- Email: [email protected]
257 Impact of polyunsaturated fatty acids on AF induction in a mouse model of RyR2 mutation
S154
250 THE CLINICAL CHARACTERISTICS AND HOSPITAL COURSE OF THE SOUTH ASIAN POPULATION PRESENTING WITH ACUTE ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION IN CANADA A Chan, H Elliott, RI Brown, J Dorval, J Charania, A Lalani, R Kuritzky, J Murray, R Sobolyeva, GJ Simkus New Westminster, British Columbia BACKGROUND: Canada is a multicultural country and a significant population residing in the lower mainland of British Columbia consists of South Asians. We compared the clinical characteristics of the South Asians who presented with ST-segment elevation myocardial infarction (STEMI) with STEMI patients from other ethnicities. METHODS/RESULTS: A tertiary cardiac center provides 24/7 acute infarct revascularization for the Fraser Health Region that encompasses 1.6 million population, including nearly 20% of which are South Asians. Patients’ demographics, clinical presentation, procedural data, and in-hospital course, were prospectively recorded in a registry. Between April 2009 and March 2011, 1,332 patients were referred for emergency cardiac catheterization for STEMI, and 139 (10.4%) were South Asians. Data of the demographic and the clinical course of all patients presenting with STEMI were prospectively collected. When compared with patients from other ethnicities, South Asians with STEMI tended to present at an earlier age (age ⬍70 years: 78% vs 65%, P ⫽ 0.002), and they are more likely to have diabetes (37% vs 21%, P ⫽ 0.001), hyperlipidemia (46% vs 36%, P ⫽ 0.029), and less likely to be a smoker (11.2% vs 34.4%, P ⫽ 0.001). They also tended to have a better left ventricular ejection fraction (47% vs 43%, P ⫽ 0.001) and cardiac arrest before the emergency procedure (10.9% vs 6.7%, P ⫽ 0.086). The location of infarct, door-toballoon times, first medical contact-to-balloon times, rates of congestive heart failure and cardiogenic shock, were similar between the 2 groups. The rates of all-cause mortality (9.5% vs 8.6%, P ⫽ 0.76) and cardiac death (7.2% vs 6.4, P ⫽ 0.71) of South Asians were similar to the rest of the population. CONCLUSION: South Asians with STEMI were younger and more likely had diabetes and hyperlipidemia than patients with other ethnic background. Primary prevention and education related to metabolic syndrome play an important role in reducing STEMI events, particularly in South Asian population.
Canadian Journal of Cardiology Volume 27 2011
tice in patients with ACS stratified according to the management strategy. METHODS/ RESULTS: We conducted a retrospective analysis on 176 consecutive patients admitted for ACS. We examined the discharge prescription of EBM defined as the combination of antiplatelets, -blockers (BB), angiotensin pathway inhibitors (ACEI/ ARB) and lipid-lowering therapy. Study population was stratified according to medical therapy alone, percutaneous coronary intervention (PCI) or surgical revascularisation. Patients mean age was 66 ⫾ 12 years, 24% were females and 31% had diabetes. Mean left ventricular ejection fraction (LVEF) was 51 ⫾ 13%. Patients were admitted for unstable angina in 27%, non-ST-elevation myocardial infarction (MI) 46% and ST-elevation MI 27% of cases. Coronary angiogram was performed in 90%. Medical therapy was allocated for 26% (cohort A), PCI for 50% (Cohort B) and surgery for 24% of patients (Cohort C). No significant difference was noted between the cohorts regarding to age, gender, diabetes, and LVEF. However, in the cohort A as compared to B and C, patients had a higher rate of hypertension (85% vs. 51% vs. 62% respectively, P ⫽ 0.002), known coronary artery disease (71% vs. 43% vs. 31% respectively, P⬍ 0.001) and higher creatinin level (mmol/dl) (148 ⫾ 96 vs. 105 ⫾ 67 vs. 112 ⫾ 88 respectively, P ⫽ 0.033). No significant difference was noted between the cohorts A, B and C regarding the treatment with Bblockers (97% vs. 86% vs. 84% respectively, P ⫽ 0.139) and lipid lowering treatment (91% vs. 94% vs. 92% respectively, P ⫽ 0.804). However, lower rate of aspirin prescription was noted in the cohort A as compared to the cohort B and C (79%, 95% vs. 97%, respectively, P ⫽ 0.010) and lower rate of angiotensin pathway inhibitors in the cohort C as compared to the cohort A and B (31% vs. 59% vs. 69% respectively, P⬍ 0.001). Finally high rate of clopidogrel was only noted in the cohort B as compared to the cohort A and C (94% vs. 29% vs. 7% respectively, P⬍ 0.001) CONCLUSION: In the setting of ACS management, higher rate of adoption to EBM was noted in PCI treated patients. There is room for improvement mainly when patients are treated with medical therapy or surgical revascularization. Canadian Cardiovascular Society (CCS) CCS169 Poster EP BASIC AND CLINICAL Monday, October 24, 2011
251 ADHERENCE TO EVIDENCE- BASED MEDICAL THERAPY ACCORDING TO MANAGEMENT STRATEGY IN PATIENTS WITH ACUTE CORONARY SYNDROME
257 IMPACT OF POLYUNSATURATED FATTY ACIDS ON AF INDUCTION IN A MOUSE MODEL OF RYR2 MUTATION
M Riahi, LM Stevens, N Noiseux, F Gobeil, A Kokis, JB Masson, S Mansour
A Otmani, H Mathison, R Wang, HJ Duff, WS Chen, AM Gillis
Montréal, Québec
Calgary, Alberta
Despite evidence supporting the pharmacological treatment in acute coronary syndrome (ACS), several registries suggested lack of adherence to guidelines. We aim to evaluate the adoption of the evidence-based medical therapy (EBM) in the clinical prac-
BACKGROUND: Polyunsaturated fatty acids (PUFA) as an upstream therapy has been proposed for preventing atrial fibrillation (AF) but its real efficacy is controversial possibly due to the heterogeneity of the models.
BACKGROUND:
S155
Abstracts
Mice with a gain of function RyR2 mutation (RyR2 mutation R4496C) have increased vulnerability to AF. The aim of this study is to assess the effect of PUFA on AF induction in this mouse model. METHODS: Adult RyR2 mice (homozygous R4496C knock in) and their corresponding wild type received fresh daily, a diet of standard mouse feed prepared to contain 10% omega 3 PUFA in the form of eicosapentaenoic and docosahexanoic in a ratio of 1.5:1. Corresponding untreated mice in each group received standard mouse feed only. Sixty three adult mice were studied. Mice were anesthetized, hearts were removed and perfused via the aorta, with modified Krebs/Henseleit buffer. Hearts were paced with electrodes positioned at the left atrium and the ECG was recorded using a silver bipolar electrode. Atrial tachycardia/atrial fibrillation (AT/AF) induction attempts were performed at baseline with S1 at 170 ms and 120 ms of cycle length, with 1,2 and 3 atrial extra stimuli (S2, S3 and S4) and followed by atrial bursts from 170 ms to 50 ms of cycle length. This protocol of stimulation was repeated in the presence of epinephrine 2uM or epinephrine 2uM and caffeine 20 uM administrated in random order. Episodes of AT/AF induction were analyzed according to their duration, cycle length and induction protocol. Data are presented as percent or mean⫹/⫺SD. Factorial analysis of variance or Chi Square test were used as appropriate. A p value ⬍ 0.05 was considered statically significant. RESULTS: PUFA tended to reduce the probability of AT/AF induction in RyR2 mutant mouse hearts at baseline (table). At baseline, the duration of AF induced was significantly shorter in RyR2/PUFA compared to RyR2 untreated hearts and wild type hearts (p ⬍ 0.05) and also tended to be shorter with epinephrine or combination of epinephrine/caffeine (table).
258 CARDIAC ARRHYTHMIAS: INSIGHTS INTO CPVT AND ARVD2 THROUGH THE CRYSTAL STRUCTURE OF THE RYANODINE RECEPTOR N-TERMINAL DISEASE HOT SPOT F Van Petegem, C Tung, PA Lobo, L Kimlicka Vancouver, British Columbia
The contraction of both cardiac and skeletal muscle requires the rapid release of calcium ions from the endoplasmic or sarcoplasmic reticulum. The release is governed by Ryanodine Receptors (RyRs), large ion channels selective for calcium. Over 200 mutations in RyRs have been associated with severe genetic diseases, including CPVT and ARVD2, which cause triggered cardiac arrhythmias. Here we present a high-resolution (2.5 Angstrom) crystal structure of an entire disease hot spot of the ryanodine receptor, harboring 57 different disease mutations. For the first time, we can now look at the effect of disease mutations on the structure and stability of the protein, and derive a mechanism by which the mutations cause a faulty channel. The mutations destabilize functional domain-domain interactions. These interactions normally act as a ’brake’ on the channel, preventing opening under resting conditions. Weakening the domain interfaces causes a leak of calcium ions into the cytoplasm, resulting in delayed after depolarizations (DADs) due to increased activity of the sodium-calcium exchanger. The high resolution structure, combined with low resolution electron microscopy reconstructions, now provides a molecular template for the development of novel drugs that can stabilize the domain-domain interactions.
CONCLUSION: PUFA may modulate propensity to AF via effects
on sarcoplasmic reticulum calcium release. Further studies will be required to directly address this mechanism.
Heart and Stroke Foundation of Canada
250 THE CLINICAL CHARACTERISTICS AND HOSPITAL COURSE OF THE SOUTH ASIAN POPULATION PRESENTING WITH ACUTE ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION IN CANADA A Chan, H Elliott, RI Brown, J Dorval, J Charania, A Lalani, R Kuritzky, J Murray, R Sobolyeva, GJ Simkus New Westminster, British Columbia BACKGROUND: Canada is a multicultural country and a significant population residing in the lower mainland of British Columbia consists of South Asians. We compared the clinical characteristics of the South Asians who presented with ST-segment elevation myocardial infarction (STEMI) with STEMI patients from other ethnicities. METHODS/RESULTS: A tertiary cardiac center provides 24/7 acute infarct revascularization for the Fraser Health Region that encompasses 1.6 million population, including nearly 20% of which are South Asians. Patients’ demographics, clinical presentation, procedural data, and in-hospital course, were prospectively recorded in a registry. Between April 2009 and March 2011, 1,332 patients were referred for emergency cardiac catheterization for STEMI, and 139 (10.4%) were South Asians. Data of the demographic and the clinical course of all patients presenting with STEMI were prospectively collected. When compared with patients from other ethnicities, South Asians with STEMI tended to present at an earlier age (age ⬍70 years: 78% vs 65%, P ⫽ 0.002), and they are more likely to have diabetes (37% vs 21%, P ⫽ 0.001), hyperlipidemia (46% vs 36%, P ⫽ 0.029), and less likely to be a smoker (11.2% vs 34.4%, P ⫽ 0.001). They also tended to have a better left ventricular ejection fraction (47% vs 43%, P ⫽ 0.001) and cardiac arrest before the emergency procedure (10.9% vs 6.7%, P ⫽ 0.086). The location of infarct, door-toballoon times, first medical contact-to-balloon times, rates of congestive heart failure and cardiogenic shock, were similar between the 2 groups. The rates of all-cause mortality (9.5% vs 8.6%, P ⫽ 0.76) and cardiac death (7.2% vs 6.4, P ⫽ 0.71) of South Asians were similar to the rest of the population. CONCLUSION: South Asians with STEMI were younger and more likely had diabetes and hyperlipidemia than patients with other ethnic background. Primary prevention and education related to metabolic syndrome play an important role in reducing STEMI events, particularly in South Asian population.
Canadian Journal of Cardiology Volume 27 2011
tice in patients with ACS stratified according to the management strategy. METHODS/ RESULTS: We conducted a retrospective analysis on 176 consecutive patients admitted for ACS. We examined the discharge prescription of EBM defined as the combination of antiplatelets, -blockers (BB), angiotensin pathway inhibitors (ACEI/ ARB) and lipid-lowering therapy. Study population was stratified according to medical therapy alone, percutaneous coronary intervention (PCI) or surgical revascularisation. Patients mean age was 66 ⫾ 12 years, 24% were females and 31% had diabetes. Mean left ventricular ejection fraction (LVEF) was 51 ⫾ 13%. Patients were admitted for unstable angina in 27%, non-ST-elevation myocardial infarction (MI) 46% and ST-elevation MI 27% of cases. Coronary angiogram was performed in 90%. Medical therapy was allocated for 26% (cohort A), PCI for 50% (Cohort B) and surgery for 24% of patients (Cohort C). No significant difference was noted between the cohorts regarding to age, gender, diabetes, and LVEF. However, in the cohort A as compared to B and C, patients had a higher rate of hypertension (85% vs. 51% vs. 62% respectively, P ⫽ 0.002), known coronary artery disease (71% vs. 43% vs. 31% respectively, P⬍ 0.001) and higher creatinin level (mmol/dl) (148 ⫾ 96 vs. 105 ⫾ 67 vs. 112 ⫾ 88 respectively, P ⫽ 0.033). No significant difference was noted between the cohorts A, B and C regarding the treatment with Bblockers (97% vs. 86% vs. 84% respectively, P ⫽ 0.139) and lipid lowering treatment (91% vs. 94% vs. 92% respectively, P ⫽ 0.804). However, lower rate of aspirin prescription was noted in the cohort A as compared to the cohort B and C (79%, 95% vs. 97%, respectively, P ⫽ 0.010) and lower rate of angiotensin pathway inhibitors in the cohort C as compared to the cohort A and B (31% vs. 59% vs. 69% respectively, P⬍ 0.001). Finally high rate of clopidogrel was only noted in the cohort B as compared to the cohort A and C (94% vs. 29% vs. 7% respectively, P⬍ 0.001) CONCLUSION: In the setting of ACS management, higher rate of adoption to EBM was noted in PCI treated patients. There is room for improvement mainly when patients are treated with medical therapy or surgical revascularization. Canadian Cardiovascular Society (CCS) CCS169 Poster EP BASIC AND CLINICAL Monday, October 24, 2011
251 ADHERENCE TO EVIDENCE- BASED MEDICAL THERAPY ACCORDING TO MANAGEMENT STRATEGY IN PATIENTS WITH ACUTE CORONARY SYNDROME
257 IMPACT OF POLYUNSATURATED FATTY ACIDS ON AF INDUCTION IN A MOUSE MODEL OF RYR2 MUTATION
M Riahi, LM Stevens, N Noiseux, F Gobeil, A Kokis, JB Masson, S Mansour
A Otmani, H Mathison, R Wang, HJ Duff, WS Chen, AM Gillis
Montréal, Québec
Calgary, Alberta
Despite evidence supporting the pharmacological treatment in acute coronary syndrome (ACS), several registries suggested lack of adherence to guidelines. We aim to evaluate the adoption of the evidence-based medical therapy (EBM) in the clinical prac-
BACKGROUND: Polyunsaturated fatty acids (PUFA) as an upstream therapy has been proposed for preventing atrial fibrillation (AF) but its real efficacy is controversial possibly due to the heterogeneity of the models.
BACKGROUND:
S155
Abstracts
Mice with a gain of function RyR2 mutation (RyR2 mutation R4496C) have increased vulnerability to AF. The aim of this study is to assess the effect of PUFA on AF induction in this mouse model. METHODS: Adult RyR2 mice (homozygous R4496C knock in) and their corresponding wild type received fresh daily, a diet of standard mouse feed prepared to contain 10% omega 3 PUFA in the form of eicosapentaenoic and docosahexanoic in a ratio of 1.5:1. Corresponding untreated mice in each group received standard mouse feed only. Sixty three adult mice were studied. Mice were anesthetized, hearts were removed and perfused via the aorta, with modified Krebs/Henseleit buffer. Hearts were paced with electrodes positioned at the left atrium and the ECG was recorded using a silver bipolar electrode. Atrial tachycardia/atrial fibrillation (AT/AF) induction attempts were performed at baseline with S1 at 170 ms and 120 ms of cycle length, with 1,2 and 3 atrial extra stimuli (S2, S3 and S4) and followed by atrial bursts from 170 ms to 50 ms of cycle length. This protocol of stimulation was repeated in the presence of epinephrine 2uM or epinephrine 2uM and caffeine 20 uM administrated in random order. Episodes of AT/AF induction were analyzed according to their duration, cycle length and induction protocol. Data are presented as percent or mean⫹/⫺SD. Factorial analysis of variance or Chi Square test were used as appropriate. A p value ⬍ 0.05 was considered statically significant. RESULTS: PUFA tended to reduce the probability of AT/AF induction in RyR2 mutant mouse hearts at baseline (table). At baseline, the duration of AF induced was significantly shorter in RyR2/PUFA compared to RyR2 untreated hearts and wild type hearts (p ⬍ 0.05) and also tended to be shorter with epinephrine or combination of epinephrine/caffeine (table).
258 CARDIAC ARRHYTHMIAS: INSIGHTS INTO CPVT AND ARVD2 THROUGH THE CRYSTAL STRUCTURE OF THE RYANODINE RECEPTOR N-TERMINAL DISEASE HOT SPOT F Van Petegem, C Tung, PA Lobo, L Kimlicka Vancouver, British Columbia
The contraction of both cardiac and skeletal muscle requires the rapid release of calcium ions from the endoplasmic or sarcoplasmic reticulum. The release is governed by Ryanodine Receptors (RyRs), large ion channels selective for calcium. Over 200 mutations in RyRs have been associated with severe genetic diseases, including CPVT and ARVD2, which cause triggered cardiac arrhythmias. Here we present a high-resolution (2.5 Angstrom) crystal structure of an entire disease hot spot of the ryanodine receptor, harboring 57 different disease mutations. For the first time, we can now look at the effect of disease mutations on the structure and stability of the protein, and derive a mechanism by which the mutations cause a faulty channel. The mutations destabilize functional domain-domain interactions. These interactions normally act as a ’brake’ on the channel, preventing opening under resting conditions. Weakening the domain interfaces causes a leak of calcium ions into the cytoplasm, resulting in delayed after depolarizations (DADs) due to increased activity of the sodium-calcium exchanger. The high resolution structure, combined with low resolution electron microscopy reconstructions, now provides a molecular template for the development of novel drugs that can stabilize the domain-domain interactions.
CONCLUSION: PUFA may modulate propensity to AF via effects
on sarcoplasmic reticulum calcium release. Further studies will be required to directly address this mechanism.
Heart and Stroke Foundation of Canada