Kalyanam Shivkumar, MD, PhDDirector, UCLA Cardiac Arrhythmia Center & EP Program

Division of Cardiology, Department of MedicineDavid Geffen School of Medicine at UCLA

Los Angeles, California

Kalyanam Shivkumar, MD, PhDDirector, UCLA Cardiac Arrhythmia Center & EP Program

Division of Cardiology, Department of MedicineDavid Geffen School of Medicine at UCLA

Los Angeles, California

Atrial Fibrillation andSudden Death in

Heart Failure

Atrial Fibrillation andSudden Death in

Heart Failure

Atrial Fibrillation in Heart Failure

• Background

• Pathophysiology

• Influence on disease state and progression

• Clinical approach

• Management

Atrial Fibrillation in HF: Background

• Heart failure and atrial fibrillation are ‘emerging epidemics’

• Tachycardia mediated cardiomyopathyin 10% patients

• Prevalence of atrial fibrillation increases with worsening ventricular dysfunction

• Atrial fibrillation may increase mortality

Correlation Between AF and HF Severity:

Atrial Fibrillation in Heart Failure

• Background

• Pathophysiology

• Influence on disease state and progression

• Clinical approach

• Management

Atrial Fibrillation in Heart Failure: Pathophysiology

• Structural changes such as fibrosis are prominent in remodeled atria in the setting of heart failure

Myocardial Fibrosis: Structural Remodeling in Atrial Fibrillation

Li D et al. Circulation. Jul 1999;100:87-95.

Atrial Fibrillation in HF:Functional Changes

ICaL and ‘window’

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Atrial Fibrillation in HF: Pathophysiology

• Reductions in L-type Ca2+ current, apparently caused by transcriptional

downregulation of the 1c pore-forming Ca2+-channel subunit, Cav1.2, are

important in mediating electrophysiological changes caused by atrial tachycardia remodeling

Shiroshita-Takeshita, Schram, Lavoie, and Nattel. Effect of simvastatin and antioxidant vitamins on atrial fibrillation promotion by atrial-tachycardia remodeling in dogs. Circulation. 2004;110:2313-2319.

Effect of Simvastatin and Antioxidant Vitamins on Atrial FibrillationDue to Remodeling: L-type Ca Channel Alpha Subunit Protein

Pathophysiology of AtrialFibrillation in Heart Failure

• Coupling• Liminal length changes secondary

to stretch• Changes in coupling/geometry of

the atrial muscle bundles at the pulmonary vein-atrial junction

• Atrial Stretch– Stretch activated channels– Anionic currents

• Modulation by autonomic influences

• Neurohumoral changes

Pathophysiology of AtrialFibrillation in Heart Failure

Stretch-Related Changes in Conduction of Electrical Impulses from the Pulmonary Veins into the Atria in an Animal Model of Atrial Fibrillation

Kalifa et al. Circulation. 2003;108:668.

Stretch-Related Changes in Frequency of Excitation of the Pulmonary Veins and Atria in an Animal Model of Atrial Fibrillation

Kalifa et al. Circulation. 2003;108:668.

Asirvatham and Friedman.

From: Shivkumar, Weiss, Fonarow, and Narula; eds. Braunwald’s Atlas of EP in HF. 2005.

Integration of Clinical andExperimental Data

AF (short duration)

AF (variable duration)

DISEASED ATRIUM + Trigger (?Accentuation of preexisting heterogeneity)

NORMAL ATRIUM + Trigger (preexisting heterogeneity)

REMODELINGPERMANENTAtrial Fibrillation

Shivkumar K and Weiss JN. Atrial fibrillation from cells to computers. Cardiovasc Res. 2001.

Atrial Fibrillationin Heart Failure

• Background

• Pathophysiology

• Influence on disease state and progression

• Clinical approach

• Management

Pozolli et al. 1998;31(1):197-204.

The DIG Investigators. Chest. 2000;118:914-922.

From: Shivkumar, Weiss, Fonarow, and Narula; eds. Braunwald’s Atlas of EP in HF.

SOLVD Investigators: J Am Coll Cardiol. 1998;32:695-703.

From: Shivkumar, Weiss, Fonarow, and Narula; eds. Braunwald’s Atlas of EP in HF.

Atrial Fibrillationin Heart Failure

• Background

• Pathophysiology

• Influence on disease state and progression

• Clinical approach

• Management

Atrial Fibrillation in Heart Failure:Clinical Approach

• Assure guideline-based medical management

• Assess structural issues (dilatation due to valve regurgitation, diastolic dysfunction, etc)

• Anticoagulation

• Rhythm management

Management of Atrial Fibrillation in Heart Failure

• Pharmacological– Heart Failure therapy– Antiarrhythmic drugs

• Non Pharmacological– Catheter ablation (atria)– AV nodal ablation and bi-V pacing– Atrial defibrillators

Anne W, Willems R, Van der Merwe N, et al. AF after RF ablation of atrial flutter: preventive effect of ACEI, ARB and diuretics. Heart. 2004;90:1025-1030.

Pharmacological Management: Effect of Heart Failure Drugs

Pharmacological Management: Effect of Heart Failure Drugs

Anne W, Willems R, Van der Merwe N, et al. AF after RF ablation of atrial flutter: preventive effect of ACEI, ARB and diuretics. Heart. 2004;90:1025-1030.

Antiarrhythmic Drugs: Efficacy MaintainingNSR ≥6 Months

CTAF TrialCTAF Trial

N Engl J Med. 2000;342:913-920.

J Am Coll Cardiol. 2003;42:20-29.

AFFIRM : Antiarrhythmic Drug SubstudyAFFIRM : Antiarrhythmic Drug Substudy

(P<0.01)

(n=106)

(n=125)

(n=116)

Diamond Study: Overall Survival

Myocardial Infarction Congestive Heart Failure

Torp-Pedersen C et al. N Engl J Med. 1999;341:857-865.

Odds Ratio for Total Mortality for PatientsOdds Ratio for Total Mortality for PatientsTreated with Quinidine Compared to ControlTreated with Quinidine Compared to Control

Coplen SE. Circulation. 1990;82:1106-1116.

Catheter Ablation of Atrial Fibrillation: How to Ablate

• Surgical Maze

• Pulmonary vein isolation

• Left atrial catheter ablation

• Mapping and ablating complex potentials

• Mapping and ablation fat pads

Initiation of ‘Focal’ Atrial FibrillationRSPV

RIPVLSPV

LIPV

Cabrera et al. Circulation. 2002;106:968.

Evolving Strategy for Ablation of ‘Focal’ Atrial Fibrillation

ABLATION OF FOCUS

ELECTRICAL ISOLATION

UCLA Cardiac Arrhythmia Center.

Who to Ablate?

• Symptomatic drug-refractoryatrial fibrillation

• Drug intolerance

• Tachycardia-induced cardiomyopathy

Catheter Ablation FocalAtrial Fibrillation: Results

• Maintenance of sinus rhythm without drugs

• Drug control of previously drug-refractory atrial fibrillation

• Failure to have any impact on the arrhythmia

• 60-80%

Catheter Ablation FocalAtrial Fibrillation: Results

Safety Issues

• Pulmonary Vein Stenosis• Cerebrovascular accident (CVA)• Bezold-Jarisch response (?RSPV)• Phrenic nerve injury (RSPV)• Cardiac tamponade• Pulmonary parenchymal hemorrhage and

bronchial vein damage• Atrioesophageal fistula formation

Permanent Atrial Fibrillation

• Catheter ‘maze’

• Cryo-‘maze’

• ?Epicardial cryogenic application

• Atrial anti-tachycardia devices

Ozcan et al. N Eng J Med. 2001;344:1043-1051.

From: Shivkumar, Weiss, Fonarow, and Narula; eds. Braunwald’s Atlas of EP in HF.

Long-Term Survival After Ablation of the AV Node and Implantationof a Permanent Pacemaker

Role of Implanted Devices

• Sick Sinus Syndrome

• Anti-tachy pacing

• Preventive algorithms (eg, DAO)

• Cardioversion

• Dual site pacing

• Monitoring capabilities

• Palliative (vent rate stabilization)

Sudden Death in HF

• Background

• Pathophysiology

• Clinical Management

Ischemic Ventricular Arrhythmiasin the USA

Acute Myocardial Infarction: (per year)

Myocardial infarctions: 1,500,000

Pre hospital deaths: 300,000 (>95% VT/VF)

In hospital deaths: 120,000 (20% VT/VF)

Post hospital deaths: 80,000 (10-50% VT/VF)

Stevenson et al. Cardiac arrhythmias, where to go from here?In: Brugada P, Wellens HJJ; eds. Futura Publishing Co; 1987:377-389.

Zipes and Wellens. Circulation. 1998;21:2334-2351.

Scope of the Problem

• 0.75-1 million ‘new’ CHF cases a year

• 50% of patients die suddenly

• Improved survival of patients ‘unmasks’ other causes of morbidity and mortality

Scope of the Problem

• Every infarct survivor is a potential congestive heart failure patient who will need CHF and sudden cardiac death risk reduction

Sudden Death in HF

• Background

• Pathophysiology

• Clinical Management

Alterations of Gross Structure: Remodeling

Reentrant circuit

Bello, Kipper, Valderrabano, and Shivkumar. Heart Rhythm. 2004.

Structure-Function-Metabolism Correlation

Alterations in Myocardial Microarchitecture

• Loss of myocytes

• Changes in cell-cell communication

• Discontinuous electrical propagation

Sudden Death in HF

• Background

• Pathophysiology

• Clinical Management

Antiarrhythmic Drugs or Conventional Therapy vs ICDs

VT/VF PatientsAVIDCASHCIDS

Post-MI Patients MADITCABG Patch

CABG PatchSCD-HeFTMADIT 2

Heart Failure Patients

Moss et al. N Engl J Med. 2002.

Primary Prevention: MADIT-II

SCD-HeFTMortality by Intention to Treat

30 60544842360 6 12 18 24

0.1

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0.3

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0

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HR 97.5%CI P Value

Amiodarone vs Placebo 1.06 0.86, 1.30 0.529ICD Therapy vs Placebo 0.77 0.62, 0.96 0.007

Amiodarone Placebo

ICD Therapy

Months of follow-upMonths of follow-up

60

70

80

90

100

0 60 120 180 240 300 360

Days in Trial

Cum

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Sur

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QRS QRS Duration Duration (msec)(msec)

<90<90

90-12090-120

120-170120-170

170-220170-220

>220>220

Wide QRS:Proportional Mortality Increase

• NYHA Class II-IV patients• 3,654 ECGs digitally scanned• Age, creatinine, LVEF,

heart rate, and QRS duration found to be independent predictors of mortality

• Relative risk of widest QRS group 5x greater than narrowest

11 Gottipaty V, Krelis S, Lu F, et al. Gottipaty V, Krelis S, Lu F, et al. J Am Coll Cardiol.J Am Coll Cardiol. 1999;33(2):145 [Abstr847-4]. 1999;33(2):145 [Abstr847-4].

Vesnarinone StudyVesnarinone Study11

(VEST study analysis)(VEST study analysis)

CRT Trials

• The most effective anti-heart failure intervention is a statin

• The most effective anti-sudden death intervention is also a statin

• Perhaps the most effective anti-atrial fibrillation drug may very well be a statin!

Conclusion