9/8/2012 Non-traumatic sudden death • ~300,000 non-traumatic sudden deaths in the US each year. 1 • In a series of consecutive sudden deaths: 2 – 75% cardiac − 4% PE – 7% respiratory − 1% acute stroke/bleed – 5% AAA − 8% other • Sudden cardiac death: – Coronary disease in 90-95% 2-4 – Acute coronary thrombus in 42-74% 2,5 – Healed MI in 48-66% 2,4,6-7 Join Us For The 17th Annual Ghirardelli Chocolate Festival! Ghirardelli Square, San Francisco, CA 1 multiple sources, none great September 8-9, 2012, 12pm-5pm 2. Soo. Resuscitation 2001;51:257-64 3. Perper. Circulation 1975;51s3:III27-33. Ghirardelli Chocolate Company is excited to invite you to the annual, two-day chocolate celebration that has transformed into a 4. Friedman. JAMA 1973;225:1319-28. true San Francisco staple. Local vendors sample and showcase delicious treats that will delight any palate! 5. Davies. N Engl J Med 1984;310:1137-40. 6. Roberts. Am J Med 1972;52:425-43 7. Crawford. Lancet 1961;7170:181-5 Sudden death after MI Post-MI ventricular arrhythmias • Findings in humans – Pathology – Electrophysiology • Acute • Chronic • Dog model of arrhythmias in the early healing phase post-MI • Pig model of arrhythmias in “healed” infarcts Solomon SD et al. N Engl J Med 2005;352:2581-8. 1
9/8/2012 Human: post-MI pathology Human: border zone histology • Necrosis: onset 6 hrs, peak d3-10, disappears by 6 weeks. • Nuclear breakdown, myocyte necrosis, inflammatory infiltrate, phagocytosis of cell breakdown products. • Fibrosis: onset d3-10, peak d8-21, stable after 6 weeks. • Appearance of fibroblasts, production of collagen/ECM, new blood vessel proliferation Bolick DR, et al. Circulation 1986;74;1266-1279 • Remodeling: onset d28, continuous Brackets enclose endocardial fibrosis (A), spared • Collagen cross-linking, scar shrinkage subendocardium (B), barrier infarct (C), patchy fibrosis (D). The chronic VT group had Deneke T, et al. J Cardiovasc Electrophysiol, 2005;16:1246-1251. predominantly large patchy myocardial infarcts Graph from: Fishbein, MC et al. Chest 1978;73:843-9. with irregular ribbons of spared subendo tissue. Infarct phases modified from Holmes, JW et al. Annu Rev Biomed Eng. 2005;7:223-53; Fishbein; Lodge-Patch. Brit Heart J 1952;13:37-42; Mallory. Am Heart J 1939;18:647-71. Human: acute post-MI EP Human: chronic post-MI EP • Cellular EP (not specific to VT circuits): 1 • First 30 days post-MI: remote infarct BZ RMP -80 -60 – Little knowledge of cellular EP APA 107 82 V-dot max 388 175 APD90 370 – Inducibility on EP study: HETEROGENIOUS • Tissue conduction (not specific to VT circuits): • SMVT: 46% of unselected sample, 20% of – Connexin lateralization 2 reperfused < 6hrs post-symptoms, 44% of non- – Slow conduction more prominent lateral to fiber orientation (0.79 reperfused, 23-28% of EF < 40%. 1-4 m/s longitudinal, 0.09 m/s transverse) 3 • PMVT: 2-18% of EF < 40%. 2,4,5 – Fractionation/split potentials/late potentials do not correlate with • VF: 4-7% of EF < 40% VT site 4-5 • EP study: MUSTT 32% SMVT, 12% PMVT/VF 6 1. Akiyama Jpn Circ J 1999;63:838-45. 2. Andressen J Am Coll Cardiol 1999;33:131-8. 3. Bourke Am J Cardiol 1995;75:431-5. 1. Dangman Circulation 1982;65:362-8. 4. de Bakker JACC 1991;18;1005-14. 4. Raviele Europace 2005;7:327-37. 2. Smith Am J Path 1991;139:801-21. 5. Kienzle Circulation 1984;70:957-65. 5. Santarelli Am J Cardiol 1985;55:391-4. 3. de Bakker Circulation 1993;88:915-26 6. Buxton N Engl J Med 1999;341:1882-90. 2
9/8/2012 Human: gaps in knowledge Dog model of acute post-MI arrhythmias • 2-stage occlusion of mid-LAD: initial partial occlusion • Early phase: followed 30’ later by full occlusion. 1 – Little information on cellular EP changes – Spontaneous NSVT and AIVR 8 hrs – 5 days post-MI. through the healing process – Inducible VT in 74-92% 1 week post-MI, decreasing to 41- 67% at 2 weeks, 36-55% at 4 weeks. 2-3 – Suggestions from clinical trials of interactions • VT circuit: between EP and heart failure risk markers but – Reentrant with spatial and temporal excitable gap 4 no solid information – Located in surviving rim of subepicardial tissue 5 • Chronic phase: – Multiple VT morphologies per animal (27% have multiple – Limited information on cellular EP. distinct circuits, all have multiple exit sites from a single circuit) 6 – Available information is not specific to the VT 1. Harris. Circulation 1950;1:1318–1328. circuit. 2. Uprichard Methods Find Exp Clin Pharmacol. 1992;14:165-73. 3. Hunt. J Am Coll Cardiol. 1989;14:765-73. 4. Peters. Circ Res 1998;82:279-293. 5. El-Sherif. Circulation 1977;55:702-19. 6. Costeas. Circulation. 1997;96:3721-31. Subacute dog model: pathology Subacute dog model: cellular EP • Action potential characteristics: 1 . RMP (mV) V max (V/s) APA (mV) APD50 (ms) APD90 (ms) normal -91 102 103 175 210 5 d -77 73 86 120 170 2 wk -88 104 101 192 115 > 2m -86 101 98 160 205 • Tissue conduction properties: – Decreased space constant in borderzone. 2 – Decreased conduction velocity: 3 5-days post-MI 16 months post-MI • Central common pathway: decreased longitudinal and transverse CV E = epicardium i = infarct zone: necrotic at 5d, fatty replacement at 16m • Outer pathway: decreased transverse CV Not shown: endocardial fibrosis, 2-4 cell layers of surviving subendocardium 1. Gardner. Circulation. 1985;72:596-611. 2. Spear. Circ Res. 1983;53:176-85. 3. Cabo. Cardiovasc Res. 72:241-9 2006. Gardner. Circulation. 1985;72:596-611. 3
9/8/2012 Subacute dog model: cellular EP Subacute dog model: novel therapies • Ion channels and connexins: • Rotagaptide – General borderzone cells: – Alters Cx43 phosphorylation to preserve gap junctional conductance during ischemia • 3-5 days post-MI: decreased and lateralized Cx43; 1 – 3-hour Rotagaptide infusion increases connexin protein levels decreased I Na , I Ca,L , I to , I Kr , I Ks . 2-5 but has no effect on CV or VT inducibility in the 5d post-MI dog • I to normalized and I Ca,L still reduced on day 60. 6 • Sodium channel gene therapy – Mapped VT circuit: – SNC4a (SkM1) active at less polarized membrane potential • Central common pathway: decreased I Na , I Ca,L , 7 no change in – Injection of AdSkM1 improves CV, decreases electrogram fractionation, reduces VT inducibility 2-3 gap junctional conductance. 8 • Connexin32 gene therapy • Outer pathway: decreased I Na , I Ca,L , 7 reduced side=side gap – Cx32 remains open at lower pH junctional conductance, no change in end=end. 8 – Injection of AdCx32 improves CV, decreases electrogram fractionation, changes VT from polymorphic to monomorphic 1. Peters. Circulation 1997;95:988-96. morphology. 4 2. Pu Circ Res 1997;81:110-9. 3. Aggarwal. Circ Res 1995;77:1180-91. 4. Lue. Circulation 1992;85:1175-88. 5. Jiang. Cardiovasc Res 2000;48:34-43. 1. Macia Circ AE 2011;4:344-51. 6. Dun. Am J Phys 2005;289:H667-73. 2. Lau. Circulation 2009;119:19-27. 7. Baba. Circulation 2005;112:2386-96. 3. Coronel Heart Rhythm 2010;7:1104-10 8. Cabo. Cardiovasc Res. 72:241-9 2006. 4. Boink Cardiovasc Res 2012;94:450-9. Chronic Pig model of post-MI arrhythmias Subacute Dog model Pigs weighing 25-35kg • Model strengths and weaknesses: + Extensive investigation of cellular EP through healing. • occlude mid-LAD with balloon catheter for 2.5 hours • Implant ICD at right ventricular apex for follow up electrophysiology study More limited investigation of VT circuit-specific changes. Weekly non-invasive EPS and Echo – Abundant, prominent collaterals – Epicardial VT circuit (prominent I to , decreased Cx43). • Extrastimuli pacing (up to S4, BCL 250, 300, 350ms) Atypical scar healing with loss of VT inducibility and • Burst pacing (CL 240-200ms) ± gene transfer post-MI week 4 loss of some cellular EP changes. • Summary of findings: • simultaneous infusion of AD into LAD/GCV – Spontaneous and inducible arrhythmias • invasive EP study – Favorable conditions for reentry: Week 4-12 termination study • Reduced cellular excitability and connectivity. • Decreased refractory period. • EP study � sacrifice • Optical mapping and patch clamp analysis Sasano et al. Nature Medicine 12:1256-8 2006 Sasano et al. Heart Rhythm 6:S91-97 2009 4
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