Idea Transcript
Tachyarrhythmias in Structural Heart Disease
Philippine Kiès
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Tachyarrhythmias in Structural Heart Disease
PROEFSCHRIFT
This thesis was prepared at the Department of Cardiology of the Leiden University Medical Center, the Netherlands.
ter verkrijging van de graad van Doctor aan de Universiteit Leiden, op gezag van de Rector Magnificus Dr. D.D. Breimer, hoogleraar in de faculteit der Wiskunde en Natuurwetenschappen en die der Geneeskunde, volgens besluit van het College voor Promoties te verdedigen op donderdag 1 juni 2006 klokke 16.15 uur
door © P. Kiès. Leiden, the Netherlands, 2006 No parts of this publication may be reproduced, stored or transmitted in any form or by any means without prior permission of the author.
Cover: Printed by :
Bulls in Pamplona, Associated Press Uitgeverij Buijten & Schipperheijn
ISBN
90-9020728-7
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Philippine Kiès geboren te Ede in 1975
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Promotiecommissie Promotores:
Prof. Dr. M.J. Schalij Prof. Dr. E.E. van der Wall
Co-promotor:
Prof. Dr. J.J. Bax
Referent:
Prof. Dr. R.N.W. Hauer (Universitair Medisch Centrum Utrecht)
Overige leden:
Dr. R. Tukkie (Kennemer Gasthuis, Haarlem) Dr. K. Zeppenfeld Dr. M. Bootsma
Voor mijn ouders
Aan Diederik
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Table of Contents Chapter 1
General introduction
8
Part I Ventricular tachyarrhythmias
42
Determinants of Recurrent Ventricular Arrhythmia or Death in 300 Consecutive Patients with Ischemic Heart Disease Who Experienced Aborted Sudden Death: Data from the Leiden Out-of-Hospital Cardiac Arrest Study J Cardiovasc Electrophysiol 2005;16:1049-1056
44
Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy: Screening, Diagnosis and Treatment Heart Rhythm 2006; 3:225-234
64
Chapter 4
Serial Reevaluation for ARVD/C Is Indicated in Patients Presenting with Left Bundle Branch Block Ventricular Tachycardia and Minor ECG Abnormalities J Cardiovasc Electrophysiol 2006;17:1-8
86
Chapter 5
Identification of Successful Catheter Ablation Sites in Patients with Ventricular Tachycardia Based on Electrogram Characteristics During Sinus Rhythm Heart Rhythm 2005;2:940-950
104
Part II Cardiac resynchronization therapy & tachyarrhythmias
126
Chapter 6
Effect of Left Ventricular Remodeling After Cardiac Resynchronization Therapy on Frequency of Ventricular Arrhythmias Am J Cardiol 2004;94:130-132
128
Chapter 7
Effect of Cardiac Resynchronization Therapy on Inducibility of Ventricular Tachyarrhythmias in Cardiac Arrest Survivors With Either Ischemic or Idiopathic Dilated Cardiomyopathy Am J Cardiol 2005;95:1111-1114
138
Chapter 2
Chapter 3
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Chapter 8
Cardiac Resynchronization Therapy in Chronic Atrial Fibrillation: impact on left atrial size and reversal to sinus rhythm Heart 2006;92:490-494
150
Chapter 9
Comparison of Effectiveness of Cardiac Resynchronization Therapy in Patients With Versus Without Diabetes Mellitus Am J Cardiol 2005;96:108-111
164
Chapter 10 Summary and conclusions/ Samenvatting en conclusies
176
List of publications
188
Acknowledgements
192
Curriculum Vitae
196
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Chapter
1
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General introduction
Arrhythmias in Structural Heart Disease
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General Introduction
10
Cardiomyopathies
Dilated cardiomyopathy Dilated cardiomyopathy is the most frequent form of cardiomyopathy. Ischemic dilated cardiomyopathy, idiopathic dilated cardiomyopathy, dilated cardiomyopathy caused by hypertension and/or valvular disease are the most commonly observed phenotypes 4. Ischemic dilated cardiomyopathy is defined as: a dilated cardiomyopathy in a patient with a history of myocardial infarction or evidence of clinically significant (≥70% narrowing of a major epicardial artery) coronary artery disease resulting in remodelling of the left ventricle and ultimately in a decreased ejection fraction (as discussed below) 3. This may occur within 12-24 months in 15-40% of patients experiencing an anterior wall myocardial infarction and in a smaller percentage of patients experiencing an inferior wall infarction 5 6.
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A. Functional Classification of cardiomypathy 1. Dilated cardiomyopathy 2. Hypertrophic cardiomyopathy 3. Restrictive cardiomyopathy 4. Arrhythmogenic right ventricular cardiomyopathy 5. Unclassified cardiomyopathies
11
B. Specific cardiomyopathies 1. Ischemic cardiomyopathy 2. Valvular cardiomyopathy 3. Hypertensive cardiomyopathy 4. Inflammatory cardiomyopathy – Idiopathic – Autoimmune – Infectious 5. Metabolic cardiomyopathy – Endocrine – Familial storage diseases and infiltrations – Deficiency – Amyloid 6. General system disease – Connective tissue disorders – Infiltrations and granulomas 7. Muscular dystrophies 8. Neuromuscular disorders 9. Sensitivity and toxic reactions 10. Peripartal cardiomyopathy
The pathogenesis of idiopathic dilated cardiomyopathy is uncertain with speculations on familial and genetic factors, chronic viral infection or an abnormal immunological response7. The disease is diagnosed by exclusion of other known causes of cardiomyopathy. Idiopathic dilated cardiomyopathy is characterized by dilatation of all four chambers and presents between the ages of 20 and 50 years in most patients. Hypertensive dilated cardiomyopathy is diagnosed when myocardial systolic function is depressed out of proportion in response to the increased wall stress. Of note, hypertensive heart disease may also result in restrictive- and/ or an unclassified cardiomyopathy 2. Valvular cardiomyopathy occurs in the presence of a valvular abnormality (mostly mitral/aortic valve regurgitation) when the systolic function is depressed out of proportion to the increase in wall stress.
General introduction – Arrhythmias in Structural Heart Disease
Nomenclature Cardiomyopathy means “disease of the heart muscle”. The only currently used classification of cardiomyopathy was developed by the World Health Organization (WHO) and the International Society and Federation of Cardiology in 1980 and was revised in 1995 1 2. Originally the term cardiomyopathy was reserved for all forms of myocardial disease of unknown cause 1. In the 1995 classification the WHO committee left that paradigm since the etiology of many previously unknown types of heart muscle disease was elucidated and since many of the pathophysiological mechanisms resulting in myocardial dysfunction appeared to be quite similar in primary versus secondary cardiomyopathies. Therefore in the 1995 classification, cardiomyopathies are classified by the dominant pathophysiological mechanism or, whenever possible, by etiologic and/or pathogenetic factors (Table 1) 2 3. Dilated and restrictive cardiomyopathies are defined based on left ventricular dimension or volume. Hypertrophic – and arrhythmogenic right ventricular cardiomyopathies are mainly genetically based and have unique myocardial phenotypic features. The term ‘specific cardiomyopathies’ refers to secondary cardiomyopathies, i.e. those associated with known cardiac or systemic processes. ‘Unclassified cardiomyopathies’ encompass all types of heart muscle disorders not meeting criteria for other categories or display features of more than 1 category (e.g. peripartum cardiomyopathy)2.
WHO Classification
Chapter 1
Ventricular tachyarrhythmias are the major cause of sudden unexpected cardiac arrest. The percentage of patients who survive an out-of-hospital cardiac arrest is very small and the subsequent risk of recurrence very high. Ventricular tachyarrhythmias occur specifically in patients with structural heart disease. In general, all types of structural heart disease may lead to chronic heart failure, a severe condition with an additional vulnerability for atrialand ventricular tachyarrhythmias.
Table 1 World Health Organization Classifications of Cardiomyopathies (adapted from Richardson P, Circulation 1996;93:841-2)
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Figure 1
Diabetes mellitus
12 Hemostatic disorders
Micro angiopathy
Coronary Artery Disease
Myocardial fibrosis
Abnormal metabolism
Comorbidities
Diabetic cardiomyopathy
+
Hypertension Dislipidaemia
+
+
Heart Failure
In addition to the above mentioned causes of dilated cardiomyopathy, virtually all specific WHO classified cardiomyopathies are of the dilated phenotype (Table 1). Amongst those, especially diabetic cardiomyopathy is of progressive importance since the prevalence of diabetes mellitus, in particular type II diabetes, increased significantly. It is estimated that in 2025, 5.4% of all adults worldwide will suffer from type II diabetes 8. Ischemic heart disease and diabetes frequently go together, and consequently many patients will develop chronic heart failure. This may be the result of a number of morphological, metabolical and functional changes commonly found in diabetic patients (Figure 1) 9-11. This will be discussed in detail in chapter 9. Hypertrophic cardiomyopathy Hypertrophic cardiomyopathy is an inheritable autosomal dominant disorder of the heart muscle, characterized by a small left ventricular cavity, myofibril disarray and often marked hypertrophy of the myocardium. The pathophysiological consequences may consist of dynamic left ventricular outflow tract obstruction, mitral regurgitation, diastolic dysfunction and myocardial ischemia. Moreover, patients with hypertrophic cardiomyopathy are prone to both atrial- and (malignant) ventricular arrhythmias. Hypertrophic cardiomyopathy is therefore the most common cause of sudden cardiac death in young people, including trained athletes12. Furthermore, patients may present with severe limiting symptoms of dyspnea, angina or syncope but may as well remain asymptomatic throughout life 13 14. The prevalence is approximately 1:500 to 1:1000 persons.15.
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Arrhythmogenic right ventricular cardiomyopathy Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an unusual cardiomyopathy that predominantly, but not exclusively, affects the right ventricle. ARVD/C is characterized pathologically by fibrofatty replacement and electrical instability of the right ventricular myocardium 19. The disease usually presents between the second and fourth decade of life and is often familial with an autosomal (dominant and recessive) inheritance 20 . Clinical manifestations include structural and functional malformations (fibrofatty infiltration, dilatation, aneurysms) of the right ventricle, electrocardiographic abnormalities, presentation with ventricular tachycardia and even sudden cardiac death 21 (see chapter 3). Because of the strong association with sudden death in young adults it is of extreme importance to optimize diagnostic accuracy, which will be discussed in chapter 4. In general, all types of cardiomyopathy may trigger the onset of the ‘chronic heart failure syndrome’. However, dilated cardiomyopathies (both primary and secondary) are the most important cause 22.
Heart Failure Epidemiology Currently an estimated 6.5 million patients in Europe and 5 million patients in the United States of America suffer from heart failure related symptoms. These already extreme numbers are expected to rise dramatically over the next few decades, with an estimated growth of the heart failure population of 290.000 patients per year 23. This growth is the result of the aging of the global population and the increasing availability of effective treatment strategies improving the survival in patients with acute coronary syndromes 24 25. The incidence of heart failure in Europe alone is estimated at 580.000 patients yearly, the yearly mortality is estimated at 50% of the annual incidence 23. However, the true incidence is uncertain as the number of population studies, including repeated assessment for the presence of heart failure in a given sample, is relatively small 26-28. In the Framingham study the incidence was noted to increase steeply with age, approximately doubling with each
13 General introduction – Arrhythmias in Structural Heart Disease
Endothelial dysfunction
Chapter 1
Potential mechanism linking diabetes mellitus to heart failure Diabetes mellitus is associated with multiple pathophysiological changes in the cardiovascular system. The consequences of (a higher risk of) coronary artery disease – due to endothelial dysfunction and haemostatic disorders – aggravated by the existence of diabetic cardiomyopathy – due to microangiopathy, myocardial fibrosis and abnormal myocardial metabolism – and the, with diabetes associated, comorbidities – dyslipidaemia and hypertension – may induce a more potent, progressive form of heart failure in diabetics. (adapted from Bauters, Cardiovascular Diabetology 2003;2:1-16)
Restrictive cardiomyopathy Restrictive cardiomyopathy is either an idiopathic or systemic myocardial disorder characterized by restrictive filling of the ventricles, reduced (or normal) left ventricular and right ventricular volumes and normal or nearly normal systolic (left ventricular and right ventricular) function. Abnormal ventricular diastolic compliance and impaired ventricular filling may lead to congestion and elevated diastolic- and pulmonary venous pressure as the major clinical manifestations 16. The clinical differentiation of restrictive cardiomyopathy from constrictive pericarditis is laborious 17. Involvement of the (endo)myocardium may be non-infiltrative or infiltrative (interstitial: e.g. amyloidosis, sarcoidosis /cellular:hemochromatosis) and occurs with or without ventricular obliteration 18.
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Figure 2 Incidence of cardiac failure by age and sex: 36-year follow-up Framingham study (Adapted from Kannel WB, Current Cardiol Reports 1999,I:11-19)
men
31
30
28 Rate per 1000:
25 20
Age
Men Women
35-64
3
2
65-94
11
9
17 13
15 9
10 5 5 1
6
3
2
0
45-54
55-64
65-74
75-84
85-94
Age
29
decade (Figure 2) . Chronic heart failure is a major health care problem and one of the most frequent reasons for patients to be admitted to the hospital30. In the 1990’s 5% of all adult general medicine and geriatric hospitalizations were heart failure related. In the United States of America heart failure continues to be the most common cause of hospitalizations in people over the age of 65 years 31. Heart failure is reported to consume 1-2% of health care expenditure in industrialized countries32. Pathophysiology The pathophysiological concept of heart failure has changed over time. The hemodynamic model which served from the 1950s through the 1980s has largely been abandoned due to new insights gained from numerous clinical trials conducted over the last 20 years. The pathophysiology of heart failure is exceedingly complex and not fully understood. The contemporary working hypothesis is based on a neuro-humoral model representing a cascade of changes following an index event. In summary, this ‘index’ event results in loss of myocardium (e.g. myocardial infarction) or excessive overload (e.g. valvular heart disease or hypertension). In response to an increased load (due to loss of myocytes/increased pressure) myocardial hypertrophy occurs 33-35 . When hypertrophy cannot sustain the increased load, ventricular dilatation occurs and the ventricle assumes a more globular shape (i.e. eccentric hypertrophy=increase in myocardial mass with only minimal increase in wall-thickness, accomplished by an elongation of the cardiac myocytes) through which the stroke volume remains intact despite
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Figure 3 Possible mechanism by which overloading can cause progressive deterioration of the heart In response to increased load (due to loss of myocytes/increased pressure) myocardial hypertrophy and subsequent elongation occurs (to normalize the load per cell) both accelerating remodeling. The same growth response simultaneously activates signal transduction systems that cause programmed cell death (apoptosis). The increased wall tension together with the overload itself increases cardiac energy expenditure that in the overloaded heart can accelerate myocyte necrosis. Reduced cardiac output activates neurohumoral responses which by increasing afterload and B-adrenergic stimulation of the heart also increase cardiac energy expenditure. In addition many mediators of the neurohumoral response promote myocardial cell growth as well and thus also accelerate remodeling. (Adapted from Hurst, the Heart, 11th ed., page 706).
Heart disease Cardiac output ↓ ↑ Load, Stretch
Myocardial growth response ↑ Myocardial hypertrophy Cell elongation
↑ Load, Stretch
Neurohumoral activation
Apoptosis
15 General introduction – Arrhythmias in Structural Heart Disease
Average annual incidence per 1000
14
women
Chapter 1
35
a reduced ejection fraction (left ventricular remodeling) 36. However, this provides only a short-term benefit. Simultaneously, neuroendocrine activation occurs in response to the need to protect perfusion pressure and circulating volume. Neurohormones also facilitate the left ventricular remodeling process and have a significant contribution to the pathogenesis and progression of heart failure related symptoms. Within this simplified model many processes take place. Ventricular remodeling first consists of cellular remodeling: myocyte hypertrophy, adding sarcomeres in parallel and lateral thickening of the myocyte. When distending forces become chronic the addition of sarcomeres also occurs in series. Excessive stretch of myocytes can lead to cell death by apoptosis 37 38 (Figure 3). Subsequent myocardial fibrosis, myocyte slippage (dissolution of the collagen struts holding the individual myocytes together) and growth of the interstitial matrix eventually lead to the changes in left ventricular size and shape 39-41. Increased cardiac mass and increased stiffness of the different compartments are the result of the combination of reactive fibrosis and myocyte hypertrophy, along with the altered cytoskeletal structure within the cardiomyocyte 42 43. Besides the process of hypertrophy and
Cardiac energy expenditure ↑ Myocyte necrosis
Myocardial cell death
Remodeling
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Figure 4
Left ventricular dysfunction
Cardiac output ↓
16
Renin-angiotensin system ↑ Increased after-load
Cytokine activation
Vasoconstriction Salt & water retention
fibrosis, the left ventricle also shows a more spherical shape after injury (e.g. myocardial infarction) as a result of increased wall stress, abnormal distribution of fiber shortening and dilatation of the mitral annulus with subsequent mitral regurgitation. In addition to these mechanical aspects, neuroendocrine factors (including angiotensin II, norepinephrine and endothelin) and cytokines (such as tumor necrosis factor-α) are associated with an increase in myocyte size and cardiac hypertrophy 44-47. These neuroendocrine factors are released in order to compensate for myocardial dysfunction 48 (Figure 4). Finally, left ventricular dysfunction progresses even more due to a diminished myocyte contractility following changes in cellular calcium metabolism and structural changes in contractile proteins due to changes in gene expression 49. Clinical implications Impaired cardiac contractility and/or ventricular remodeling are not necessarily directly associated with clinical signs of heart failure. The clinical symptoms appear to be related to compensatory mechanisms such as an activated renin-angiotensin system, increased sympathetic tone and possibly to activation of cytokines 50. As a result of these mechanisms the failing heart has a greater metabolic need and a predisposition to myocardial ischemia. In addition, these activated compensatory mechanisms may exert direct toxic effects on myocardial cells and may exert adverse electrophysiological effects provoking life-threatening ventricular arrhythmias 51.
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Table 2 Causes of sudden cardiac death in heart failure (Adapted from Crawford Cardiology) Causes of sudden cardiac death in heart failure Arrythmia
Underlying condition
Ventricular tachycardia / Ventricular fibrillation
Myocardial ischemia/infarction Myocardial fibrosis/scar Bundle-branch re-entry Electrolyte disturbances (hyper-/ hypokalemia) Drug-related proarrhythmia (torsades de pointes)
Bradyarrhythmia / Asystole
Myocardial ischemia/infarction/rupture Pulmonary emboli Embolic stroke Drug toxicity Sinus node or conduction system disease
Electromechanical dissociation
Myocardial ischemia Pulmonary emboli
17 General introduction – Arrhythmias in Structural Heart Disease
Sympathetic tone ↑
Increased pre -load
Modes of death in heart failure Heart failure generally leads to death by either 1 of 2 mechanisms: sudden death or death from progressive heart failure 58 59. The relative proportion of patients dying from these two mechanisms varies with severity of heart failure. Patients with mild symptoms of heart failure most commonly die suddenly. A sudden cardiac arrest is most often caused by malignant ventricular arrhythmias although vascular events (myocardial infarction, stroke) and/or thrombo-embolic events may also cause a sudden death (Table 2) 58-60. The percentage of patients who survive an out-of-hospital cardiac arrest is very small (6%) 61 62 and the subsequent risk of a recurrence is very high 63 64. The magnitude of this problem resulted in a growing interest in identifying different patient populations who will benefit most from different therapeutic approaches (chapter 2). In contrast, patients who survive
Chapter 1
Vicious cycle by which activation of the neurohumoral axis exerts unfavorable long-term effects Impaired cardiac output activates the sympathetic nervous system, the rennin-angiotensin system, cytokines and other neurohumoral factors to maintain systemic blood pressure. However increased systemic vascular resistance, sodium and water retention and the direct cardiac effects of these factors have adverse long-term implications (Adapted from Crawford Cardiology, page 5/1.10)
Prognosis The long-term prognosis associated with chronic heart failure is still poor despite improvements in treatment strategies 52. In the Framingham study, from 1948 to 1988 the median survival time after diagnosis was 1.7 years in men and 3.2 years in women. Five years after diagnosis, only 25% of men and 38% of women remained alive. This mortality rate was four to eight times the general population 53. After 1998, new drug regimens resulted only in a modest improvement in survival 54. It is now estimated that 50% of all patients with chronic heart failure will die within 4 years after diagnosis, whereas of those diagnosed with severe chronic heart failure, more than 50% will die within 1 year 55-57.
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Figure 5 Severity of heart failure and mode of death Data from the MERIT-HF study 183 showed that with a more progressive stage in heart failure relatively more patients died from progressive pump failure than from sudden cardiac death (SCD).
NYHA II 12%% 12
18
NYHA III
26%
NYHA IV
56%
SCD CHF
64%
33%
59%
Other n = 232
n = 27
MERIT -HF Study Group, The Lancet 1999; 353:2001-07
Figure 6 The action potential The action potential is classically divided into five phases. Phase 0 is the depolarization phase, opening of the rapid sodium channels causing a rapid sodium inward current. The repolarization phase corresponds roughly to phase 1 trough 3. Phase 1 is the first phase of the repolarization consisting of a rapid outward current of potassium ions (Ito = transient outward current). Phase 2 is the plateau phase (equilibrium between in-and outward current) consisting of calcium influx through L-type and T-type Ca channels and potassium efflux (Ik = delayed rectifier). Phase 3 The third phase of potassium efflux (IK1=Inward rectifying current) contributes to the terminal phase of repolarization and maintains the resting membrane potential through continuous ion leakage during Phase 4, the resting phase.
Figure 7 Re-entry may occur if there is block of antegrade conduction in parts of myocardial tissue (unidirectional block, A), so the impulse may not be able to enter this zone. An appropriately timed impulse may conduct antegradely one way (B) and retrogradely the other (antegradely blocked, C) way.
to the advanced stages of heart failure predominantly die from progressive heart failure (i.e. a gradual loss of ventricular function that leads to inadequate systemic perfusion and death) (Figure 5) 59 65 66. Ventricular Arrhythmias in heart failure Regardless of the underlying cause, prolongation of the action potential is the pathofysiological feature of cells and tissues isolated from failing hearts 67 68. Alteration in the func-
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19 General introduction – Arrhythmias in Structural Heart Disease
n = 163
Chapter 1
MERIT -HF
tional expression of ion channels and transporters (specifically down-regulation of the Ito and Ik –currents Figure 6) may result in spatially and temporarily unstable repolarization predisposing to for example afterdepolarization-mediated triggered activity. After-depolarizations occur during phase 3 and early phase 4 of the transmembrane potential before repolarization is completed (early after-depolarizations) or after repolarization is completed (delayed after-depolarizations). These depolarizations may give rise to premature action potentials or even trains of potentials, which have been referred to as triggered activity. The reason for occurrence of delayed afterdepolarizations seems to be abnormal calciumhandling (activation of Na/Ca exchanger leading to transient inward current) by the sarcoplasmatic reticulum triggered by rapid rhythms and elevated levels of catecholamines in heart failure69. Because numerous patients with heart failure have a history of coronary artery disease or cardiomyopathic disease with subsequent healing, fibrosis and remodeling, re-entrant mechanisms contribute significantly to the occurrence of arrhythmias in this patient population. Unidirectional conduction block and a zone of slow conduction are essential for reentry to occur (Figure 7) 70. In ischemic cardiomyopathy sustained monomorphic ventricular tachycardia generally arises from surviving myocytes within extensive areas of infarction (anatomical substrate for reentry) 71 72. Even though normal sodium dependent action potentials are recorded from these surviving myocytes in the border zone after infarct healing there may be conduction delay. This conduction delay is a result of the altered myocardial architecture (invasion of fibrosis), abnormal gap junction distribution and function and an increased path length 72 73 74. Extracellular recordings during sinus rhythm from sites of ventricular tachycardia origin therefore demonstrate low-amplitude,
A B
C
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Table 3 Underlying mechanisms of tachy-arrhythmias in heart failure (adapted from Kjekshus J, AJC 1990;65:42I-48I).
Figure 8
Basic mechanisms
Reentrant activity Enhanced automaticity Delayed after depolarizations
Myocardial substrates
Scar tissue Aneurysm Hypertrophy Ventricular dilatation Ventricular dysfunction
Modulating factors
Myocardial ischemia Electrolyte deficits Myocardial release of cathecholamines Sympaticoadrenergic activation Myocardial stretch Antiarrhythmic drugs Inotropic drugs Diuretics
Prevalence of atrial fibrillation in several major heart failure trials 1 = Studies of Left Ventricular Dysfunction (SOLVD) Prevention184; 2 = Studies of Left Ventricular Dysfunction (SOLVD) Treatment 185 186; 3 = Vasodilator in Heart Failure Trial (V-HeFT)187; 4 = Congestive Heart Failure Survival Trial of Antiarrhythmic Therapy (CHF-STAT) 188; 5 = Danish Investigations of Arrhythmia and Mortality on Dofetilide Congestive Heart Failure study (DIAMOND CHF)189; 6 = Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina (GESICA)190; 7 = Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS)191. Adapted from Maisel, Am J Cardiol 2003;91 (suppl):2D-8D
Prevalence of Atrial Fibrillation (%)
Arrhythmias in heart failure
Atrial fibrillation in heart failure Atrial fibrillation and heart failure frequently co-exist. The prevalence of atrial fibrillation increases as the severity of heart failure increases (Figure 8). The pathophysiological changes occurring in patients with heart failure and atrial fibrillation are complex and incompletely understood. The hemodynamic and neurohumoral changes as well as the cellular and extra-cellular remodeling occurring in heart failure patients may alter atrial refractory periods, increase automaticity and triggered activity and may promote extra-cellular matrix fibrosis83.The onset of atrial fibrillation and thus the loss of atrio-ventricular synchronicity results in impaired diastolic filling, reduced stroke volume, increased mean diastolic atrial pressure and an approximately 20% reduction in cardiac output 83-85. Thereby contributing to worsening heart failure symptoms.
60 49,8 50
21 General introduction – Arrhythmias in Structural Heart Disease
cells) is likely to cause ectopic beats or even tachycardia. During ischemia, conduction may be depressed thereby further increasing the risk of unidirectional block to occur and the induction of a reentrant arrhythmia 79. Despite the differences in the underlying arrhythmogenic mechanisms the risk of a fatal ventricular arrhythmia is similar for patients with ischemic and non-ischemic causes of heart failure 80-82. This may be explained by the fact that the changes in electrophysiological milieu accompanying chronic heart failure occur irrespective of the underlying etiology.
Chapter 1
20
prolonged multi-component potentials 75. In arrhythmogenic right ventricular cardiomyopathy the arrhythmia mechanism arises from the development of marked fibrofatty infiltration. Anatomical reentry causes ventricular tachycardia, also based on the phenomenon of viable myocytes embedded in fibrofatty tissue having poor intercellular communications 76 . No single mechanism, but multiple factors contribute to the arrhythmogenicity in idiopathic dilated cardiomyopathy. Subendocardial scarring and multiple patchy areas of fibrosis may act as sites for reentry. In addition, in more advanced stages of heart failure, the electrophysiological milieu changes through several mechanisms serving as modulating factors (Table 3). The presence of elevated circulating catecholamines (heterogeneity within the myocardium), electrolyte abnormalities (hypokalemia and hypomagnesemia), ventricular hypertrophy (depression of resting membrane potential, reduction in cell-tocell coupling, interstitial fibrosis) 77 and ventricular dilatation (mechano-electrical feedback = stretch-activated ion channels lead to shortening of the action potential and refractoriness 78) in these heart failure patients may lead to an appropriate precondition for arrhythmias to occur. Finally, acute transient myocardial ischemia may emerge frequently in heart failure patients. Enhanced automaticity (the automaticity of myocardial tissue is greater than that of pacemaker cells, therefore becoming the leading focus of impulse formation) originating from cells with reduced resting membrane potentials (e.g. through reduced Ik1 in ischemic
7
40 30
28,9
25,8
6 5
20 10 0
15,4
14,4 10,1
3
4
2
4,2 1
I
II-III
III-IV
IV
New York Heart Association Functional Class
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Management of arrhythmias in cardiomyopathies
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Radiofrequency catheter ablation Drug treatment is often ineffective and implantable cardioverter defibrillators can terminate ventricular tachycardia, but cannot prevent them. Radiofrequency (RF) catheter ablation is the only antiarrhythmic therapy (with the exception of the above mentioned surgical techniques) that can potentially cure patients with drug-refractory incessant ventricular tachycardia or patients with frequently recurring ventricular tachycardia 104-106. The efficacy and safety of this technique depend on the particular type of tachycardia and its likely origin. These factors can be predicted from the underlying heart disease and the electrocardiographic characteristics of the tachycardia. The majority of sustained monomorphic ventricular tachycardia are caused by reentry involving a region of ventricular scar. The scar is most commonly caused by an old myocardial infarction but for example arrhythmogenic right ventricular cadiomyopathy can also cause scar-related reentry. Dense fibrotic scar creates areas of anatomic conduction block and fibrosis between surviving myocyte
23 General introduction – Arrhythmias in Structural Heart Disease
Amiodarone is a unique antiarrhythmic agent that blocks cardiac sodium, potassium and calcium currents and has an antiadrenergic effect (Class I, II, III and IV effects). It is an effective anti-ischemic agent, has only limited hemodynamic effects, and the use of amiodarone is associated with a low incidence of ventricular proarrhythmia. Given these characteristics amiodarone has been tested in several clinical settings. First amiodarone has been tested in post myocardial infarction patients. The European Myocardial Infarction Amiodarone (EMIAT) and the Canadian Amiodarone Myocadial Infarction Arrhythmia (CAMIAT) Trials assessed the effects of amiodarone on mortality and sudden cardiac death in patients after myocardial infarction having left ventricular dysfunction (EMIAT) or frequent ventricular ectopy (CAMIAT) 87 88. Patients enrolled in each study were randomly assigned to treatment with amiodarone or placebo. Both studies reported significant reductions in resuscitated ventricular fibrillation and cardiac death in the amiodarone treated groups compared with the placebo treated patients. Amiodarone, however, did not have a favorable impact on all-cause mortality. This discrepancy was confirmed by 2 meta-analyses 89 90. Next the impact of amiodarone on mortality in patients with heart failure has been studied. The Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina (GESICA) trial reported a 28% reduction in mortality in patients with mostly non-ischemic cardiomyopathy, receiving amiodarone versus patients who received placebo 91. In contrast, the Congestive Heart Failure Survival Trial Antiarrhythmic Therapy (CHF-STAT) trial failed to demonstrate a difference in mortality between amiodarone versus placebo treated patients 92. However more patients with ischemic heart disease were enrolled in the CHF-STAT study than in the GESICA trial. Subgroup analysis of patients with coronary artery disease indeed confirmed no survival benefit of amiodarone in this group compared to placebo. In contrast, there was a trend towards a mortality reduction in the non-ischemic
Surgery The first reported surgical intervention for the management of cardiac arrhythmias dates back to 1959 when Couch excised a left ventricular aneurysm in a patient who had ventricular tachycardia 95. Since then, the surgical management of ventricular tachycardia has gone through several phases, sympathectomy, aneurysmectomy accompanied by coronary revascularization and encircling endocardial ventriculotomy 96-98. None of these procedures resulted in more than a limited success. With the initiation of programmed stimulation and mapping techniques, directed, mapping-guided ventricular tachycardia surgery has become the most important surgical approach. Antiarrhythmic surgery can be considered in ischemic cardiomyopathy patients with ventricular tachycardia and an indication for revascularization/ aneurysm resection/ mitral valve surgery 99-102. In a series of 289 patients who underwent surgical subendocardial resection for refractory ventricular tachycardia due to coronary disease, the operative mortality rate was 15%. Approximately 93% of patients who survived the procedure remained free of clinical ventricular tachycardia and 60-70% of patients did not require suppressive antiarrhythmic therapy 103.
Chapter 1
22
Antiarrhythmic drug therapy The role of antiarrhythmic drug therapy in the prevention of sudden cardiac arrest has changed considerably since their evaluation in placebo-controlled trials. The Cardiac Arrhythmia Suppression Trial (CAST) is placebo-controlled evaluating the effect of antiarrhythmic therapy (encainide, flecainide, or moricizine) in patients with asymptomatic or mildly symptomatic ventricular arrhythmia (six or more ventricular premature beats per hour) after myocardial infarction 86. Despite the positive effects of the class Ic drugs on the original ventricular arrhythma 9.5% of the treated patients suffered from a sudden cardiac death versus only 3.6% in the placebo arm. The reason for the excess mortality was contributed to the pro-arrhythmogenic effect of the used class Ic antiarrhythmic drugs. Since the CAST study, there is no role for class Ic antiarrhythmic drugs in the prevention of sudden cardiac arrest (and also the use of these drugs in patients with atrial fibrillation with a low ejection fraction should be discouraged).
cardiomyopathy group. Thus, on the one hand, the lack of a proarrhythmogenic effect supports the use of amiodarone in the setting of heart failure or coronary artery disease if needed to suppress symptomatic arrhythmias (atrial fibrillation/nonsustained ventricular tachycardia) 93. In addition, prophylactic amiodarone results in an overall reduction of 13% in total mortality in high risk patients with recent myocardial infarction or heart failure 89. On the other hand, a correlation between amiodarone treatment and increased non-arrhythmic mortality in patients with heart failure and depressed left ventricular function has been reported by others94. This may be the result of an amiodarone induced delayed ventricular activation resulting in increased left ventricular dyssynchrony and depressed LV function 94 (see also chapter 2).
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Representation of a double-loop (figure-eight) circuit consisting of a central common pathway and two outer loops. Depolarization of the common pathway occurs during diastole. The QRS onset after the wavefront emerges from the exit. It returns to the common pathway by propagating through outer loops (see also text).
Outer Loop
Common Pathway
Exit Site
Entrance Site
Outer Loop
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Scar
Implantable Cardioverter Defibrillator therapy In 1980 Mirowski introduced the implantable cardioverter defibrillator (ICD)114. Although the ability of an ICD to convert ventricular arrhythmias was demonstrated, it was controversial whether this implied a meaningful increase in the patient’s life expectancy. Consequently, several randomized trials were initiated. A first randomized study of 60 patients by Wever et al, demonstrated a significant survival benefit for ICD implantation versus antiarrhythmic drugs in postinfarct sudden death survivors115. The, Cardiac Arrest Study Hamburg (CASH) trial was the first large-scale randomized controlled study comparing the effect of antiarrhythmic drugs versus ICD therapy on all-cause mortality in sudden cardiac death survivors116. The antiarrhythmic drugs used in the CASH trial were metoprolol, amiodarone and propafenone (the latter was stopped early due to high mortality rates). After follow-up (≥ 2 years, mean 57±34 months) a 23% reduction in all cause mortality and a 61% reduction in arrhythmic death rate was reported in the ICD treated patients compared to the amiodarone/metoprolol treated group. However this mortality reduction was statistically not significant. Similarly the Canadian Implantable Defibrillator Study (CIDS) comparing amiodarone with ICD in survivors of sudden cardiac arrest or hemodynamically unstable ventricular arrhythmias117, reported a statistically non-significant 20% relative risk reduction in all-cause mortality and 33% relative risk reduction in arrhythmic death. The Antiarrhythmics versus Implantable Defibrillators (AVID) trial was the first largescale randomized study confirming a significant survival benefit for ICD therapy versus antiarrhythmic drug therapy (mainly amiodarone). The patients included in this study were survivors of sudden cardiac arrest due to ventricular arrhythmias or unstable ventricular tachycardia with an ejection fraction < 40% 118. As shown by a meta-analysis of CASH, CIDS and AVID ICD therapy results in a 28% mortality reduction in survivors of hemodynamically unstable ventricular tachycardia or cardiac arrest119. Additionally, subgroup analysis of these studies showed that improved survival with the ICD was primarily achieved in patients with an ejection fraction 70% in postinfarction patients 107 108 109. However, identification of the critical isthmus by activation mapping is time-consuming and is often complicated by the frequent presence of multiple potential reentry circuits. The presence of multiple morphologies and/or hemodynamically unstable ventricular tachycardia basically precludes the application of the conventional mapping techniques. Therefore, alternative mapping techniques are explored. One approach in-
Next, a series of trials investigated the prophylactic role of the ICD in postinfarction patients. The Multicenter Automatic Defibrillator Implantation Trial (MADIT) enrolled patients after myocardial infarction with an ejection fraction < 35%, non-sustained ventricu-
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Finally, also combined cardiomyopathy trials have been perfomed. The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) recently reported a positive effect of ICD therapy in both ischemic and non-ischemic heart failure patients. 128. Patients with a low ventricular ejection fraction (10/hour) or non-sustained ventricular tachycardia to medical therapy versus ICD treatment 126. The total mortality in the ICD arm was 34% lower at 2 years follow-up, which approached but did not reach statistical significance. The cardiomyopathy trial (CAT) did not provide evidence in favor of prophylactic ICD implantation in idiopathic dilated cardiomyopathy either. Most probably, due to the small number of patients enrolled in the study and the very low overall mortality as well. This study.enrolled 104 patients with recent onset (≤ 9 months) of idiopathic dilated cardiomyopathy and an
ejection fraction ≤ 30%. After a mean follow-up of 5.5±2.2 years 30 deaths had occurred, 13/50 in the ICD group versus 17/54 in the control group127.
Chapter 1
26
lar tachycardia and inducible sustained ventricular tachycardia (not suppressible by class I drug)121. Patients were randomized to an ICD or conventional therapy (80% amiodarone, 11% class I antiarrhythmic drugs). During an average follow-up of 27 months, the risk of death was reduced by 54% in the ICD arm. MADIT was the first to show that selected high risk patients could derive survival benefit from ICD therapy analogous to cardiac arrest survivors. The second primary prevention trial, the Multicenter Unsustained Tachycardia Trial (MUSTT) was conducted in patients with similar characteristics to the MADIT study 122 . The purpose of this trial was to assess the ability of antiarrhythmic therapy guided by electrophysiological studies to improve survival. Patients were randomized into 2 groups, maximal conservative therapy versus maximal conservative therapy plus antiarrhythmic therapy. Antiarrhythmic drugs were tested first during an electrophysiological study, patients who failed to respond to drugs received an ICD. Over a 5-year follow-up, the patients randomized to antiarrhythmic therapy experienced a 27% lower risk for arrhythmic death or cardiac arrest compared to the maximal conservative treated group. The improved survival in the antiarrhythmic therapy arm was however entirely due to ICD therapy 123. The event rate in patients treated with antiarrhythmic drugs was similar as the event rate in the maximal conservative treated control patients. Seeking to broaden the applicability of prophylactic ICD treatment, the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) enrolled patients with prior myocardial infarction and an ejection fraction ≤30% (without requiring an inducible ventricular tachycardia)124. Again ICD therapy resulted in a 31% mortality reduction (compared to the conventional therapy arm). Thus even in the absence of symptomatic ventricular arrhythmias, implantation of an ICD improves survival in ischemic cardiomyopathy patients with an ejection fraction ≤30%.
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Since then, nearly 5000 patients have been evaluated in a randomized setting (Table 4). These randomized trials demonstrated statistically significant improvements in quality of life, NYHA functional class ranking, exercise capacity, left ventricular systolic performance and left ventricular reverse remodeling144 146 161 174-180. The MUltisite Stimulation In Cardiomyopathy (MUSTIC) trial174 was the first randomized, controlled trial in which the trans-
Table 4 Landmark randomized controlled trials of cardiac resynchronization therapy in heart failure Study MIRACLE144
Study design
No of randomized patients
NYHA class
Rhythm
ICD
Parallel-arm
524
III, IV
SR
No
174
Crossover
58
III
SR
No
161
Crossover
43
III
AF
No
MUSTIC SR MUSTIC AF
146 175
PATH CHF
Crossover
42
III, IV
SR
No
CONTAK CD 176
Crossover & Parallel-arm
581
III, IV
SR
Yes
MIRACLE ICD177
Parallel-arm
362
III, IV
SR
Yes
Crossover
89
III, IV
SR
No
Parallel-arm
1520
III, IV
SR
No
178
PATH CHF II
179
COMPANION
180
MIRACLE ICD II CARE HF181
Parallel-arm
186
II
SR
Yes
800
III, IV
SR
No
29 General introduction – Arrhythmias in Structural Heart Disease
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Clinical trials on resynchronization therapy Numerous observational studies and a series of randomized controlled trials have been completed, demonstrating the safety, efficacy and the long-term beneficial effects of CRT in patients with chronic systolic heart failure and ventricular dyssynchrony. Early observational studies supported the concept of resynchronization therapy by demonstrating acute and chronic improvements in hemodynamics, echocardiographic measures, cardiac performance and functional status163-173. One of these early observational studies was the InSync trial173; a prospective nonrandomized trial of CRT for moderate to severe heart failure. The primary objective of the InSync Trial was to evaluate the safety and effectiveness of CRT in these patients. In this trial a significant improvement in quality of life, New York Heart Association class ranking and exercise capacity as determined by 6-minute hall walk distance was established. The results of this trial encouraged the initiation of randomized controlled trials to evaluate CRT as a treatment of chronic heart failure.
Chapter 1
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the internal shuffle of blood from the early-activated region to the late-activated (lateral) region. Secondly, the late stretch of the contracting muscle can break cross-bridges, diminishing systolic force development. Additionally, this may result in repolarization inhomogeneity and stretch-activated calcium channel stimulation. Both predisposing to the initiation of life threatening arrhythmias134-136. Next, inhomogeneous contraction results in delayed muscle relaxation which may also contribute to diastolic dysfunction137. Moreover, with ventricular dyssynchrony, mitral valve closure might not be complete because atrial contraction is not followed by a properly timed ventricular systole 138 139. Globally, the effect of resynchronization is immediate140. However, there is increasing evidence that CRT is also accompanied by more chronic adaptations such as an improved neurohormonal milieu, a restored autonomic balance and an improved heart rate variability 141-143. Overall, in large randomized clinical trials, CRT has been shown to improve New York Heart Association functional class, quality of life and exercise capacity 144 145 146 as well as LV systolic performance 147 148 in New York Heart Association class III and IV patients with a wide QRS complex and low left ventricular ejection fraction (see below). In addition, CRT resulted in a significant decrease in morbidity, expressed as hospitalization rate/duration for decompensated heart failure and a 51% relative reduction in death from progressive heart failure as compared to optimized medical therapy 149. Finally, CRT resulted in significant left ventricular reverse remodeling150 151. The effect of CRT on ventricular arrhythmias is currently unknown 152. Since the patient population eligible for CRT is at an increased risk of sudden cardiac death due to ventricular tachy-arrhythmias153(see above), knowledge of potential effects of CRT on arrhythmogenicity is of major importance. Fish et al154described an increased QT interval and increased transmural dispersion of repolarization as a result of reversal of the direction of activation of the left ventricular wall, as it occurs during CRT. The increased transmural dispersion of repolarization created the substrate for the development of torsade de pointes under long-QT conditions. These experimental data were derived from a computer model simulating transmural conduction and from arterially perfused canine hearts. All clinical studies however (although with only small numbers of patients) suggest a reduction in ventricular arrhythmogenicity after CRT152 155-159. 155-157It may be hypothesized that the reverse remodeling reduces left ventricular wall stress and therefore may result in less ventricular arrhythmias. This is further discussed in chapter 6 and 7. The same issue counts for atrial fibrillation. Several studies have demonstrated that CRT can be beneficial in heart failure patients with concomitant atrial fibrillation in terms of improved symptoms, exercise capacity, systolic left ventricular function and survival.145 160162 However, minimal data exist on the impact of long-term CRT on left atrial and/or left ventricular reverse remodeling and the relation to a possible reversal to sinus rhythm. This issue was studied in chapter 8.
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Conclusion In general, all types of cardiomyopathy may trigger the onset of the chronic heart failure syndrome. Heart failure is a severe pathophysiological state with a poor prognosis. Fifty % of the patients diagnosed with heart failure die within 5 years after diagnosis as a result of either sudden death or death from progressive heart failure. Before, primary prevention trials have established the efficacy of ICD therapy in the prevention of sudden cardiac arrest in heart failure patients with a low ejection fraction due to ischemic cardiomyopathy. More recently, several randomized controlled trials have demonstrated a significant reduction in death from progressive heart failure in NYHA functional class III or IV heart failure patients. Additionally, heart failure patients with an indication for ICD implantation (based on large primary prevention trials) will experience benefit from a combined device (CRT-D). As CRT has proven to be of great benefit in the treatment of heart failure patients with NYHA functional class III and IV, it may be of future interest to establish the value of CRT in NYHA class I and II patients as well.
31 General introduction – Arrhythmias in Structural Heart Disease
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calculated that for every nine devices implanted, one death and three hospitalizations for major cardiovascular events are prevented. CARE-HF is the first randomized controlled trial that establishes a significant reduced risk of death in patients treated with CRT versus optimal medical therapy. Chapter 1
30
venous approach for left ventricular lead placement was utilized. The MUSTIC study was distinctive since both the efficacy of atrial-synchronized biventricular pacing (by evaluating patients in sinus rhythm only174) and of biventricular pacing alone (by evaluating patients in atrial fibrillation only161) were evaluated separately. The MUSTIC and the Pacing Therapies for Congestive Heart Failure (PATH-CHF175) studies had a cross-over design, whereas the Multicenter Insync RAndomized CLinical Evaluation (MIRACLE144) was the first prospective, randomized, double-blind, parallel-controlled (i.e. device implanted but pacing inactivated) clinical trial. As compared to the control group, patients randomized to the CRT group demonstrated a significantly improved quality-of-life score, 6-minute hall walk distance and NYHA class ranking. In addition, these patients required fewer hospitalizations (50% reduction), a reduced length of stay and/or less intravenous medications for the treatment of worsening heart failure. Subgroup analyses revealed a greater benefit in ejection fraction and reverse remodeling in patients with non-ischemic as compared to patients with ischemic cardiomyopathy. Greater benefits were also seen in patients with less severe baseline mitral regurgitation. The MIRACLE ICD177 and the CONTAK CD176 trial had similar study designs, but with the prerequisite that eligible patients required an implantable cardioverter defibrillator (ICD). No pro-arrhythmia was observed and arrhythmia termination capabilities were not impaired. Both studies demonstrated that heart failure patients with an ICD indication benefit as much from CRT as those without an indication for an ICD. The COmparison of Medical therapy, Pacing ANd defibrillatION in heart failure trial (COMPANION) was a 3arm study (1:2:2 ratio) that evaluated the effect of medical therapy versus CRT versus CRTICD on the composite endpoint of all-cause mortality and all-cause hospitalization179. Ischemic and non-ischemic etiologies were approximately equally included. The trial was terminated prematurely in November 2002 because of a significant reduction of nearly 20% in the primary endpoint in the CRT groups as compared to the OPT group. In addition, CRT with ICD back-up significantly reduced the risk of death from any cause (secondary endpoint) by 36%, i.e. 27% in patients with ischemic- and 50% in patients with nonischemic cardiomyopathy. The 27% reduction in risk is similar to the 31% reduction reported in Madit II, whereas the 50% reduction provides evidence of the efficacy of adjunctive defibrillator therapy in patients with nonischemic cardiomyopathy. The CArdiac REsynchronization in Heart Failure (CARE-HF 181 182) study compared optimized medical therapy alone with optimized medical therapy plus CRT (without an ICD). Unlike previous trials, CARE-HF enrolled enough patients and followed them long enough to assess the impact on mortality of CRT alone. CRT substantially reduced the risk of complications and death (both sudden death and death from worsening heart failure) with similar benefits among patients with ischemic and non-ischemic heart disease. The hazard ratio for death, of CRT versus OPT in this study, of 0.64 (95%CI 0.48-0.85; p