Canadian Cardiovascular Society (CCS) CCS605 Oral: Imaging in Ischemic Heart Disease: Novel Concepts for Diagnosis, Prognosis and Therapeutics Monday, October 25, 2010

Canadian Cardiovascular Society (CCS) CCS605 Oral: Imaging in Ischemic Heart Disease: Novel Concepts for Diagnosis, Prognosis and Therapeutics Monday, October 25, 2010

Abstracts dysfunction is associated with impaired vasodilation, increased vasospasm, decreased eNOS expression, and generation of free radicals. Conco...

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Abstracts dysfunction is associated with impaired vasodilation, increased vasospasm, decreased eNOS expression, and generation of free radicals. Concomitant treatment with the ET-1 receptor antagonist bosentan (BOS) and the eNOS cofactor tetrahydrobiopterin (BH4) attenuates this dysfunction. It is unknown whether administration of BOS and BH4 subsequent to the development of CyA-induced endothelial dysfunction is beneficial. CONCLUSION: In rat thoracic aortic segments, CyA significantly impaired endothelium-dependent relaxation, shown by elevated ED50 and reduced Emax. This was attenuated by initiation of ET-1 blockade and NO augmentation after the onset of injury. CyA also increased sensitivity to vasospasm (increased Cmax and lower ED50); however, this was not altered by BOS and BH4 treatment. CyA withdrawal improved endothelial function and reduced sensitivity to ET-1 more effectively than treatment with ET-1 blockade plus NO augmentation. These results suggest that it may be possible to reduce the incidence of endothelial dysfunction post cardiac transplantation in patients receiving cyclosporine, and potentially reduce the incidence of CAV.

Canadian Cardiovascular Society (CCS) CCS605 Oral IMAGING IN ISCHEMIC HEART DISEASE: NOVEL CONCEPTS FOR DIAGNOSIS, PROGNOSIS AND THERAPEUTICS Monday, October 25, 2010 354

INTRA-THORACIC FAT DISTRIBUTION IN PATIENTS WITH METABOLIC SYNDROME WITH AND WITHOUT MYOCARDIAL INFARCTION: POTENTIAL FOR A NOVEL RISK STRATIFICATION TOOL IN PATIENTS WITH METABOLIC SYNDROME US Jolly, M Brymer, N Fine, M Drangova, T Joy, JA White London, Ontario BACKGROUND: Adipose fat distribution is recognized as an important biomarker in the evaluation of patients considered at risk for coronary artery disease. CMR is able to accurately detect established myocardial injury due to unstable coronary artery disease using delayed enhancement imaging and may simultaneously accurately evaluate the volume of intrathoracic fat. No study to date has evaluated the thoracic distribution of fat in patients with and without myocardial infarction and/or metabolic syndrome. We sought to examine the relative volume of fat found within the thorax of patients with and without metabolic syndrome and with and without a prior myocardial infarction. CONCLUSION: The intra-thoracic fat volume index is incrementally increased in patients with MetS and in those with evidence of prior MI. These findings suggests an association between increased intrathoracic fat distribution and the risk of unstable coronary artery disease in patients with MetS. Future studies evaluating the prognostic value of the intra-thoracic fat volume index for the prediction of cardiovascular events in patients with MetS are warranted.

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CAN CTA CONTRAST GRADIENTS PREDICT ABNORMAL RESTING CORONARY ARTERY FLOW? BJ Chow, O Gagne, M Kass, L Chen, Y Yam, A Dick, G Wells Ottawa, Ontario BACKGROUND: Though computed tomographic coronary angiography (CTA) can be used for the detection of obstructive coronary artery disease (CAD), it cannot reliably differentiate between anatomical versus functional stenoses. A proof-of concept study was undertaken to determine if corrected coronary attenuation (CCA) gradients within coronary lumen can identify arteries with abnormal resting coronary flow. CONCLUSION: Corrected contrast agent gradients in coronary vessels appears to predict abnormal (TIMI <3) resting coronary blood flow.

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Further studies are needed to understand its incremental diagnostic value and its potential to measure stress flow.

Featured Research 356

RELATIONSHIP BETWEEN T2-WEIGHTED CARDIAC MR IMAGES AND LEFT VENTRICULAR WALL THICKNESS IN ACUTE MYOCARDIAL ISCHEMIA Y Mikami, A Kumar, H Abdel-Aty, MG Friedrich Calgary, Alberta BACKGROUND: T2-weighted cardiac magnetic resonance imaging can sensitively identify infarct-related myocardial edema and has been shown to detect acute ischemic myocyte injury before the onset of irreversible injury. Experimental studies using echocardiography have shown that reperfusion of acutely infarcted segments, with an intact microvascular circulation, induces changes in end-diastolic myocardial wall thickness (EDWT) likely caused by myocardial edema. The purpose of this study is to assess the relationship between regional EDWT and high signal intensity on T2-weighted CMR after acute ischemia and reperfusion. CONCLUSION: The high SI area on T2-weighted CMR is strongly associated with the regionally increased EDWT. However, the increase in EDWT is too small to be of a diagnostic value, especially after brief episodes of myocardial ischemia. For a reliable assessment of the myocardium for acute ischemic injury, T2-weighted CMR is required and cannot be replaced by wall thickness measurements.

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MYOCARDIAL PERFUSION IMAGING HAS PROGNOSTIC VALUE AT VARYING THRESHOLDS OF EXERCISE CAPACITY DS Lee, F Verocai, M Husain, D Al Khdair, X Wang, RM Iwanochko Toronto, Ontario BACKGROUND: The prognostic information that can be obtained from myocardial perfusion imaging (MPI) with concomitant exercise treadmill stress has not been fully evaluated for a wide range of outcomes including death, myocardial infarction (MI), and coronary revascularization. We examined the association of MPI findings with clinical outcome events at 2-year follow-up throughout the range of exercise capacity. We hypothesized that MPI results would be associated with increased events even in patients who attained high exercise workload. CONCLUSIONS: MPI had significant prognostic implications at all levels of treadmill exercise, even after accounting for high workload attained and the presence or absence of ST-segment shifts.

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IMPAIRED MYOCARDIAL FLOW RESERVE USING RUBIDIUM-82 PET PREDICTS OUTCOMES IN PATIENTS WITH SUSPECTED MYOCARDIAL ISCHEMIA MC Ziadi, RA deKemp, A Guo, K Williams, JM Renaud, BJ Chow, T Ruddy, L Garrard, RB Beanlands Ottawa, Ontario Whether quantification of myocardial flow reserve (MFR) with PET yields added clinical utility to standard perfusion imaging (MPI) and alters management remains unknown. Our goal was to assess the prognostic value of impaired MFR with Rubidium-82 (82Rb) PET in patients with suspected myocardial ischemia. We hypothesized that patients with impaired MFR would present worse outcomes compared to those with normal MFR. This data support that in patients with suspected ischemia, 82Rb MFR and SSS are independent predictors of adverse events. Quantification of MFR with 82Rb PET is a useful clinical tool to advance risk stratification of patients. Further large prospective studies are still required.

Can J Cardiol Vol 26 Suppl D October 2010

Abstracts

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TEMPORALLY SEPARATED DELIVERY OF VEGF AND ANG1 PROMOTES SUSTAINED IMPROVEMENT IN RESTING FLOW AND FLOW RESERVE AFTER ULTRASOUNDMEDIATED PLASMID DELIVERY AH Smith, MA Kuliszewski, C Liao, D Rudenko, JR Lindner, H Leong-Poi Toronto, Ontario Previously, we demonstrated that ultrasound-mediated plasmid delivery (UMPD) of vascular endothelial growth factor (VEGF) DNA promotes therapeutic angiogenesis. However, single gene delivery of VEGF results in primarily immature vessels, leading to late vascular regression. Endogenously, VEGF initiates angiogenesis and drives endothelial cell proliferation, while Angiopoietin (Ang)-1 acts at later time points to stabilize the neovasculature. We hypothesized that gene therapy using temporally separated delivery of VEGF and Ang-1 would result in a more sustained and functional angiogenic response, as compared to VEGF alone or co-delivery of VEGF and Ang-1, in the setting of severe chronic ischemia. Compared to delivery of VEGF alone, delivery of Ang-1 plasmid DNA at 2wks post-VEGF gene delivery results in sustained improvement in resting flow and flow reserve, with prevention of excessive capillary growth and late vascular regression. Compared to VEGF/Ang-1 co-delivery, temporally separated delivery VEGF and Ang-1 provides a more significant and sustained improvement in resting flow and higher vessel density. Amplifying VEGF and Ang-1 growth factor expression by UMPD according to endogenous timeline amplifies angiogenesis and leads to a long-lasting improvement in resting blood flow and flow reserve. Canadian Institutes of Health Research and from the Ontario Government Ministry of Research and Innovation’s Early Researcher Award

Canadian Society for Atherosclerosis, Thrombosis and Vascular Biology (CSATVB) CSATVB180 Oral VASCULAR AND VALVULAR DISEASE Monday, October 25, 2010 Featured Research 362

ROLES OF SIRT1 DEACETYLASE IN THE TRANSCRIPTIONAL CONTROL OF MACROPHAGES IMPLICATED IN AORTIC STENOSIS S Carter, Z Li, S Miard, P Mathieu, F Picard Québec, Québec BACKGROUND: Aortic stenosis is associated with physiological changes of aortic valve, macrophages infiltration and differential gene expression. In 70 + year old patients, higher levels of plasma resistin have been associated with increased calcification and inflammation. Resistin is a pro-inflammatory hormone secreted by macrophages in humans but how its expression is regulated is not established. AP-1, a dimeric transcription factor, is implicated in the regulation of pro-inflammatory cytokines in macrophages. Since Sirt1 is an AP-1 cofactor and because it is implicated in the ageing process, we hypothesized that Sirt1 controls resistin expression by repressing AP-1 in macrophages. CONCLUSION: Our study demonstrates that Sirt1 controls resistin expression by linking to its promoter and inhibiting AP-1 activity. This effect is reduced upon LPS treatment, thereby increasing resistin transcription. C-Jun was identified as a member of the AP-1 dimer but c-Fos was excluded. Our experiments on human tissues and cells showed that human calcified aortic valves and U-937 cell model over expressing non functional Sirt1 both displayed a pro-inflammatory gene expression profile promoting foam cell formation. Whether Sirt1-mediated repression of resistin promoter transactivation is lost in stenotic aortic valves in humans remains to be tested. This study will contribute to the actual research on

Can J Cardiol Vol 26 Suppl D October 2010

Sirt1 agonists in the treatment of cardiovascular diseases. Québec Heart Institute

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SIDE-SPECIFIC ENDOTHELIAL-DEPENDENT REGULATION OF AORTIC VALVE CALCIFICATION I El-Hamamsy, Z Sarang, R Patel, P Sarathchandra, A Chester, MH Yacoub Montréal, Québec BACKGROUND: Aortic valve calcification (AVC) occurs exclusively on the aortic side of the valve. The role of nitric oxide (NO) on AVC remains unknown. The aims of the present study were to evaluate the influence of endothelial cells on either side of the valve on AVC and to investigate the mechanisms involved, particularly the role of endothelialderived nitric oxide. CONCLUSION: There is an increased pro-calcification potential on the aortic side of the AV partly due to the differential secretion of endogenous NO by both sides of the valve. The release of NO appears to be protective against valve calcification. This could have important therapeutic implications. Canadian Institutes of Health Research (CIHR)

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DECREASE IN MATRIX GLA PROTEIN LEVEL DURING FOLLOW-UP IS ASSOCIATED WITH FASTER PROGRESSION OF AORTIC VALVE STENOSIS: A SUBSTUDY OF THE AORTIC STENOSIS PROGRESSION OBSERVATION MEASURING EFFECTS OF ROSUVASTATIN (ASTRONOMER) N Côté, R Capoulade, P Pibarot, JG Dumesnil, KL Chan, KK Teo, JW Tam, J Després, P Moreau, P Mathieu Québec, Québec BACKGROUND: Matrix Gla protein (MGP) is a potent inhibitor of cardiovascular calcification. The objective of this substudy was to examine, in a large prospective multicenter study, the relationship between change in MGP levels over time and progression of aortic stenosis (AS). CONCLUSION: This is the first prospective study to demonstrate an inverse relationship between change in circulating MGP level and progression rate of AS. Future studies are needed to determine if a reduction in MGP over time is a surrogate marker of disease progression or a factor contributing to disease process.

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THE EFFECT OF CAROTID ENDARTERECTOMY ON ARTERIAL STIFFNESS AJ Dawson, N Punjani, RJ Doonan, K Antonucci, P Scheffler, SS Daskalopoulou Montréal, Québec BACKGROUND: Internal carotid artery stenosis is produced by atherosclerotic plaques and is a major etiological factor causing cerebrovascular events. Carotid endarterectomy (CEA), used to manage carotid stenosis, has been shown to reduce the risk of future cerebrovascular events. Arterial stiffness, assessed by vessel hemodynamics, is a well-established vascular risk factor. Arterial stiffness is strongly associated with the development of atherosclerosis, and has been used to monitor its progression. The ‘gold standard’ measurement of arterial stiffness is carotid-femoral pulse wave velocity (cfPWV). However, it has not been investigated whether CEA modifies arterial stiffness, which is the objective of this study. CONCLUSION: To our knowledge this is the first study to provide evidence that removal of atherosclerotic plaque (by CEA) decreases arterial stiffness, as assessed by cfPWV (‘gold standard’). These results show a significant reduction in cfPWV on the surgical side post-operatively (approximately 7 weeks). This change was significantly greater than the change in peripheral systolic BP. Differences were not observed in other arterial stiffness parameters post-operatively. Specifically, the absence of change in ipsilateral crPWV, therefore, suggests a more complex mechanism of vascular remodeling than the simple restoration of regular blood flow. Longer follow-up and a larger sample size will determine whether these changes in

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