP-2 levels between systolic HF (SHF) and diastolic HF (DHF), particularly in light of acute exacerbation of HF. We assessed 110 HF patients who were admitted because of an acute exacerbation. They were divided into two groups: SHF [n = 68, left ventricular ejection fraction (LVEF) <45%] or DHF (n = 42, LVEF > or =45%). Ten patients without HF served as controls. Serum MMP-1 and MMP-2, and plasma brain natriuretic peptide (BNP) levels were examined on admission and at discharge. Serum MMP-1 level was higher on admission in both SHF and DHF than in controls. It was higher in SHF than in DHF and did not change at discharge in both groups. Serum MMP-2 level was equally higher on admission in SHF and DHF than in controls. It decreased in both groups at discharge. Treatment-induced changes in LVEF and BNP level correlated with those in MMP-2 level in SHF but not in DHF. Circulating MMP-1 and MMP-2 levels showed different dynamics between SHF and DHF in acute exacerbation and after treatment. These differences in circulating MMP-1 and MMP-2 levels may be related to the phenotype of HF.

The mechanism of distinct diurnal variations of renin-angiotensin system in aorta and heart of spontaneously hypertensive rats.

Diurnal variations in plasminogen activator inhibitor-1 mRNA expression are different between the spontaneously hypertensive rats (SHRs) and the Wistar-Kyoto (WKY) rats, and between the aorta and the heart. To elucidate the mechanisms, we examined diurnal changes in the circulating renin-angiotensin system in the SHR and WKY rats. Diurnal variations in plasma renin activity (PRA), plasma angiotensin I, and aldosterone concentrations were similar between the SHR and WKY rats. On the other hand, plasma angiotensin II (Ang II) concentration in the SHR was lower than that in the WKY rats at most time points, but increased to the level of the WKY rats in the late light phase. Treatment with AT1 receptor antagonist candesartan increased plasma Ang II concentration except at ZT 8 and lessened its diurnal variation in the SHR. At the peak in plasma Ang II in the SHR, Ang II regulated genes such as transforming growth factor-beta1 and p22phox were upregulated in the aorta. On the other hand, these genes were upregulated throughout the day in the heart of SHR. Candesartan treatment increased AT1a receptor mRNA expression in the heart but not in the aorta of SHR. These findings suggest that an AT1 receptor-mediated mechanism might cause a surge in plasma Ang II concentration at the late light phase in the SHR. Homologous down-regulation of AT1a receptor by Ang II may dampen the effect of a surge in plasma Ang II concentration in the heart of SHR.

High salt intake elevated blood pressure but not changed circadian blood pressure rhythm in Otsuka Long-Evans Tokushima Fatty (OLETF) rat.

We examined the effect of high salt intake on mean arterial pressure and circadian blood pressure rhythm in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type II diabetes mellitus. Mean arterial pressure, fasting blood glucose, and fasting plasma insulin in OLETF rats were higher than those in LETO rats, their normoglycemic controls. The amplitude of circadian blood pressure rhythm in LETO rats was smaller than that in OLETF rats. High salt intake elevated blood pressure and exacerbated hyperinsulinemia, but did not change the circadian blood pressure rhythm in OLETF rats.

[Management of hepatitis C and fatty liver: a consciousness survey among gastroenterologists and general internists].

A questionnaire survey including hepatic function test values was performed to elucidate the medical treatment of hepatic diseases by gastroenterologists and general internists. Serum ALT level was considered to be an index of destruction of hepatic cells in 94 and 80% of gastroenterologists and general internists, respectively. Serum gamma-GTP values were used as an index of bile stasis and destruction of the bile duct cells by 93% and 70% of the gastroenterologists, respectively and in 61% and 49% of the internists, respectively. In addition, for hepatitis C, gastroenterologists considered the mean serum ALT values (standard values for drug therapy introduction) as > or =62IU/L, while general internists considered it as > or =79IU/L. In the case of fatty liver, the mean serum ALT values considered by gastroenterologists and general internists were > or =93IU/L and > or =90IU/L, respectively. These survey results suggest that there is a need for research-based clarification of hepatic function test values regulating therapy and unification of guidelines for standard values in medical treatment.

Evaluation of Moisturizing Effect of Heparinoid Ointment (Hirudoid Soft Ointment) Diluted by White Petrolatum (Propeto).

Steroid ointments are frequently mixed with moisturizer. It was reported that steroid ointments mixed with moisturizer increase permeability. There are only few studies done on the permeability of the moisturizer. We researched moisturizing effect of heparinoid ointment (Hirudoid Soft ointment) diluted with white petrolatum (Propeto) on the dry skin models by measuring water content of stratum. Two to four fold dilution of Hirudoid to white petrolatum resulted in a significant decrease in the moisturizing effect of the active ingredient. There was no significant difference in moisturizing effect between four times diluted mixture and white petrolatum alone. This leads to the conclusion that steroid ointment mixture with moisturizer is frequently used, but we should take more caution regarding the decrease of moisturizing effect.

Histone H3 Lysine 36 Trimethylation Is Established over the Xist Promoter by Antisense Tsix Transcription and Contributes to Repressing Xist Expression.

One of the two X chromosomes in female mammals is inactivated by the noncoding Xist RNA. In mice, X chromosome inactivation (XCI) is regulated by the antisense RNA Tsix, which represses Xist on the active X chromosome. In the absence of Tsix, PRC2-mediated histone H3 lysine 27 trimethylation (H3K27me3) is established over the Xist promoter. Simultaneous disruption of Tsix and PRC2 leads to derepression of Xist and in turn silencing of the single X chromosome in male embryonic stem cells. Here, we identified histone H3 lysine 36 trimethylation (H3K36me3) as a modification that is recruited by Tsix cotranscriptionally and extends over the Xist promoter. Reduction of H3K36me3 by expression of a mutated histone H3.3 with a substitution of methionine for lysine at position 36 causes a significant derepression of Xist. Moreover, depletion of the H3K36 methylase Setd2 leads to upregulation of Xist, suggesting H3K36me3 as a modification that contributes to the mechanism of Tsix function in regulating XCI. Furthermore, we found that reduction of H3K36me3 does not facilitate an increase in H3K27me3 over the Xist promoter, indicating that additional mechanisms exist by which Tsix blocks PRC2 recruitment to the Xist promoter.

Primary cardiac malignant fibrous histiocytoma with abdominal wall metastasis.

We present a rare case of cardiac malignant fibrous histiocytoma (MFH; undifferentiated pleomorphic sarcoma); to date, fewer than 100 cases of cardiac MFH have been reported. In this case, transthoracic echocardiography revealed cardiac tumors in the left atrium (LA) of a 53-year-old woman with a 3-month history of worsening dyspnea; the largest tumor was found to protrude through the mitral valve in diastole, causing stenosis. Three of the four tumors were resected during emergency surgery; however, the residual tumor extension into the left pulmonary vein could not be removed. Histological findings of the resected tumors, such as organized thrombus and myxomatous tissue changes, indicated that the tumors were benign. After 3 months, the patient underwent total resection for a small mass that developed on her right abdominal wall, which was revealed histologically to be MFH; additionally, the residual mass in the LA had enlarged progressively. After undergoing radiation therapy without further surgery, she died of cerebral bleeding 6 months after cardiac surgery. Postmortem examination revealed that the tumor in the LA was an MFH. Thus, cardiac MFH should be considered as a differential diagnosis for tumors on the posterior wall of the LA. .

[Effect of admixture of betamethasone butyrate propionate ointment on preservative efficacy].

Twenty percent of dermatologists have experienced a separation of water or deterioration of topical corticosteroids mixed with commercially available ointments and/or creams. However, few investigations of this deterioration of admixtures have been reported. To assess the effects of preservatives in preventing microbial contamination of these admixtures, we attempted to investigate the concentration of preservative agents in admixtures and the microbial contamination of these admixtures with a topical corticosteroid ointment (Antebate). The concentration of parabens was reduced by half using an admixture of corticosteroid ointment with four types of moisturizing creams, Urepearl, Pastaronsoft, Hirudoid, and Hirudoidsoft. After a further 3 months, no decrease in parabens was seen. No microbial contamination was found in any admixture stored at room temperature for 1 week and touched two times daily with a finger. The concentration and ratio of the parabens in the aqueous phase and oil phase were entirely different in the admixtures before being centrifuged. The aqueous phase of the admixtures of the oil/water (O/W)-type emulsions of Urepearl and Hirudoid was not found to have microbial contamination immediately after being centrifuged. All aqueous phases stored at room temperature or in a refrigerator for 1 week and touched with a finger twice daily exhibited microbial contamination. These experiments demonstrated that O/W-type emulsions, in which the water easily separates from the bases, should be thoroughly mixed to prevent microbial contamination.

Atorvastatin ameliorates cardiac fibrosis and improves left ventricular diastolic function in hypertensive diastolic heart failure model rats.

OBJECTIVE: Clinical studies have suggested the beneficial effects of statin therapy on diastolic heart failure. However, the mechanism of the beneficial effects of statin on diastolic heart failure remains unknown. We examined the effect of atorvastatin on the cardiac function of Dahl salt-sensitive rat, a model of hypertensive diastolic heart failure. METHODS: Dahl salt-sensitive rats were divided into three groups: the low-salt group (given standard diet), the high-salt group (given 8% NaCl diet from 7 weeks of age), and the high-salt + atorvastatin (HS + Ato) group (given 8% NaCl diet from 7 weeks of age and atorvastatin from 17 weeks of age). We evaluated left ventricular hypertrophy (LVH), fibrosis, and function by using echocardiography and histology. We also examined the expression of molecules related to fibrosis in the hearts of Dahl salt-sensitive rats and cultured rat cardiac fibroblasts. RESULTS: Left ventricular hypertrophy, diastolic dysfunction, and cardiac fibrosis were observed in the high-salt group. Atorvastatin ameliorated cardiac fibrosis and normalized left ventricular diastolic function without altering blood pressure. Atorvastatin also decreased the expression of heat shock protein 47 (HSP47), an essential chaperone for type 1 collagen processing, without changing in expression of transforming growth factor beta. In rat cardiac fibroblast cells, atorvastatin also reduced HSP47 level induced by transforming growth factor beta. The effect of atorvastatin was reversed by mevalonate and geranylgeranyl-pyrophosphate and mimicked by Rho kinase inhibitor. CONCLUSION: Atorvastatin administration ameliorates cardiac fibrosis and improves left ventricular diastolic function in Dahl salt-sensitive rats. Lowering HSP47 by atorvastatin via inhibition of Rho-Rho kinase pathway is suggested as a mechanism.