Kalyanam Shivkumar, MD, PhD

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Atrial Fibrillation andSudden Death inHeart
Failure
Kalyanam Shivkumar, MD, PhD Director, UCLA
Cardiac Arrhythmia Center EP Program Division
of Cardiology, Department of Medicine David
Geffen School of Medicine at UCLA Los Angeles,
California
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Atrial Fibrillation in Heart Failure

• Background
• Pathophysiology
• Influence on disease state and progression
• Clinical approach
• Management

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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

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Correlation Between AF and HF Severity
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Atrial Fibrillation in Heart Failure

• Background
• Pathophysiology
• Influence on disease state and progression
• Clinical approach
• Management

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Atrial Fibrillation in Heart Failure
Pathophysiology

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

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Myocardial Fibrosis Structural Remodeling in
Atrial Fibrillation
Li D et al. Circulation. Jul 199910087-95.
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Atrial Fibrillation in HFFunctional Changes
Ito
ICaL and window
INa
Transmembrane Potential (Millivolts)
Ikr, Ikur, Iksus

Ik1 If
Threshold
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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

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Effect of Simvastatin and Antioxidant Vitamins on
Atrial FibrillationDue to Remodeling L-type Ca
Channel Alpha Subunit Protein
Shiroshita-Takeshita, Schram, Lavoie, and Nattel.
Effect of simvastatin and antioxidant vitamins on
atrial fibrillation promotion by
atrial-tachycardia remodeling in dogs.
Circulation. 20041102313-2319.
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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

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Pathophysiology of AtrialFibrillation in Heart
Failure

• Atrial Stretch
• Stretch activated channels
• Anionic currents
• Modulation by autonomic influences
• Neurohumoral changes

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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. 2003108668.
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Stretch-Related Changes in Frequency of
Excitation of the Pulmonary Veins and Atria in an
Animal Model of Atrial Fibrillation
Kalifa et al. Circulation. 2003108668.
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Asirvatham and Friedman. From Shivkumar, Weiss,
Fonarow, and Narula eds. Braunwalds Atlas of EP
in HF. 2005.
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Integration of Clinical andExperimental Data
NORMAL ATRIUM Trigger (preexisting
heterogeneity)
AF (short duration)
PERMANENT Atrial Fibrillation
REMODELING
DISEASED ATRIUM Trigger
(?Accentuation of preexisting heterogeneity)
AF (variable duration)
Shivkumar K and Weiss JN. Atrial fibrillation
from cells to computers. Cardiovasc Res. 2001.
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Atrial Fibrillationin Heart Failure

• Background
• Pathophysiology
• Influence on disease state and progression
• Clinical approach
• Management

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Pozolli et al. 199831(1)197-204.
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The DIG Investigators. Chest. 2000118914-922.
From Shivkumar, Weiss, Fonarow, and Narula
eds. Braunwalds Atlas of EP in HF.
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SOLVD Investigators J Am Coll Cardiol.
199832695-703. From Shivkumar, Weiss,
Fonarow, and Narula eds. Braunwalds Atlas of EP
in HF.
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Atrial Fibrillationin Heart Failure

• Background
• Pathophysiology
• Influence on disease state and progression
• Clinical approach
• Management

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Atrial Fibrillation in Heart FailureClinical
Approach

• Assure guideline-based medical management
• Assess structural issues (dilatation due to valve
  regurgitation, diastolic dysfunction, etc)
• Anticoagulation
• Rhythm management

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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

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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.
2004901025-1030.
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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.
2004901025-1030.
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Antiarrhythmic Drugs Efficacy MaintainingNSR 6
Months
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CTAF Trial
N Engl J Med. 2000342913-920.
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AFFIRM Antiarrhythmic Drug Substudy
(n106)
(P
(n125)
(n116)
J Am Coll Cardiol. 20034220-29.
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Diamond Study Overall Survival
Myocardial Infarction
Congestive Heart Failure
Torp-Pedersen C et al. N Engl J Med.
1999341857-865.
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Odds Ratio for Total Mortality for
PatientsTreated with Quinidine Compared to
Control
Coplen SE. Circulation. 1990821106-1116.
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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

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Initiation of Focal Atrial Fibrillation
RSPV
LSPV
RIPV
LIPV
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Cabrera et al. Circulation. 2002106968.
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Evolving Strategy for Ablation of Focal Atrial
Fibrillation
ELECTRICAL ISOLATION
ABLATION OF FOCUS
UCLA Cardiac Arrhythmia Center.
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Who to Ablate?

• Symptomatic drug-refractoryatrial fibrillation
• Drug intolerance
• Tachycardia-induced cardiomyopathy

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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

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Catheter Ablation FocalAtrial Fibrillation
Results

• 60-80

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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

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Permanent Atrial Fibrillation

• Catheter maze
• Cryo-maze
• ?Epicardial cryogenic application
• Atrial anti-tachycardia devices

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Long-Term Survival After Ablation of the AV Node
and Implantationof a Permanent Pacemaker
Ozcan et al. N Eng J Med. 20013441043-1051. From
Shivkumar, Weiss, Fonarow, and Narula eds.
Braunwalds Atlas of EP in HF.
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Role of Implanted Devices

• Sick Sinus Syndrome
• Anti-tachy pacing
• Preventive algorithms (eg, DAO)
• Cardioversion
• Dual site pacing
• Monitoring capabilities
• Palliative (vent rate stabilization)

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Sudden Death in HF

• Background
• Pathophysiology
• Clinical Management

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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 1987377-389. Zipes and
Wellens. Circulation. 1998212334-2351.
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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

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Scope of the Problem

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

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Sudden Death in HF

• Background
• Pathophysiology
• Clinical Management

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Alterations of Gross Structure Remodeling
Reentrant circuit
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Structure-Function-Metabolism Correlation
Bello, Kipper, Valderrabano, and Shivkumar. Heart
Rhythm. 2004.
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Alterations in Myocardial Microarchitecture

• Loss of myocytes
• Changes in cell-cell communication
• Discontinuous electrical propagation

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Sudden Death in HF

• Background
• Pathophysiology
• Clinical Management

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Antiarrhythmic Drugs or Conventional Therapy vs
ICDs
AVIDCASHCIDS
VT/VF Patients
MADIT CABG Patch
Post-MI Patients
CABG Patch SCD-HeFT MADIT 2
Heart Failure Patients
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Primary Prevention MADIT-II
Moss et al. N Engl J Med. 2002.
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SCD-HeFTMortality by Intention to Treat
HR 97.5CI P Value Amiodarone vs
Placebo 1.06 0.86, 1.30 0.529 ICD Therapy vs
Placebo 0.77 0.62, 0.96 0.007
0.4
0.3
Amiodarone Placebo ICD Therapy
Mortality
0.2
0.1
0
54
42
30
48
0
6
12
24
60
36
18
Months of follow-up
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Wide QRSProportional Mortality Increase
QRS Duration (msec)
Vesnarinone Study1(VEST study analysis)
100
90

• 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

90-120
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Cumulative Survival ()
120-170
170-220
70
220
60
0
60
120
180
240
300
360
Days in Trial
1 Gottipaty V, Krelis S, Lu F, et al. J Am Coll
Cardiol. 199933(2)145 Abstr847-4.
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CRT Trials
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Conclusion

• 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!