Atrial Fibrillation And Sudden Death In Hf K Shivkumar Md
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Atrial Fibrillation and Sudden Death in Heart 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
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 cardiomyopathy in 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 Transmembrane Potential (Millivolts)
50
Ito ICaL and ‘window’
0 INa Ikr, Ikur, Iksus Ik1 If
-50
-100
Threshold
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
Effect of Simvastatin and Antioxidant Vitamins on Atrial Fibrillation Due 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. 2004;110:2313-2319.
Pathophysiology of Atrial Fibrillation 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
Pathophysiology of Atrial Fibrillation in Heart Failure • Atrial Stretch – Stretch activated channels – Anionic currents
• Modulation by autonomic influences • Neurohumoral changes
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 and Experimental Data NORMAL ATRIUM + Trigger (preexisting heterogeneity)
AF (short duration)
REMODELING DISEASED ATRIUM + Trigger
PERMANENT Atrial Fibrillation
AF (variable duration)
(?Accentuation of preexisting heterogeneity) Shivkumar K and Weiss JN. Atrial fibrillation from cells to computers. Cardiovasc Res. 2001.
Atrial Fibrillation in 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 Fibrillation in 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
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.
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 Maintaining NSR ≥6 Months
CTAF Trial
N Engl J Med. 2000;342:913-920.
AFFIRM : Antiarrhythmic Drug Substudy
(n=106)
(P<0.01) (n=125) (n=116 )
J Am Coll Cardiol. 2003;42:20-29.
Diamond Study: Overall Survival Myocardial Infarction
Torp-Pedersen C et al. N Engl J Med. 1999;341:857-865.
Congestive Heart Failure
Odds Ratio for Total Mortality for Patients Treated 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 Fibrillation RSPV
LSPV
LIPV
RIPV
Cabrera et al. Circulation. 2002;106:968.
Evolving Strategy for Ablation of ‘Focal’ Atrial Fibrillation
ABLATION OF FOCUS UCLA Cardiac Arrhythmia Center.
ELECTRICAL ISOLATION
Who to Ablate? • Symptomatic drug-refractory atrial fibrillation • Drug intolerance • Tachycardia-induced cardiomyopathy
Catheter Ablation Focal Atrial Fibrillation: Results • Maintenance of sinus rhythm without drugs • Drug control of previously drug-refractory atrial fibrillation • Failure to have any impact on the arrhythmia
Catheter Ablation Focal Atrial Fibrillation: Results • 60-80%
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
Long-Term Survival After Ablation of the AV Node and Implantation of a Permanent Pacemaker
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.
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 Arrhythmias in 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
Structure-Function-Metabolism Correlation
Bello, Kipper, Valderrabano, and Shivkumar. Heart Rhythm. 2004.
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 Patients
AVID CASH CIDS
Post-MI Patients
MADIT CABG Patch
Heart Failure Patients
CABG Patch SCD-HeFT
Primary Prevention: MADIT-II
Moss et al. N Engl J Med. 2002.
SCD-HeFT Mortality by Intention to Treat HR
97.5%CI
P Value
1.06 0.77
0.86, 1.30 0.62, 0.96
0.529 0.007
0.4
Amiodarone vs Placebo ICD Therapy vs Placebo 0.3
Mortality
Amiodarone Placebo
0.2
ICD Therapy
0.1
0 0
6
12
18
24
30
36
Months of follow-up
42
48
54
60
Wide QRS: Proportional Mortality Increase Vesnarinone Study1 (VEST study analysis)
1
100 Cumulative Survival (%)
• 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
QRS Duration (msec)
90
<90 90-120
80
120-170 170-220
70
60 0
>220 60 120 180 240 300 360
Days in Trial
Gottipaty V, Krelis S, Lu F, et al. J Am Coll Cardiol. 1999;33(2):145 [Abstr847-4].
CRT Trials
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!
Director, UCLA Cardiac Arrhythmia Center & EP Program Division of Cardiology, Department of Medicine David Geffen School of Medicine at UCLA Los Angeles, California
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 cardiomyopathy in 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 Transmembrane Potential (Millivolts)
50
Ito ICaL and ‘window’
0 INa Ikr, Ikur, Iksus Ik1 If
-50
-100
Threshold
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
Effect of Simvastatin and Antioxidant Vitamins on Atrial Fibrillation Due 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. 2004;110:2313-2319.
Pathophysiology of Atrial Fibrillation 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
Pathophysiology of Atrial Fibrillation in Heart Failure • Atrial Stretch – Stretch activated channels – Anionic currents
• Modulation by autonomic influences • Neurohumoral changes
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 and Experimental Data NORMAL ATRIUM + Trigger (preexisting heterogeneity)
AF (short duration)
REMODELING DISEASED ATRIUM + Trigger
PERMANENT Atrial Fibrillation
AF (variable duration)
(?Accentuation of preexisting heterogeneity) Shivkumar K and Weiss JN. Atrial fibrillation from cells to computers. Cardiovasc Res. 2001.
Atrial Fibrillation in 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 Fibrillation in 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
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.
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 Maintaining NSR ≥6 Months
CTAF Trial
N Engl J Med. 2000;342:913-920.
AFFIRM : Antiarrhythmic Drug Substudy
(n=106)
(P<0.01) (n=125) (n=116 )
J Am Coll Cardiol. 2003;42:20-29.
Diamond Study: Overall Survival Myocardial Infarction
Torp-Pedersen C et al. N Engl J Med. 1999;341:857-865.
Congestive Heart Failure
Odds Ratio for Total Mortality for Patients Treated 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 Fibrillation RSPV
LSPV
LIPV
RIPV
Cabrera et al. Circulation. 2002;106:968.
Evolving Strategy for Ablation of ‘Focal’ Atrial Fibrillation
ABLATION OF FOCUS UCLA Cardiac Arrhythmia Center.
ELECTRICAL ISOLATION
Who to Ablate? • Symptomatic drug-refractory atrial fibrillation • Drug intolerance • Tachycardia-induced cardiomyopathy
Catheter Ablation Focal Atrial Fibrillation: Results • Maintenance of sinus rhythm without drugs • Drug control of previously drug-refractory atrial fibrillation • Failure to have any impact on the arrhythmia
Catheter Ablation Focal Atrial Fibrillation: Results • 60-80%
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
Long-Term Survival After Ablation of the AV Node and Implantation of a Permanent Pacemaker
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.
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 Arrhythmias in 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
Structure-Function-Metabolism Correlation
Bello, Kipper, Valderrabano, and Shivkumar. Heart Rhythm. 2004.
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 Patients
AVID CASH CIDS
Post-MI Patients
MADIT CABG Patch
Heart Failure Patients
CABG Patch SCD-HeFT
Primary Prevention: MADIT-II
Moss et al. N Engl J Med. 2002.
SCD-HeFT Mortality by Intention to Treat HR
97.5%CI
P Value
1.06 0.77
0.86, 1.30 0.62, 0.96
0.529 0.007
0.4
Amiodarone vs Placebo ICD Therapy vs Placebo 0.3
Mortality
Amiodarone Placebo
0.2
ICD Therapy
0.1
0 0
6
12
18
24
30
36
Months of follow-up
42
48
54
60
Wide QRS: Proportional Mortality Increase Vesnarinone Study1 (VEST study analysis)
1
100 Cumulative Survival (%)
• 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
QRS Duration (msec)
90
<90 90-120
80
120-170 170-220
70
60 0
>220 60 120 180 240 300 360
Days in Trial
Gottipaty V, Krelis S, Lu F, et al. J Am Coll Cardiol. 1999;33(2):145 [Abstr847-4].
CRT Trials
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!
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