Imatinib Mesylate Attenuates Cardiac Fibrosis in Spontaneously Hypertensive Rats

BACKGROUND: Hypertensive myocardial fibrosis promotes abnormalities of cardiac function that may adversely affect the clinical outcome of hypertensive patients. Imatinib mesylate blocks receptor tyrosine kinase and is clinically used to treat leukemia. Platelet-derived growth factor (PDGF) is a downstream target of receptor tyrosine kinases. Cardiac fibroblasts can be activated by PDGF. Thus we evaluated whether imatinib attenuate myocardial fibrosis and prevents diastolic dysfunction in spontaneously hypertensive rats (SHR). METHODS: 8 weeks old male SHRs were subjected to treatment with 8 weeks of low dose imatinib (SHR-10; 10 mg/kg), high dose imatinib (SHR-30; 30 mg/kg) or saline (SHR-C; n = 6 in each group). At the age of 16 weeks, all rats underwent hemodynamic studies and Doppler echocardiography, and were sacrificed. Their hearts were extracted for histopathological, immunoblotting and quantitative reverse transcriptase-polymerase chain reaction analyses. RESULTS: While imatinib did not affect blood pressure (BP), it markedly reduced perivascular and interstitial fibrosis in the hearts of SHR. Echocardigram showed that high-dose imatinib significantly reduced left ventricular (LV) wall thickness (septal/posterior wall; SHR-C vs. SHR-30: 18 +/- 2/19 +/- 2 mm vs. 15 +/- 1/14 +/- 1 mm; p < 0.05) and improved the parameters of LV diastolic function such as E/A ratio (SHR-C vs. SHR-30: 1.60 +/- 0.10 vs. 1.86 +/- 0.20; p < 0.05). Imatinib also significantly reduced mRNA expression of collagen III and PDGF beta-receptor tyrosine phosphorylation in the hearts of SHR. CONCLUSIONS: These results suggest that imatinib, especially high dose, could attenuate myocardial fibrosis and prevent LV diastolic dysfunction in hypertensive rat model by decreased activity of PDGF. Imatinib may provide a potential therapeutic approach for hypertensive heart disease.

Clinical Implication of Natriuretic Peptides and Left Atrial Volume for the Screening Methods of Advanced Diastolic Dysfunction in the Community

BACKGROUND: Recently, B-natriuretic peptide (BNP) level and left atrial volume index (LAVi) were known to correlate with indices of LV diastolic function. As a screening method, we tried to evaluate the efficacy to BNP, ANP, and LAVi to predict the advanced diastolic dysfunction that means myocardial relaxation abnormality and elevated LV filling pressure. METHODS: In 100 patients who referred for echocardiography, Doppler recording of the mitral inflow and tissue Doppler imaging of the mitral annulus were obtained and classified into 4 diastolic function grades (normal, impaired relaxation, pseudonormal, and restrictive). Advanced diastolic dysfunction was defined as pseudonormal and restrictive physiology. LAVi was measured by modified Simpson's method in apical 4-chamber view at end-systole. Plasma levels of BNP and ANP were measured on the same day as echocardiogram was done. RESULTS: BNP and ANP levels were increased as diastolic function grade was worsening (BNP : 60+/-92, 108+/-204, 778+/-1,023 and 1,426+/-1,421 pg/ml, p<0.001; ANP: 22+/-30, 23+/-26, 94+/-92, 96+/-61 pg/ml, p<0.001). LAVi was also increased as diastolic dysfunction was advanced: 24+/-7 ml/m2, 27+/-9 ml/m2, 37+/-12 ml/m2, 45+/-12 ml/m2, p<0.001. The areas under the curve of receiver-operator characteristic curve for BNP, ANP and LAVi to detect the advanced diastolic dysfunction were 0.91, 0.88 and 0.84, respectively. BNP of 137 pg/ml, ANP of 34 pg/ml, and LAVi of 30 ml/m2 were the best values of sensitivity and specificity, respectively. CONCLUSION: These data suggest that BNP, ANP and LAVi provide meaningful sensitivity and specificity for the detection of advanced diastolic dysfunction, respectively. Among these, BNP is better than ANP or LAVi for the screening method to predict the advanced diastolic dysfunction.

PPAR-gamma Agonist Attenuates Myocardial Fibrosis in a Type 2 Diabetic Rat Model

BACKGROUND AND OBJECTIVES: Receptor for advanced glycosylation end product (RAGE) plays an important role in the development of myocardial fibrosis in diabetics. Activation of peroxisome proliferator activated receptor (PPAR)-gamma agonist, rosiglitazone, reduces the RAGE expression. We investigated whether rosiglitazone could prevent left ventricle (LV) diastolic dysfunction and attenuate the myocardial fibrosis in a type 2 diabetic rat model. MATERIALS AND METHODS: Otsuka Long-Evans Tokushima Fatty (OLETF) rats were treated with rosiglitazone (20 mg/kg/d) for 20 weeks. At the age of 20 and 40 weeks, all rats underwent intraperitoneal glucose tolerance tests, hemodynamic studies and Doppler echocardiography. At the age of 40 weeks, the hearts were examined by performing histopathological and immunohistochemical analyses. RESULTS: At the age of 40 weeks, rosiglitazone significant improved the parameters of the LV diastolic function such as the E/A ratio (treated vs. untreated: 1.7+/-0.1 vs. 1.5+/-0.1, p<0.05), the deceleration time and the isovolumic relaxation time in the OLETF rats, and this was correlated histologically to the reduced LV collagen volume fraction in the rosiglitazonetreated OLETF rats (3.2+/-1.3% vs. 5.7+/-2.0%, respectively, p<0.001). Rosiglitazone also significantly reduced the percentage of staining of the LV CTGF (7.4+/-2.5% vs. 15.4+/-4.7%, respectively, p<0.001) and RAGE (1.1+/-0.4% vs. 2.0+/-0.8%, respectively, p<0.001), as compared with the untreated OLETF rats. CONCLUSION: These results suggest that rosiglitazone could prevent LV diastolic dysfunction and attenuate myocardial fibrosis in type 2 diabetic rats by its inhibition of the RAGE and CTGF expression. PPAR-gamma agonist may provide a potential therapeutic approach for diabetic heart disease.

Relationship of QT Dispersion to Echocardiographic Left Ventricular Function, Dimension and Mass in Patients with Coronary Artery Disease

BACKGROUND: Previous studies showed that increased QT dispersion has been observed during episodes of myocardial ischemia or infarction and identified the patients at risk of arrhythmia or sudden death. The aim of this study was to investigate the relation between QT dispersion and left ventricular (LV) function (systolic and diastolic), dimension and mass as well as to analyze the differences of this relationship according to the extent of angiographic coronary stenosis in patients with coronary artery disease. METHODS: The study population included 262 patients (male 129, female 133;average age 60 years). Echocardiography was done for the measurement of left ventricular function, dimension and mass on admission. Electrocardiography for QT and QTc (corrected QT) dispersion were recorded 25 mm/sec paper speeds before the coronary angiography. Patients were divided into two groups; Group A where angiographic coronary stenosis or =50%. RESULTS: The results were as follows: 1) QT dispersion was higher in those with depressed LV systolic function (EF or =50%) of the coronary artery were independent prognostic factors of prolonged QT dispersion (p<0.05). 6) QTc dispersion showed the same result as QT dispersion. CONCLUSION: LV systolic function (EF), some diastolic function (IVRT), dimension (LVDd, LVDs, LAD IVS), and mass are associated with the increased QT dispersion in patients with coronary artery disease, especially minimal angiographic stenosed (<50%) patients. So, we consider echocardiography is an important tool to predict the QT dispersion in patients with coronary artery disease.