Effect of human C-reactive protein on cardiac function and angiotensin 2 signaling in diabetic cardiomyopathy

S170 Journal of Cardiac Failure Vol. 14 No. 7S September 2008 including brain natriuretic peptide (BNP) gene. Several signal transduction pathways have been shown to be involved in hypertrophic responses to mechanical stress in cardiac myocytes. However, the precise mechanism that confers the mechanical stress to the transcriptional activation of hypertrophic gene program still remains less understood. Here we show that mechanical stretch-induced nuclear translocation of MRTF-A, a co-activator of SRF transcriptional factor, contributes to the mechanical stress-induced hypertophic response of cardiac gene expression. Mechanical stretch of cultured myocytes induced nuclear accumulation of MRTF-A in a Rho and actin dynamics-dependent manner. MRTF-A null mice showed a blunted response in acute pressure overload-induced expression of BNP and other SRF-dependent fetal cardiac genes such as skeletal alpha-actin and smooth muscle alpha-actin. We identified a conserved and functional SRF-binding site in BNP promoter and mutation of the site or knockdown of MRTF-A using siRNA reduced the response of BNP promoter activity to mechanical stress. Collectively, we defined the Rho-dependent nuclear translocation of MRTF-A as a novel signaling mechanism mediating mechanical stretch-induced hypertrophic response in cardiac myocytes.

100 Prognostic Significance of Diastolic Filling Pattern in Cardiac Resynchronization Therapy YASUE TSUKISHIRO, KENSUKE MATSUMOTO, TAKATOSHI HAYASHI, YASUYO TANIGUCHI, KAZUO MIZUTANI, KATSUNORI OKAJIMA, AKIRA SHIMANE, MANABU KANDA, TEISHI KAJIYA Cardiology, Himeji cardiovascular center, Hyogo, Japan Purpose: In patients with heart failure, left ventricular filling pattern (LVFP) abnormalities are recognized as predictors of outcome. We studied to evaluate the prognostic value of LVFP, and the effects of Cardiac resynchronization therapy (CRT) on diastolic function. Methods: 42 consecutive patients were evaluated by echocardiography prior to and 6 months after CRT. We measured left ventricular (LV) volumes, ejection fraction (EF), pulsed-wave Doppler (PWD)-derived transmitral filling indices (E- and A-wave velocities, E/A ratio, deceleration time, diastolic filling time, and isovolemic relaxation time) and diastolic (Em) velocities at two mitral annular sites, and calculated mitral E-wave/Em ratio. Results: At baseline, restrictive LVFP (RFP) was present in 6 patients, whereas 36 patients showed no-RFP. Among both groups, characteristics, LV end diastolic volume (LVEDV), LV end systolic volume (LVESV), and LVEF were similar at baseline. At 6 months after CRT, only noRFP group exhibited volumetric response (LVEDV: 189.4 6 81.2 vs. 143.9 6 82.6 ml p 5 0.001, LVESV: 138.5 6 65.6 vs. 92.7 6 60.0 ml p 5 0.001). On the other hand, all PWD-derived transmitral filling indices and Em remained unchanged at 6 months after CRT in both groups. Conclusions: CRT exhibited only neutral effect on LV diastolic function. Patients with RFP did not exhibit LV reverse remodeling, on the contrary, patients with no-RFP favorably responded to CRT.

101 A case of cardiac sarcoidosis with spontaneous remission and re-exacerbation TOSHIMI KOITABASHI, TAKAYUKI INOMATA, EMI MAEKAWA, TAKASHI NARUKE, TOMOYOSHI YANAGISAWA, TOMOYASU MIZUTANI, MOTOTSUGU NISHII, ICHIRO TAKEUCHI, HITOSHI TAKEHANA, TOHRU IZUMI Department of Cardio-angiology, Kitasato University of Medicine, Kanagawa, Japan A 47-year-old woman suffered from heart failure (HF) initially in 2004. Contraction of the left ventricle (LV) was severely impaired with an ejection fraction (EF) of 22%. Intensive in-hospital management using anti-HF medical therapy for 8 months relieved her signs and symptom from NYHA class IV to II. She was diagnosed at predischarge as idiopathic chronic myocarditis due to the findings of myocardial inflammation demonstrated by a Ga-67 scintigram and endomyocardial biopsy, without the evidence of systemic sarcoidosis.After the stable clinical status with improvement of LVEF up to 47% and found negative for serum cardiac troponin T for 3 years, she was re-admitted for HF exacerbation with NYHA class 4. The LV function had deteriorated again with LVEF of 30% complicated with severe mitral regurgitation due to the tethering apparatus. In contrast with previous surveys, the increased serum angiotensin-converting enzyme level and uveitis implying sarcoidosis were found. Myocardial biopsy during operative intervention of mitral valvoplasty demonstrated cardiac sarcoidosis histologically due to findings of non-caseating granulomas. Unlike sarcoidosis suffered in other organ such as lungs, it has been considered that cardiac sarcoidosis a has straightforwardly progressive course without the administration of steroid. It should be worthwhile to investigate the pathomechanisms of the peculiar clinical history such as spontaneous remission and re-exacerbation in this case with cardiac sarcoidosis.

102 Prediction of Functional Improvement in Patients with Idiopathic Dilated Cardiomyopathy by Myocardial Blood Volume Using Contrast Echocardiography 1 1 1 HIROYUKI IWANO , SATOSHI YAMADA , MASAKO OKADA , HIROSHI KOMATSU1, KAORU KOMURO1, HISAO ONOZUKA2, TAISEI MIKAMI2, HIROYUKI TSUTSUI1 1 Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan, 2Faculty of Health Science, Hokkaido University, Sapporo, Japan Background: Contractile reserve assessed by low-dose dobutamine echocardiography (LDE) and heart/mediastinum ratio (H/M) on delayed 123I-MIBG scintigraphy have been shown to predict the functional improvement after b-blocker therapy in patients with dilated cardiomyopathy (DCM). Myocardial blood volume (MBV), which represents the relative volume of intramyocardial vessels, may be associated with the potential for functional recovery in patients with DCM. We thus elucidated whether MBV could better predict the functional improvement by b-blocker therapy in patients with DCM than LDE or H/M. Methods: Myocardial contrast echocardiography (MCE) was performed in 19 patients with DCM before initiation of bblocker therapy and 10 age-matched control subjects. MBV was estimated as previously reported. LDE and MIBG scintigraphy were also performed in the patients. LV ejection fraction was measured at baseline (EFbase), during LDE (EFdob) and at 9e12 month follow-up period (EFf/u). Results: MBV was significantly lower in patients than in controls (2.6 6 0.6 vs 3.6 6 0.9%, p ! 0.01). In the patients, EFdob and EFf/u were significantly higher than EFbase. H/M was 1.8 6 0.4. dEFdob (EFdob-EFbase) and H/M did not correlate with dEFf/u (EFf/u-EFbase), whereas MBV correlated significantly with dEFf/u (r 5 0.69, p 5 0.001). MBV was significantly higher in responders than in non-responders (2.83 6 0.52 vs 2.24 6 0.63%, p ! 0.05). Conclusions: MBV assessed by MCE can better predict the functional improvement in patients with DCM than LDE or H/M.

103 Effect of human C-reactive protein on cardiac function and angiotensin 2 signaling in diabetic cardiomyopathy YOSHINORI MANO1, TOSHIHISA ANZAI1, TOSHIYUKI TAKAHASHI1, YUJI NAGATOMO1, KIMI KOIDE1, HIDEHIRO KANEKO1, TOMOMI MEGURO2, TSUTOMU YOSHIKAWA1, SATOSHI OGAWA1 1 Keio University School of Medicine, Tokyo, Japan, 2Tokyo Electric Power Company Hospital, Tokyo, Japan Backgrounds: Although growing evidence suggests that elevated level of C-Reactive Protein (CRP) is associated with development of heart failure independent of coronary artery disease, the effect of CRP on cardiac function has not been elucidated. We sought to determine whether overexpression of human CRP deteriorates cardiac dysfunction induced by diabetes mellitus (DM). Methods: DM was induced in 30 male wild type mice (Wt-DM) or human CRP overexpression mice (CRP-DM) by a single injection of streptozotocin (STZ, 200 mg/kg ip). Wild type mice treated with vehicle were served as control (Wt-Con). Hemodynamic measurement, echocardiography, and molecular analyses were performed 6 weeks after injection. Results: Mean blood pressure did not differ in the 3 groups. Induction of DM resulted in decreased fractional shortening (FS), peak dP/dt, E/A and peak -dP/dt. In CRP-DM, FS, peak dP/dt, E/A are further decreased compared with Wt-DM (all p ! 0.05). Realtime RT-PCR analyses indicate the mRNA level of angiotensin type1 receptor in left ventricular (LV) myocardium, that were upregulated in Wt-DM compared with Wt-Con, were further upregulated in CRP-DM compared with Wt-DM (p ! 0.05). The mRNA level of glutathione peroxidase 3 (GPx3) was 1.3 fold upregulated in Wt-DM and 2.4 fold (p ! 0.01) in CRP-DM compared with Wt-Con. Conclusions: Overexpression of human CRP exacerbates diabetic cardiomyopathy in association with AT1R activation and augmention of oxidative stress.

104 Effect of increased C-reactive protein expression on left ventricular function and remodeling after myocardial infarction in mice TOSHIYUKI TAKAHASHI, TOSHIHISA ANZAI, HIDEHIRO KANEKO, ATSUSHI ANZAI, YOSHINORI MANO, YUICHIRO MAEKAWA, SATOSHI OGAWA, TSUTOMU YOSHIKAWA Department of Medicine, Keio University School of Medicine, Tokyo, Japan Background: We have previously reported that elevated serum C-reactive protein (CRP) level after acute myocardial infarction (MI) is associated with adverse