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Non-traumatic sudden death ~300,000 non-traumatic sudden deaths in - - PowerPoint PPT Presentation

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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%

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SLIDE 1

9/8/2012 1

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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

1 multiple sources, none great

  • 2. Soo. Resuscitation 2001;51:257-64
  • 3. Perper. Circulation 1975;51s3:III27-33.
  • 4. Friedman. JAMA 1973;225:1319-28.
  • 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

Solomon SD et al. N Engl J Med 2005;352:2581-8.

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

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SLIDE 2

9/8/2012 2

Human: post-MI pathology

Graph from: Fishbein, MC et al. Chest 1978;73:843-9. 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.

  • 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

  • Remodeling: onset d28, continuous
  • Collagen cross-linking, scar shrinkage

Human: border zone histology

Bolick DR, et al. Circulation 1986;74;1266-1279 Brackets enclose endocardial fibrosis (A), spared subendocardium (B), barrier infarct (C), patchy fibrosis (D). The chronic VT group had predominantly large patchy myocardial infarcts with irregular ribbons of spared subendo tissue. Deneke T, et al. J Cardiovasc Electrophysiol, 2005;16:1246-1251.

Human: acute post-MI EP

  • First 30 days post-MI:

– Little knowledge of cellular EP – Inducibility on EP study:

  • SMVT: 46% of unselected sample, 20% of

reperfused < 6hrs post-symptoms, 44% of non- reperfused, 23-28% of EF < 40%.1-4

  • PMVT: 2-18% of EF < 40%.2,4,5
  • VF: 4-7% of EF < 40%

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. 4. Raviele Europace 2005;7:327-37. 5. Santarelli Am J Cardiol 1985;55:391-4.

Human: chronic post-MI EP

  • Cellular EP (not specific to VT circuits):1
  • Tissue conduction (not specific to VT circuits):

– Connexin lateralization2 – Slow conduction more prominent lateral to fiber orientation (0.79 m/s longitudinal, 0.09 m/s transverse)3 – Fractionation/split potentials/late potentials do not correlate with VT site4-5

  • EP study: MUSTT 32% SMVT, 12% PMVT/VF6

remote infarct BZ RMP

  • 80
  • 60

APA 107 82 V-dot max 388 175 APD90 370

HETEROGENIOUS

  • 1. Dangman Circulation 1982;65:362-8.
  • 4. de Bakker JACC 1991;18;1005-14.
  • 2. Smith Am J Path 1991;139:801-21.
  • 5. Kienzle Circulation 1984;70:957-65.
  • 3. de Bakker Circulation 1993;88:915-26
  • 6. Buxton N Engl J Med 1999;341:1882-90.
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SLIDE 3

9/8/2012 3

Human: gaps in knowledge

  • Early phase:

– Little information on cellular EP changes through the healing process – Suggestions from clinical trials of interactions between EP and heart failure risk markers but no solid information

  • Chronic phase:

– Limited information on cellular EP. – Available information is not specific to the VT circuit. Dog model of acute post-MI arrhythmias

  • 2-stage occlusion of mid-LAD: initial partial occlusion

followed 30’ later by full occlusion.1

– Spontaneous NSVT and AIVR 8 hrs – 5 days post-MI. – Inducible VT in 74-92% 1 week post-MI, decreasing to 41- 67% at 2 weeks, 36-55% at 4 weeks.2-3

  • VT circuit:

– Reentrant with spatial and temporal excitable gap4 – Located in surviving rim of subepicardial tissue5 – Multiple VT morphologies per animal (27% have multiple distinct circuits, all have multiple exit sites from a single circuit)6

1.

  • Harris. Circulation 1950;1:1318–1328.

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

16 months post-MI 5-days post-MI E = epicardium i = infarct zone: necrotic at 5d, fatty replacement at 16m Not shown: endocardial fibrosis, 2-4 cell layers of surviving subendocardium

  • Gardner. Circulation. 1985;72:596-611.

Subacute dog model: cellular EP

  • Action potential characteristics:1
  • Tissue conduction properties:

– Decreased space constant in borderzone.2 – Decreased conduction velocity:3

  • Central common pathway: decreased longitudinal and

transverse CV

  • Outer pathway: decreased transverse CV

RMP (mV) Vmax (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

.

  • 1. Gardner. Circulation. 1985;72:596-611.
  • 2. Spear. Circ Res. 1983;53:176-85.
  • 3. Cabo. Cardiovasc Res. 72:241-9 2006.
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SLIDE 4

9/8/2012 4

Subacute dog model: cellular EP

  • Ion channels and connexins:

– General borderzone cells:

  • 3-5 days post-MI: decreased and lateralized Cx43;1

decreased INa, ICa,L, Ito, IKr, IKs.2-5

  • Ito normalized and ICa,L still reduced on day 60.6

– Mapped VT circuit:

  • Central common pathway: decreased INa, ICa,L,7 no change in

gap junctional conductance.8

  • Outer pathway: decreased INa, ICa,L,7 reduced side=side gap

junctional conductance, no change in end=end.8

1.

  • Peters. Circulation 1997;95:988-96.

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.

6.

  • Dun. Am J Phys 2005;289:H667-73.

7.

  • Baba. Circulation 2005;112:2386-96.

8.

  • Cabo. Cardiovasc Res. 72:241-9 2006.

Subacute dog model: novel therapies

  • Rotagaptide

– Alters Cx43 phosphorylation to preserve gap junctional conductance during ischemia – 3-hour Rotagaptide infusion increases connexin protein levels but has no effect on CV or VT inducibility in the 5d post-MI dog

  • Sodium channel gene therapy

– SNC4a (SkM1) active at less polarized membrane potential – Injection of AdSkM1 improves CV, decreases electrogram fractionation, reduces VT inducibility2-3

  • Connexin32 gene therapy

– Cx32 remains open at lower pH – Injection of AdCx32 improves CV, decreases electrogram fractionation, changes VT from polymorphic to monomorphic morphology.4

1. Macia Circ AE 2011;4:344-51. 2.

  • Lau. Circulation 2009;119:19-27.

3. Coronel Heart Rhythm 2010;7:1104-10 4. Boink Cardiovasc Res 2012;94:450-9.

Subacute Dog model

  • Model strengths and weaknesses:

+ Extensive investigation of cellular EP through healing. More limited investigation of VT circuit-specific changes. – Abundant, prominent collaterals – Epicardial VT circuit (prominent Ito, decreased Cx43). Atypical scar healing with loss of VT inducibility and loss of some cellular EP changes.

  • Summary of findings:

– Spontaneous and inducible arrhythmias – Favorable conditions for reentry:

  • Reduced cellular excitability and connectivity.
  • Decreased refractory period.

Chronic Pig model of post-MI arrhythmias

  • EP study sacrifice
  • Optical mapping and patch clamp analysis

Pigs weighing 25-35kg

Sasano et al. Nature Medicine 12:1256-8 2006 Sasano et al. Heart Rhythm 6:S91-97 2009

  • simultaneous infusion of AD into LAD/GCV
  • invasive EP study

Week 4-12 termination study

  • cclude mid-LAD with balloon catheter for 2.5 hours
  • Implant ICD at right ventricular apex for follow up electrophysiology study

± gene transfer post-MI week 4

  • Extrastimuli pacing (up to S4, BCL 250, 300, 350ms)
  • Burst pacing (CL 240-200ms)

Weekly non-invasive EPS and Echo

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SLIDE 5

9/8/2012 5

Pathology

Chronic Pig model: infarct pathology

Sasano et al. Nature Medicine 12:1256-8 2006

(A) endocardial fibrosis (B) spared subendocardium (C) barrier infarct (D) patchy fibrosis

D B C A

Chronic Pig model: tissue/cellular EP

100 µm

Cx43, cadherin-merge 25% of Cx43 localizes to intercalated disk RMP (mV) APA (mV) APD90 (ms) CV (m/s) control

  • 73 ± 3

135 ± 3 275 ± 61 58 ± 22 infarct-anterior septal BZ

  • 67 ± 11

119 ± 11 340 ± 136 31 ± 11 infarct-lateral BZ

  • 67 ± 2

115 ± 10 311 ± 120 38 ± 16

  • 20

20 40 60 80 mV 0.5 1.0 1.5 2.0 IKs pA/pF

  • 20

20 40 60 80 mV 0.1 0.2 0.3 0.4 0.5 0.6 0.7 IKr (pA/pF)

  • 120
  • 100
  • 80
  • 60
  • 40-20

20 40 60 80 mV

  • 30
  • 25
  • 20
  • 15
  • 10
  • 5

5 IK1 (pA/pF)

  • 40
  • 20

20 40 60 mV

  • 10
  • 8
  • 6
  • 4
  • 2

ICa,L (pA/pF)

control infarct-anterior septum Infarct-lateral

I II III aVR aVL aVF V1 V2 V3 V4 V5 V6

Post-MI: 3 weeks 4 weeks

80 60 40 20 100 1 2 3 4 5

Time post-MI (weeks) Inducible arrhythmia (%) SMVT PMVT/VF

Chronic Pig model: EP study

Sasano et al. Heart Rhythm 6:S91-97 2009

  • Spontaneous NSVT 1-2 days post-MI
  • Sudden death in 1-2% over first 2 weeks

3D activation/entrainment mapping

V < 0.2 mV V < 1.5 mV

VT * Entrainment Pacing

Pig model: VT circuit

Sasano et al. Heart Rhythm 6:S91-97 2009

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SLIDE 6

9/8/2012 6 Chronic Pig model: gene therapies

  • Hypothesis: disrupting reentry will prevent

sustained VT

– KCNH2-G628S: dominant negative IKr mutation – Connexin43: principle ventricular gap junction protein

Chronic Pig model: KCNH2-G628S

* p < 0.01, + p < 0.05

  • Sasano. Nature Medicine 12:1256-8 2006

(0%) G628S

Post- Pre- Post-

20 40 60 80 100 VT inducibility (%)

Pre-

Controls

Pre-AdKCNH2-G628S Post-AdKCNH2-G628S

S2 S1 S4 S3 S2 S1 S4 S3 S2 S1 S4 S3 S1 S1 S1 S1 S1

MAPD90 (ms) control KCNH2-G628S non ms ds lat 200 250

+ +

ERP (ms) nonmsds lat 200 250

+ + *

Chronic Pig model: connexin43

* p = 0.015 + p = 0.024

Pre-AdCx43 Post-AdCx43

S1 S1 S1 S2 S3 S4 S1 S1 S1 S2 S4 S3

AdCx43

Post- Pre- Post-

20 40 60 80 100 VT inducibility (%)

Pre-

Controls

*

Control Endo Epi AdCx43

+

control AdCx43

10 20 30 40 50 60 Transmural CV (cm/s)

Greener J Am Coll Cardiol 2012; in press.

Chronic Pig model

  • Model strengths and weaknesses:

+ Pathology very similar to human. Cellular EP changes, VT circuits mirror some human data – Unique Purkinje fiber anatomy. VF induced more frequently than in other species.

  • Summary of findings:

– Low level spontaneous arrhythmias, Very reliable VT inducibility – Persistent EP changes that favor reentry:

  • Impaired RMP, APA
  • Heterogeneous repolarization
  • Increased ICa,L, decreased IKr, variable IKs,

decreased/lateralized Cx43

– VT can be eliminated by interventions that prevent reentry

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SLIDE 7

9/8/2012 7

Take-home lessons

  • Limited information in humans demonstrates

reentrant VT mechanism with altered cellular connectivity, excitability and repolarization.

  • Animal models supplement human data with

caveat that models are not perfect reflection

  • f human situation

– Alterations in connectivity from connexin remodeling and fibrosis – Alterations in excitability and repolarization from sodium, calcium and potassium current alterations.

  • Interventions to disrupt reentry prevent

sustained VT

Acknowledgements

  • Donahue Lab
  • Ian Greener
  • Tetsuo Sasano
  • Kamilla Kelemen
  • Emanuel Finet
  • Tomonori Igarashi
  • Kan Kikuchi
  • Collaborators:
  • David Rosenbaum
  • Xiaoping Wan
  • Guy Amit
  • Maria Strom
  • Lizhu Yang
  • Karen Wu
  • Amy McDonald
  • Gary Pawlowski
  • Danielle Maleski
  • Funding
  • NIH: NHLBI, Gene Therapy

Resource Program

  • Fondation Leducq Transatlantic

CaMKII Alliance

DISCLOSURES: Equity in Excigen, Inc., Research grant St. Jude, Research supplies: St. Jude, Medtronic, Boston Scientific, Biosense Webster