S32-2 BENEFIT OF CARDIAC RESYNCHRONIZATION THERAPY FOR HEART FAILURE PATIENTS WITH MECHANICAL ASYNCHRONY

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Abstracts of the 16th Asian Pacific Congress of Cardiology, Taipei, Taiwan, 13-16 December, 2007

polymer, the endosomal uptake of the polyplex, and its subsequent release into the cytosol may identify an adjunctive role for USE.

S30-6 ACTIVATION OF ENDOTHELIAL CELLS TO PATHOLOGICAL STATUS BY DOWN-REGULATION OF CONNEXIN43

Hsueh-Hsiao Wang, Chang-I. Kung, Yuen-Yi Tseng, Yi-Chun Lin, Chi-Hau Chen, Cheng-Ho Tsai, Hung-I. Yeh. Departments of Internal Medicine and Medical Research, Mackay Memorial Hospital, Taipei, Taiwan Background. Endothelial connexin43 (Cx43) gap junctions are down-regulated in several vascular disorders closely linked to atherosclerosis, in which endothelial function is impaired. However, whether the down-regulation of Cx43 per se contributes to endothelial dysfunction remained unclear. Methods and Results. Reduced expression of Cx43 proteins and gap junctions as well as inhibited gap-junctional communication were achieved in human aortic endothelial cells (HAEC) after transfection with Cx43 specific siRNA of different sequences. Examination of the expression profile of HAEC during the period of connexin43 reduction showed that plasminogen activator inhibitor 1 and von Willebrand factor were up-regulated. In addition, bromodeoxyuridine (BrdU) incorporation assay demonstrated reduced proliferation and 3-[4,5-dimethylthiazol2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay revealed reduced viability. Furthermore, angiogenic activity was attenuated, as evaluated by capillary-like tube formation assay. During the down-regulation of Cx43, JNK and its downstream c-jun were found activated, while caspase-3, p38, and ERK remained unchanged. Inhibition of JNK by SP600125 partially recovered the impaired angiogenesis capability. Conclusion. Transfection with different synthetic siRNA specific to Cx43 results in similar inhibition of Cx43 expression and gap-junctional communication, which activates endothelial cells to pathological status, as characterized by upregulation of coagulatory molecules and inhibition of proliferation, viability, and angiogenesis. The processes are associated with activation of JNK signaling pathways and partially reversed by inhibition of the activation. These results suggest that inadequate expression of Cx43 per se impairs endothelial function via the activation of stress activated protein kinase.

S30-7 PROSPECTIVE STUDY OF WARFARIN DOSAGE REQUIREMENTS BASED ON CYP2C9 AND VKORC1 GENOTYPES

Ming-Shien Wen 1 , M.T. Michael Lee 2 , Jin-Jer Chen 3 , Hui-Ping Chuang 2 , Liang-Suei Lu 2 , Chien-Hsiun Chen 2 , Tsong-Hai Lee 1 , Chi-Tai Kuo 1 , Feng-Mei Sun 2 , Yeu-Jhy Chang 1 , Pei-Liang Kuan 3 , Ying-Fu Chen 4 , Min-Ji Charng 5 , Chin-Ying Ray 1 , Jer-Yuan Wu 2 , Yuan-Tsong Chen 2 . 1 Chang Gung Memorial Hospital, Taoyan; 2 Institute of Biomedical Sciences, Academia Sinica, Taipei; 3 Department of internal medicine, National Taiwan University Hospital, Taipei; 3 Department of medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei; 4 Department of cardiovascular surgery, Kaohsiung Medical University Hospital, Kaohsiung; 5 Department of Medicine, division of cardiology, Taipei Veterans General Hospital, Taipei, Taiwan Background: Warfarin therapy exhibits large inter-individual and inter-ethnic differences in the dose required for its anti-coagulation effect. Polymorphisms in CYP2C9 and VKORC1 have been shown to associate with warfarin dose requirements and could be used to predict warfarin dose. Methods: We conducted a prospective study which warfarin dose was prescribed based on CYP2C9 and VKORC1 polymorphisms in 108 Han Chinese patients who had no prior warfarin treatments. Endpoints included time to reach stable therapeutic INR, numbers of adverse events and proportion of patients with maintenance dose matched the genotype-based predicted dose. Linear regression models were fitted backwards to detect significant effects to generate a dosing algorithm. Protein Induced by Vitamin K Absence (PIVKA-II) was measured for each participant as a measure of warfarin action and also an indication of patient compliance. Results: Using the genotype-based dosing, 85% of patients reached stable INR within two weeks of treatment initiation. None of the patients developed clinical bleeding or thromboembolism events. At 12 weeks of follow-up, 69% of the patients had their maintenance doses matched the predicted doses. A dosing

algorithm was developed from this study to better predict warfarin dose. The algorithm incorporated genetic factors, age and body surface area which could explain up to 62% of the total variation (R2 of 0.62). Conclusion: This study demonstrated that pharmacogenetics-based dosing can improve the time to stable dosing, reduce adverse events and achieve high sensitivity. The algorithm can be used in a randomized, controlled trial for further evaluation.

SYMPOSIUM 32

HYPERTENSION & CONGESTIVE HEART FAILURE S32-1 CALCIFIC AORTIC STENOSIS, CAN STATINS STOP IT? A META-ANALYSIS

Arnold De Guzman, Peter Jay Dumana, Rodney Jiménez. Heart Institute, St. Luke’s Medical Center, Philippines Background: Aortic stenosis (AS) is the most common cause of valve replacement in developed countries. Compelling data suggest AS is an active disease process similar to atherosclerosis and that statins may be effective in delaying its progression. The objective of this meta-analysis is to determine the efficacy of statin treatment among patients with calcific AS. Methods: Clinical trials were identified with keywords: statins, aortic valve calcification, randomized controlled trials. A total of 7 articles were queried, 2 of which are RCTs. They were subjected to data extraction, quality scale and included in the study. Included studies reported a total of 294 patients with mild to moderate calcific AS (Vmax 2.0 – 3.9m/s); these were the subjects of our analysis. Patients were excluded if they also had more than mild aortic regurgitation, severe mitral valve stenosis, left ventricular dysfunction (ejection fraction, < 35%), planned aortic valve replacement, intolerance to statins, statin therapy or to potential benefit from statin therapy (according to the treating physician) and baseline serum cholesterol of less than 150mg per decilitre, and presence of a permanent pacemaker or cardiodefibrillator. Results: The use of statins did not significantly improve the rate of annual peak aortic-jet velocity from baseline between the treatment group (0.17±0.24 m/s/yr) and the placebo group (0.18±0.20 m/s/yr, p=0.75) during a mean follow-up of >24 months (test for heterogeneity, I2 =0%) Conclusions: As inferred from meta-analyzed data, in patients with mild to moderate AS, statin therapy does not slow the rate of change of aortic-jet velocity nor does it induce regression of obstruction during 2 years of treatment. Additional prospective, randomized trials, possibly with longer follow-up, will be necessary to more completely evaluate the use of these drugs in this setting. Baseline characteristics

Treatment group (N=198)

Placebo group (N=199)

P value

AGE; years Male Hypertension Diabetes Smoking CAD

68 + 10 143 126 35 27 105

68 + 9 147 121 21 24 46

1.00 0.71 0.56 0.04 0.60 0.00001

S32-2 BENEFIT OF CARDIAC RESYNCHRONIZATION THERAPY FOR HEART FAILURE PATIENTS WITH MECHANICAL ASYNCHRONY

Y.S. Chong, K.H. Lam, K.H. Ng, S.G. Tay, M. Zakaria, H. Azlan, R. Azhari, O. Razali. Department of Cardiology, National Heart Institute, Kuala Lumpur, Malaysia Background: Cardiac Resynchronization Therapy (CRT) is new treatment option for heart failure patients. Despite compliance to the current CRT guideline, there are 30% non-responders. This study was designed to evaluate the role of cardiac resynchronization therapy in heart failure (HF) patients with echocardiography evidence of mechanical asynchrony. Methodology: This is a prospective study involving 42 subjects with NYHA class III to IV were enrolled. All subjects fulfill the current guideline for CRT im-

Abstract of the 16th Asian Pacific Congress of Cardiology, Taipei, Taiwan, 13–16 December, 2007 plantation. Tissue Doppler imaging determines the present of systolic asynchrony prior to implantation; all patients with demonstrated mechanical asynchrony were implanted with CRT device. Clinical and echocardiography assessments were performed at baseline, 6 months and 24 months after CRT implantation. Results: At 6 months, there was a significant left ventricular modeling after CRT implantation as demonstrated by 17.1% improved in the left ventricular ejection fraction, 20.1% reduction in the end systolic volume and 12.7% reduction in the end diastolic volume. The left ventricular remodeling was maintained and remained stable from 6-month till 24 months of follow up. Clinical parameter demonstrate improvement in 6 minutes walk test from 401±120 meters to 455±87 meter with p=0.046, the functional class improved from 3.1±0.4 to 1.3±0.8 with p<0.001. Conclusion: Cardiac Resynchronization Therapy (CRT) demonstrates significant benefit in heart failure patients with demonstrate mechanical asynchrony. There were significant remodeling of the left ventricular function and dimension during the first 6 months after implantation and these improvements were maintained in the next 24 months in patients with systolic asynchrony. There are also significant clinical improvement in 6 minute walk, functional class and QRS complexes after CRT implantation.

S32-3 ASSOCIATION OF CAROTID HEMODYNAMICS WITH 10-YEAR CORONARY HEART DISEASE RISK IN PATIENTS WITH ESSENTIAL HYPERTENSION

Min-Yi Lee 1 , Chan-Ming Wu 1 , Chih-Sheng Chu 2 , Kun-Tai Lee 2 , Sheng-Hsiung Sheu 2 , Wen-Ter Lai 2 . 1 Division of Cardiology, Department of Internal Medicine, Kaohsiung Municipal United Hospital; 2 Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital Background and Purpose: The resistive index (RI) of the carotid artery is a hemodynamic parameter that depends on the degree of atherosclerosis in patients with vascular risk factors. The pulsatility index (PI) of the carotid artery was also shown to be associated with microangiopathy in diabetic patients. In contrast to carotid intima-media thickness (IMT), no study has yet applied the carotid RI and PI to estimate coronary heart disease (CHD) risk. Methods: The Framingham risk score was determined in 62 patients (30 men and 32 women; mean age 65 [range 35 to 83] years) with essential hypertension. Duplex sonography of the common carotid artery (CCA) was then performed, with determination of RI, PI and IMT. Results: The mean risk score of all patients was 14.3 (range 1 to 30), the mean IMT value in the CCA was 0.89±0.23 mm, the mean RI in CCA was 0.71±0.07, and the mean PI in CCA was 1.46±0.39. The risk score was found to have highly significant correlations with RI and PI in the CCA (r=0.512, P<0.001 and r=0.488, P<0.001) (Figure). The risk score–CCA IMT correlation was much less marked (r=0.389, P=0.002). The intraobserver and interobserver agreement was less for IMT than for RI and PI of CCA. A multiple stepwise regression analysis showed that RI was the only factor related to the risk score. Conclusions: Although RI reflects the atherosclerotic process in an indirect manner, the correlation between the RI in CCA and the Framingham risk score is comparable to that of the well-known carotid IMT. Hence, RI in CCA can be used as a tool for risk stratification in patients with essential hypertension.

Figure. Correlation between Framingham risk score (FRS,%) and resistive index and pulsatility index in common carotid artery (CCA RI and CCA PI).

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S32-4 RIGHT VENTRICULAR APICAL PACING ACUTELY IMPAIRS LEFT VENTRICULAR FUNCTION AND INDUCES MECHANICAL DYSSYNCHRONY IN PATIENTS WITH SICK SINUS SYNDROME: A REAL-TIME THREE-DIMENSIONAL ECHOCARDIOGRAPHIC STUDY

Wen-Hao Liu, Yung-Lung Chen, Mien-Cheng Chen, Bih-Fang Guo, Kuo-Li Pan. From the Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan, R.O.C. Background: Chronic right ventricular apical (RVA) pacing can lead to an increased risk of heart failure. However, assessment of left ventricular mechanical dyssynchrony in the whole left ventricle simultaneously with acute RVA pacing has never been investigated. Methods and results: This study included thirty-five patients with sick sinus syndrome and intact intrinsic atrioventricular conduction. All patients received dual-chamber pacemaker implants with atrial leads placed in the right atrial appendage and RV leads positioned in the RVA. Transthoracic 2D echocardiography, tissue Doppler echocardiography and real-time 3D echocardiography (RT3DE) were performed to determine the chamber size, dyssynchronization index, myocardial performance index and global left ventricular ejection fraction. Myocardial performance index was significantly higher with RVA pacing (with RVA 0.42±0.18 vs. without RVA 0.31±0.14; p=0.004), and left ventricular ejection fraction derived by RT3DE was significantly lower with RVA pacing (with RVA 54.4±7.7% vs. without RVA 56.7±7.9%; p=0.013), indicating deteriorated left ventricular function with RVA pacing. Additionally, there was significant difference in the intraventricular delays in favor of without RVA pacing when assessed by the septal-to-posterior wall motion delay on the midventricular level (with RVA 91.9±52.5 msec vs. without RVA 38.6±28.9 msec; p<0.0001) and when assessed by RT3DE-derived systolic dyssynchrony index (with RVA 7.00±2.54% vs. without RVA 5.36±2.17%; p=0.0003). Conclusion: Acute RVA pacing can induce left ventricular mechanical dyssynchrony and impair left ventricular function in patients with sick sinus syndrome.

S32-5 APICAL HYPERTROPHIC CARDIOMYOPATHY WITH VARIANT LEFT VENTRICULAR MORPHOLOGY: A STUDY OF 38 CASES IN TAIWANESE

Chao-Chin Chen, Meng-Huan Lei, Yu-Cheng Hsu, Sheng-Liang Chung. Section Of Cardiology, Lo-Tung Po-Hai Hospital, Ilan,Taiwan,R.O.C. Objective: The aim of this study was to evaluate the clinical features of apical hypertrophic cardiomyopahty (ApHCM) by both noninvasive and invasive techniques. Background: This is the second cohort study of ApHCM in Taiwan. The enrolled patients were all from a regional general hospital in I-Lan county. Methods: 38 consecutive cases with ApHCM (63.0±14.9 years; 22 men) were studied by clinical features, ECG, echocardiography, myocadial perfusion imaging, coronary and LV angiography (LVG) during 3 years period (between 2004 and 2007). Results: All patients in our study populations are symptomatic and the major clinical manifestation was chest pain or tightness (25/38 of patients). The classical giant negative T waves(GNT) were found in 21/38 (55%) patients.There were 25 patients (66%) with the “pure” form of ApHCM and 13 patients (34%) with the “mixed” form of ApHCM. Nine of 21 of patients with LV cavity obliteration showed paradoxical diastolic jet flow. 24 of the 38 patients underwent coronary and LV angiography. All showed abnormal in end diastolic ventriculograms, which was classified into 3 types: type 1 (13/38): "ace of spades"in configuration (with or without apical outpouching), type 2 (8/38): a squestered apical small cavity with intraventricular cannel, and type 3 (3/38): apical aneurysm. Significant stenosis (greater than 50%) of 1 or more coronary arteries was detected in 7 cases. There was no difference in age, classical giant T waves, LVG pattern and clinical outcome compared with cases without significant CAD. Three patients died during follow-up, including 2 noncardiac deaths (1 patient with apical aneurym died of CVA) and 1 sudden cardiac death (with apical aneurym in LVG). Another patient with apical aneurysm had episodes of sustained ventricular tachycardia. Conclusion: Similar ECG and echocardiographic features as “Japanese” type of HCM was observed in the present “Oriental” study population, but “Ace of spades” is not the only configuration of LVG. Patients with apical aneurysm of