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VESSEL WALL HETEROGENEITY IS AN IMPORTANT FACTOR IN ABDOMINAL AORTIC ANEURYSM RUPTURE RISK PREDICTION
Abstracts
179 STATIN THERAPY INITIATED PRE- INSTEAD OF POSTCHOLESTEROL DIET IS MORE BENEFECIAL IN ATTENUATING HYPERCHOLESTEROLEMIA-INDUCED CARDIOVASCULAR CELL APOPTOSIS J Tsoporis, IC Rizos, V Salpeas, S Izhar, I Toumpoulis, N Oikonomidis, A Rigopoulos, E Sakadakis, E Voltyrakis, TG Parker Toronto, Ontario
Hypercholesterolemia is a common health problem that significantly increases risk of cardiovascular disease in part through the activation of apoptotic pathways. We evaluated the impact of dietary and statin therapy modification (measures known to favorably influence hypercholesterolemia outcome) on the incidence of cardiovascular apoptosis and modulators of the apoptotic response, the S100 proteins B, A1, and A6 and their receptor, the receptor for advanced glycation end- products (RAGE). Male New Zealand white rabbits (16 weeks old) were fed either a normal diet for 8 weeks, a high cholesterol diet (HCD) (containing 2% cholesterol) for 8 weeks, simvastatin (SIM) (3 mg/kg/day) for 8 weeks, HCD for 8 weeks and SIM for an additional 8 weeks, or SIM for 8 weeks and HCD for an additional 8 weeks. HCD compared to a normal diet increased plasma and cardiovascular (cardiac and aortic) tissue cholesterol, triglycerides and LDL levels that were attenuated to a greater extent in the SIM+HCD compared to the HCD+SIM. HCD induced cardiovascular cell (cardiac myocyte and aortic smooth muscle cell) apoptosis as defined by increases in terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive nuclei (1.75-fold), caspase-3 activity (1.3fold), BAX/BCL2 mRNA ratio (3-fold), compared to control. Cardiovascular cell apoptosis was progressively more attenuated in SIM+HCD compared to HCD+SIM. HCD induced the pro-apoptotic S100B 8-fold, RAGE 5-fold and decreased anti-apoptotic S100A6 by 65 per cent. SIM+HCD attenuated the expression of S100B and RAGE (3-4 fold) and increased S100A6 (3-fold) to a greater extent than HCD+SIM. S100A1 was not affected by HCD or SIM therapy. Thus, we conclude that statin therapy, initiated prior to rather than after the development of hypercholesterolemia is more beneficial in attenuating hypercholesterolemia-induced cardiovascular cell apoptosis by a mechanism that may involve the up-regulation of anti-apoptotic S100A6 and down-regulation of proapoptotic S100B.
180 PROMPT ADMISSION AND INTERVENTION SIGNIFICANTLY REDUCE IN-HOSPITAL MORTALITY FOR ACUTE PULMONARY EMBOLISM R Munakata, O Kurihara, H Okazaki, M Tsurumi, N Kobayashi, D Murakami, T Shinada, M Takano, T Ohba, N Hata, Y Seino, W Shimizu Chiba, Japan
S93 BACKGROUND: Although acute pulmonary embolism (APE) may be fatal and several guidelines recommend prompt initiation of anticoagulation if suspicion for PE is high, it is still uncertain whether the delay of admission and intervention after the appearance of symptoms may worsen the outcome in patients with APE. METHODS: We retrospectively analyzed the medical records of the consecutive 108 patients with APE who were diagnosed from May 1996 through December 2013. Patients consisted of two groups according to the timing of admission after the appearance of symptoms; delayed group (DL-G) admitted later than 48 hours and promptgroup (P-G) within 48 hours. We evaluated the differences between two groups in terms of the clinical and hemodynamic data and in-hospital mortality. RESULTS: 108 patients (34.3% male, mean age 6114 years old) were divided into DL-G (n¼42; 38.9%) and PG (n¼66; 61.1%). In-hospital mortality had occurred in 16 patients (14.8%), and was significantly higher in DL-G compared than in P-G (26.2% vs. 7.6%; p¼0.008). There were significant differences in male gender, heart rate on admission and the value of hemoglobin levels (47.6 vs 25.8%, p¼0.024, 90.5 vs 68.2%; p¼ 0.007, 96.3 vs. 79.5 / bpm; p¼0.006, 13.0 vs 11.9 g/dl, p¼ 0.024, respectively). The significant differences was not found in age, prevalence of deep vein thrombus, prevalence of massive PE, systolic blood pressure on admission, PaCO2 and PaO2 / FiO2 ratio. (61.8 12.6 vs. 59.7 16.3 year old; p¼0.45, 73.4 vs 79.2%; p¼ 0.493, 23.8 vs. 22.7%; p¼0.89, 108 47 vs. 110 36 mmHg, 36.4 17.2 vs. 35.9 9.5 Torr; p¼0.85, 229 123 vs. 234 117; p¼0.10, respectively). Multivariate logistic regression analysis revealed the delayed admission was an independent predictive factor for in-hospital mortality with adjusted odds ratio of 4.6 (95% confidence interval 1.2 to 17.7, p ¼ 0.025) even after adjusting for age, gender and heart rate on admission, and the severity of APE. CONCLUSION: The present study demonstrated that the timing of admission and intervention the appearance of symptoms related to the outcome of APE. , This finding strongly suggesting importance of the prompt admission and intervention.
181 VESSEL WALL HETEROGENEITY IS AN IMPORTANT FACTOR IN ABDOMINAL AORTIC ANEURYSM RUPTURE RISK PREDICTION G Martufi, S Nobakth, A Forneris, RD Moore, KD Rinker, ES Di Martino Calgary, Alberta BACKGROUND:
Current indications for the repair of abdominal aortic aneurysms (AAA) emphasize aortic diameter as a marker for risk of rupture. However, the use of aortic size alone may overlook the role that vessel heterogeneity plays in assessing the risk of rupture. Biomechanics may provide a more nuanced approach to predict
S94
the behavior of AAA. The current study was undertaken as a feasibility trial to use pre-operative CT scanning to compute mechanical and fluid mechanical stress profiles on the aortic wall for patients undergoing open AAA repair, and to correlate these stress characteristics with aortic wall histopathology obtained via a sampling grid during aortic reconstruction. METHODS: One patient with non-ruptured AAA (maximum diameter of 57mm) underwent routine CTA scan examination two weeks prior to the scheduled surgery. The pre-operative mechanical wall stress (MWS) and the time average wall shear stress (TAWSS) fields were predicted by means of finite element analysis (FEA) and computational fluid dynamics (CFD) simulations, respectively. The derived stress maps served as a guide during surgery to collect specimens from patient diseased aorta. Elastin fragmentation and collagen content was evaluated on the collected samples and the correlation between MWS, TAWSS and the underlying histological structure was investigated. RESULTS: The macroscopic MWS and TAWSS were distributed non-uniformly over the wall and large variability of collagen content and elastin fragmentation was observed within the aortic sampling grid.There was a moderate negative correlation between thrombus thickness (TT) and MWS (Pearson’s r¼-0.43, p¼0.03) and between TT and TAWSS (r¼ -0.47, p¼0.02). Elastin fragmentation was strongly correlated with the percentage of collagen content in the media (r¼0.94, p¼0.02). CONCLUSION: The observed regional differences are a consequence of local response of tissue to both mechanical and biological triggers. Therefore, the use of aortic size alone is insufficient to characterize the large degree of heterogeneity present in AAA walls even when considering a single patient. Non- invasive methods to infer local properties would greatly increase the reliability of the pre-operative risk of rupture prediction.
Canadian Journal of Cardiology Volume 31 2015
182 ADIPONECTIN REGULATES MONOCYTE MICROPARTICLE PRODUCTION AND ENDOTHELIAL ACTIVATION M Ehsan, F Lovren, Y Pan, A Quan, L Mantella, P Sandhu, K Singh, H Teoh, M Al-Omran, S Verma Toronto, Ontario BACKGROUND:
Monocyte derived microparticles (mono-MPs) have emerged as critical transducers of inflammatory signals, and have been postulated to link cardiovascular risk factors to vascular injury. Specifically, mono-MPs are elevated in patients with inflammatory diseases, cause endothelial activation in vitro and accelerate atherogenesis in vivo. Given that adiponectin has been associated with multiple anti-inflammatory and vasculoprotective mechanisms, we hypothesized that it might also limit mono-MP generation and the ensuing downstream effects. METHODS: THP-1 monocytes, HUVECs and peritoneal monocytes isolated from adiponectin knockout (Adipoq-/-) mice and their littermate controls (Adipoq+/+) were processed for flow cytometry, quantitative reverse transcription polymerase chain reaction, western blot and microscopy analyses. RESULTS: Adiponectin suppressed MP release from lipopolysaccharide (LPS)-treated THP-1 monocytes (30% difference, P<0.05 vs. unstimulated THP-1 cells). Peritoneal monocytes from Adipoq-/- mice generated significantly more MPs (Cd11b+/Ly6Chi/AnnexinV+) than those from Adipoq+/+ littermates in the absence (2.3 fold difference, P<0.05 vs. data from Adipoq+/+ mice-derived samples) and presence (1.6 fold difference, P<0.05 vs. data from Adipoq+/+ mice-derived samples) of LPS. MP expression of the NLRP3 inflammasome and its key components cleaved ASC, caspase-1, and IL-1b (pro- and cleaved) were markedly elevated by LPS (P<0.05 vs. treatment-naïve group). In the presence of adiponectin, however, these increases were appreciably lower (P<0.05 vs. LPStreated group). Likewise, LPS-associated increases in mono-MP phospho-IkBa and NFkB (p65) were significantly less evident in the presence of adiponectin (P<0.05 for both vs. LPStreated group). Coupled with western blot analysis targeting (p-) AMPK and (p-)Akt proteins, it would appear that adiponectin inhibited MP release and molecular signaling in part through activation of AMPK and Akt as well as inhibition of the NFkB pathway. While HUVECs incubated with MPs from LPS-treated THP-1 cells exhibited a significant increase in VCAM-1 expression (P<0.05 vs. unstimulated group), those similarly treated but in the presence of adiponectin demonstrated much lower levels of VCAM-1 (P<0.05 vs. LPS-treated group). These protective effects of adiponectin were mediated via the endothelial NFkB pathway. CONCLUSION: Our results reveal a novel mechanism by which adiponectin exerts its atheroprotective effects. Specifically, our results suggests that adiponectin, via the AMPK, Akt and NF-kB pathways, suppresses mono-MP generation, reduces MP inflammasome activation and limits mono-MP-induced endothelial activation.
179 STATIN THERAPY INITIATED PRE- INSTEAD OF POSTCHOLESTEROL DIET IS MORE BENEFECIAL IN ATTENUATING HYPERCHOLESTEROLEMIA-INDUCED CARDIOVASCULAR CELL APOPTOSIS J Tsoporis, IC Rizos, V Salpeas, S Izhar, I Toumpoulis, N Oikonomidis, A Rigopoulos, E Sakadakis, E Voltyrakis, TG Parker Toronto, Ontario
Hypercholesterolemia is a common health problem that significantly increases risk of cardiovascular disease in part through the activation of apoptotic pathways. We evaluated the impact of dietary and statin therapy modification (measures known to favorably influence hypercholesterolemia outcome) on the incidence of cardiovascular apoptosis and modulators of the apoptotic response, the S100 proteins B, A1, and A6 and their receptor, the receptor for advanced glycation end- products (RAGE). Male New Zealand white rabbits (16 weeks old) were fed either a normal diet for 8 weeks, a high cholesterol diet (HCD) (containing 2% cholesterol) for 8 weeks, simvastatin (SIM) (3 mg/kg/day) for 8 weeks, HCD for 8 weeks and SIM for an additional 8 weeks, or SIM for 8 weeks and HCD for an additional 8 weeks. HCD compared to a normal diet increased plasma and cardiovascular (cardiac and aortic) tissue cholesterol, triglycerides and LDL levels that were attenuated to a greater extent in the SIM+HCD compared to the HCD+SIM. HCD induced cardiovascular cell (cardiac myocyte and aortic smooth muscle cell) apoptosis as defined by increases in terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive nuclei (1.75-fold), caspase-3 activity (1.3fold), BAX/BCL2 mRNA ratio (3-fold), compared to control. Cardiovascular cell apoptosis was progressively more attenuated in SIM+HCD compared to HCD+SIM. HCD induced the pro-apoptotic S100B 8-fold, RAGE 5-fold and decreased anti-apoptotic S100A6 by 65 per cent. SIM+HCD attenuated the expression of S100B and RAGE (3-4 fold) and increased S100A6 (3-fold) to a greater extent than HCD+SIM. S100A1 was not affected by HCD or SIM therapy. Thus, we conclude that statin therapy, initiated prior to rather than after the development of hypercholesterolemia is more beneficial in attenuating hypercholesterolemia-induced cardiovascular cell apoptosis by a mechanism that may involve the up-regulation of anti-apoptotic S100A6 and down-regulation of proapoptotic S100B.
180 PROMPT ADMISSION AND INTERVENTION SIGNIFICANTLY REDUCE IN-HOSPITAL MORTALITY FOR ACUTE PULMONARY EMBOLISM R Munakata, O Kurihara, H Okazaki, M Tsurumi, N Kobayashi, D Murakami, T Shinada, M Takano, T Ohba, N Hata, Y Seino, W Shimizu Chiba, Japan
S93 BACKGROUND: Although acute pulmonary embolism (APE) may be fatal and several guidelines recommend prompt initiation of anticoagulation if suspicion for PE is high, it is still uncertain whether the delay of admission and intervention after the appearance of symptoms may worsen the outcome in patients with APE. METHODS: We retrospectively analyzed the medical records of the consecutive 108 patients with APE who were diagnosed from May 1996 through December 2013. Patients consisted of two groups according to the timing of admission after the appearance of symptoms; delayed group (DL-G) admitted later than 48 hours and promptgroup (P-G) within 48 hours. We evaluated the differences between two groups in terms of the clinical and hemodynamic data and in-hospital mortality. RESULTS: 108 patients (34.3% male, mean age 6114 years old) were divided into DL-G (n¼42; 38.9%) and PG (n¼66; 61.1%). In-hospital mortality had occurred in 16 patients (14.8%), and was significantly higher in DL-G compared than in P-G (26.2% vs. 7.6%; p¼0.008). There were significant differences in male gender, heart rate on admission and the value of hemoglobin levels (47.6 vs 25.8%, p¼0.024, 90.5 vs 68.2%; p¼ 0.007, 96.3 vs. 79.5 / bpm; p¼0.006, 13.0 vs 11.9 g/dl, p¼ 0.024, respectively). The significant differences was not found in age, prevalence of deep vein thrombus, prevalence of massive PE, systolic blood pressure on admission, PaCO2 and PaO2 / FiO2 ratio. (61.8 12.6 vs. 59.7 16.3 year old; p¼0.45, 73.4 vs 79.2%; p¼ 0.493, 23.8 vs. 22.7%; p¼0.89, 108 47 vs. 110 36 mmHg, 36.4 17.2 vs. 35.9 9.5 Torr; p¼0.85, 229 123 vs. 234 117; p¼0.10, respectively). Multivariate logistic regression analysis revealed the delayed admission was an independent predictive factor for in-hospital mortality with adjusted odds ratio of 4.6 (95% confidence interval 1.2 to 17.7, p ¼ 0.025) even after adjusting for age, gender and heart rate on admission, and the severity of APE. CONCLUSION: The present study demonstrated that the timing of admission and intervention the appearance of symptoms related to the outcome of APE. , This finding strongly suggesting importance of the prompt admission and intervention.
181 VESSEL WALL HETEROGENEITY IS AN IMPORTANT FACTOR IN ABDOMINAL AORTIC ANEURYSM RUPTURE RISK PREDICTION G Martufi, S Nobakth, A Forneris, RD Moore, KD Rinker, ES Di Martino Calgary, Alberta BACKGROUND:
Current indications for the repair of abdominal aortic aneurysms (AAA) emphasize aortic diameter as a marker for risk of rupture. However, the use of aortic size alone may overlook the role that vessel heterogeneity plays in assessing the risk of rupture. Biomechanics may provide a more nuanced approach to predict
S94
the behavior of AAA. The current study was undertaken as a feasibility trial to use pre-operative CT scanning to compute mechanical and fluid mechanical stress profiles on the aortic wall for patients undergoing open AAA repair, and to correlate these stress characteristics with aortic wall histopathology obtained via a sampling grid during aortic reconstruction. METHODS: One patient with non-ruptured AAA (maximum diameter of 57mm) underwent routine CTA scan examination two weeks prior to the scheduled surgery. The pre-operative mechanical wall stress (MWS) and the time average wall shear stress (TAWSS) fields were predicted by means of finite element analysis (FEA) and computational fluid dynamics (CFD) simulations, respectively. The derived stress maps served as a guide during surgery to collect specimens from patient diseased aorta. Elastin fragmentation and collagen content was evaluated on the collected samples and the correlation between MWS, TAWSS and the underlying histological structure was investigated. RESULTS: The macroscopic MWS and TAWSS were distributed non-uniformly over the wall and large variability of collagen content and elastin fragmentation was observed within the aortic sampling grid.There was a moderate negative correlation between thrombus thickness (TT) and MWS (Pearson’s r¼-0.43, p¼0.03) and between TT and TAWSS (r¼ -0.47, p¼0.02). Elastin fragmentation was strongly correlated with the percentage of collagen content in the media (r¼0.94, p¼0.02). CONCLUSION: The observed regional differences are a consequence of local response of tissue to both mechanical and biological triggers. Therefore, the use of aortic size alone is insufficient to characterize the large degree of heterogeneity present in AAA walls even when considering a single patient. Non- invasive methods to infer local properties would greatly increase the reliability of the pre-operative risk of rupture prediction.
Canadian Journal of Cardiology Volume 31 2015
182 ADIPONECTIN REGULATES MONOCYTE MICROPARTICLE PRODUCTION AND ENDOTHELIAL ACTIVATION M Ehsan, F Lovren, Y Pan, A Quan, L Mantella, P Sandhu, K Singh, H Teoh, M Al-Omran, S Verma Toronto, Ontario BACKGROUND:
Monocyte derived microparticles (mono-MPs) have emerged as critical transducers of inflammatory signals, and have been postulated to link cardiovascular risk factors to vascular injury. Specifically, mono-MPs are elevated in patients with inflammatory diseases, cause endothelial activation in vitro and accelerate atherogenesis in vivo. Given that adiponectin has been associated with multiple anti-inflammatory and vasculoprotective mechanisms, we hypothesized that it might also limit mono-MP generation and the ensuing downstream effects. METHODS: THP-1 monocytes, HUVECs and peritoneal monocytes isolated from adiponectin knockout (Adipoq-/-) mice and their littermate controls (Adipoq+/+) were processed for flow cytometry, quantitative reverse transcription polymerase chain reaction, western blot and microscopy analyses. RESULTS: Adiponectin suppressed MP release from lipopolysaccharide (LPS)-treated THP-1 monocytes (30% difference, P<0.05 vs. unstimulated THP-1 cells). Peritoneal monocytes from Adipoq-/- mice generated significantly more MPs (Cd11b+/Ly6Chi/AnnexinV+) than those from Adipoq+/+ littermates in the absence (2.3 fold difference, P<0.05 vs. data from Adipoq+/+ mice-derived samples) and presence (1.6 fold difference, P<0.05 vs. data from Adipoq+/+ mice-derived samples) of LPS. MP expression of the NLRP3 inflammasome and its key components cleaved ASC, caspase-1, and IL-1b (pro- and cleaved) were markedly elevated by LPS (P<0.05 vs. treatment-naïve group). In the presence of adiponectin, however, these increases were appreciably lower (P<0.05 vs. LPStreated group). Likewise, LPS-associated increases in mono-MP phospho-IkBa and NFkB (p65) were significantly less evident in the presence of adiponectin (P<0.05 for both vs. LPStreated group). Coupled with western blot analysis targeting (p-) AMPK and (p-)Akt proteins, it would appear that adiponectin inhibited MP release and molecular signaling in part through activation of AMPK and Akt as well as inhibition of the NFkB pathway. While HUVECs incubated with MPs from LPS-treated THP-1 cells exhibited a significant increase in VCAM-1 expression (P<0.05 vs. unstimulated group), those similarly treated but in the presence of adiponectin demonstrated much lower levels of VCAM-1 (P<0.05 vs. LPS-treated group). These protective effects of adiponectin were mediated via the endothelial NFkB pathway. CONCLUSION: Our results reveal a novel mechanism by which adiponectin exerts its atheroprotective effects. Specifically, our results suggests that adiponectin, via the AMPK, Akt and NF-kB pathways, suppresses mono-MP generation, reduces MP inflammasome activation and limits mono-MP-induced endothelial activation.