Arrhythmia Mechanisms Disclosures Honoria Abbott Biotronik - - PDF document

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Arrhythmia Mechanisms

William G. Stevenson, MD Professor of Medicine Vanderbilt University Medical Center Nashville, Tennessee USA

VanderbiltHeart.com

William G Stevenson, MD

• Disclosures

– Honoria

• Abbott
• Biotronik
• Boston Scientific
• Medtronic

– Intellectual Property

• Patent for irrigated needle ablation consigned to Brigham Hospital

Sustained Ventricular Tachycardias

• Monomorphic

–

similar QRS beat to beat indicates repetitive ventricular activation from the same focus

• r substrate
• Polymorphic

– Continually changing ventricular activation – A fixed substrate is not required

• Sinusoidal

– Similar duration QRS and ST- T segment – Slow myocardial conduction: hyperkalemia , metabolic abnormality, ischemia

Mechanisms of Tachyarrhythmias

Abnormal Impulse Generation Abnormal Impulse Conduction Automaticity Triggered Automaticity Reentry

Enhanced Normal Automaticity Abnormal Automaticity EADs DADs Anatomically Defined Functionally Defined

AIVR JET sinus tach polymorphic VT Torsade de pointes Dig toxicity CPVT MFAT AT RVOT VT AVRT AVNRT A flutter Scar- related VT

• Spiral

wave reentry

• Leading

Circle

Combined

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Early Afterdepolarizations ▪ Arise during plateau phase, prior to completion of

repolarization

▪ Mechanisms: reactivation of ICaL or persistent

activation of voltage gated Na channels during prolonged AP

▪ Likely clinical manifestation: torsade de pointes,

polymorphic VT

George JCI 2013 Maruyama et al Heart Rhythm 2014;

Yan et al Circulation 2001;103

▪ Occur after completion of repolarization ▪ Mechanisms: intracellular Ca+2 release leads to

increase Ca+2 efflux through the electrogenic Na+/CA2+ exchanger (NCX; 3Na : 1 Ca) causing a transient inward current

▪ Facilitated by cellular Ca+2 loading ▪ beta-adrenergic stimulation, rapid pacing ▪ suppressed by adenosine through inhibition of

cAMP generation

▪ Arrhythmias: digoxin toxicity, CPVT, idiopathic

RVOT VT

B Lerman Circ Arrhythm Ep 2015;8:483-491 A George JCI 2013

Delayed Afterdepolarizations Abnormal Automaticity ▪ Abnormal automaticity arises from partially

depolarized cells

▪ Sensitive to adrenergic stimulation,

calcium channel blockers

▪ Not responsive to programmed stimulation or

adenosine

B Lerman. Circ Arrhythm Electrophysiol. 2015;8:483-491

0 mV normal abnormal automaticity

leading circle reentry

Reentry around a functional area of block

Functionally defined reentry circuits

Spiral Wave Reentry in cultured cardiomyocytes. Rohr S Circ Arrhythm

• Electrophysiol. 2012;5:442

▪ Does not require a structural substrate ▪ Reentry circuits can meander through the tissue or

anchor on anatomic discontinuities (eg blood vessels)

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Spiral Wave Reentry:

• Functionally determined reentry
• circuits can anchor on tissue discontinuity
• circuits can meander
• waves can break up into daughter wavelets

KLEBER, A. G. et al. Physiol. Rev. 84: 431-488 2004

Spiral Wave Reentry in cultured cardiomyocytes. Rohr S Circ Arrhythm

• Electrophysiol. 2012;5:442

AE Panfilov et al www- binf.bio.uu.nl/~panfil

• v/research.html

Initiation In 3 dimensions a spiral wave is a scroll wave

block

Polymorphic VT/VF with a structurally normal heart:

• The sinus rhythm ECG may suggest a cause:
• repolarization abnormalities
• possibly genetic

Long QT

(genetic)

Short QT

(genetic)

Brugada

(genetic)

Early repolarization

Catecholaminergic polymorphic VT

(genetic, normal resting ECG)

Scar-related Reentrant VT

• VT substrate is “stable”
• Repeated VT episodes may occur over yrs
• VT is inducible at EP study
• Drug efficacy for prevention is poor

monomorphic VT

Initiation of scar- related reentry

sinus rhythm Slow conduction to allow recovery from block Focal region of conduction block

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Slow conduction: Zig - zag conduction caused by fibrotic

separation of myocyte bundles

De Bakker, et al. Circulation 1988; 77:589. Circulation 1993;88:915.

Human papillary muscle in cross section Fibrosis Myocyte bundles

Sa source sink

• - - - - - -

+ + + + + + +

• - - - - - -

+ + + + + + +

intracellular current

As cell to cell coupling decreases, conduction slows but the “safety factor” for conduction increases because less current is dissipated to surrounding cells

less likely to block poorly coupled well coupled

Safety factor – excess current available above that required for conduction

Unidirectional conduction block due to source sink mismatch

Roden and Tomaselli. Conceptual basis for arrhythmology 2005

small source large sink large source small sink promotes conduction block Stable conduction

variations in geometry can promote unidirection conduction block and reentry

Fibrosis in ventricular scars: Anatomy defines reentry paths, slows conduction, facilitates block

Wijnmaalen A P et al. Circulation 2010;121:1887

Fibroblasts / myofibroblast as bridges that slow conduction?

Gaudesius et al. Circ Res 2003;93:421 Magoli et al Circ Res 2006; 98:801

Myocytes in infarct fibrosis Dense fibrosis myocytes myocytes fibroblasts Time (ms)

Smaill B H et al. Circulation

• Research. 2013;112:834-848

Geometry of myocytes surrounded by fibrosis

Nguyen, Qu, Weiss. Fibrosis and

• arrhythmogensis. J Mol Cell Cardiol 2014

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Remodeling of Cardiac Scars is Dynamic

Myocyte Hypertrophy Fibroblast proliferation Myofibroblasts Myocyte Death

Synthesis of extracellular matrix proteins

Fibrosis: interstitial / replacement

• impaired contraction
• impaired relaxation
• cellular uncoupling
• reduced capillary density
• Electrophysiologic effects: conduction slowing and block

Matrix metaloproteinases degradation of ECM proteins

Burchfield et al Circulation 2013; 128:388.

• Brown. Cardiac extracellular matrix: a dynamic entity. AJP Heart Circ Physiol 289: 2005;

replacement fibrosis

Sustained monomorphic VT in non-ischaemic cardiomyopathy is associated with fibrosis

Glashan and Zeppenfeld et al EHJ 2018

variable patterns of fibrosis

Piers S R et al. Circ Arrhythm Electrophysiol. 2013. Ororiz et al Circ Arrhythm Electrophysiol 2014;

Nonischemic Cardiomyopathy Sustained Monomorphic VT: Scar location predicts VT morphologies, ablation approach and outcomes

Basal Septal - Antero Septal Scar Basal Lateral LV Scar Septal ablation is required

• Epicardial ablation not usually helpful
• Risk of AV block
• Lower efficacy?

Basal lateral LV ablation required

• Epicardial ablation often needed

Anter et al Circulation 2016

High resolution mapping and entrainment of reentry in 6 – 8 wk old swine infarct model

A stable reentry circuit isthmus can be defined by slow propagation transverse to fiber

• rientation and wavefront

collision. Slow conduction occurs at areas of high wavefront curvature at entrance and exit regions Reentry circuits defined by functional block and wave collision

Exit Entrance

high curvature radius

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Propagation during VT Voltage map

Fibrosis: Diminished Myocyte Coupling

• Slow conduction
• Unidirectional conduction block
• Promotes automaticity

–makes it easier for automaticity to

• vercome electronic effects of neighboring

cells

Myocardial Fibrosis: a substrate for ventricular arrhythmias

• Myocardial infarction
• Dilated cardiomyopathies
• ARVC/D
• Inflammatory cardiomyopathies

– Sarcoidosis, Chagas, post myocarditis

• Surgically repaired congenital heart disease
• Mitral valve prolapse
• Elderly, hypertension
• Elite athletes
• LV assist devices

Thank You