Tachyarrhythmias in structural heart disease Kiès, P.

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Tachyarrhythmias in structural heart disease

Kiès, P.

Citation

Kiès, P. (2006, June 1). Tachyarrhythmias in structural heart disease. Buijten & Schipperheijn, Amsterdam. Retrieved from https://hdl.handle.net/1887/4422

Version: Corrected Publisher’s Version

License: Licence agreement concerning inclusion of doctoral thesis in_{the Institutional Repository of the University of Leiden}

Downloaded from: https://hdl.handle.net/1887/4422

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Tachyarrhythmias in Structural Heart Disease

Philippine Kiès

Kies boek nieuw.indb 1

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Tachyarrhythmias in

Structural Heart Disease

PROEFSCHRIFT

ter verkrijging van

de graad van Doctor aan de Universiteit Leiden,

op gezag van de Rector Magnifi cus 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

Philippine Kiès

geboren te Ede

in 1975

This thesis was prepared at the Department of Cardiology of the Leiden University Medical Center, the Netherlands.

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: Bulls in Pamplona, Associated Press Printed by : Uitgeverij Buijten & Schipperheijn

ISBN 90-9020728-7

Kies boek nieuw.indb 2-3

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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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1

Chapter

General introduction

Arrhythmias in Structural Heart Disease

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Cha p te r 1 Gener al introduction – Arr hythmias in Structur al Hear t Disease

General Introduction

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 specifi cally 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 atrial- and ventricular tachyarrhythmias.

Cardiomyopathies

Nomenclature

Cardiomyopathy means “disease of the heart muscle”. The only currently used classifi ca-tion of cardiomyopathy was developed by the World Health Organizaca-tion (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 classifi cation 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 ap-peared to be quite similar in primary versus secondary cardiomyopathies. Therefore in the 1995 classifi cation, cardiomyopathies are classifi ed by the dominant pathophysiological mechanism or, whenever possible, by etiologic and/or pathogenetic factors (Table 1) 2 3_.

Dilated and restrictive cardiomyopathies are defi ned based on left ventricular dimen-sion or volume. Hypertrophic – and arrhythmogenic right ventricular cardiomyopathies are mainly genetically based and have unique myocardial phenotypic features. The term ‘specifi c cardiomyopathies’ refers to secondary cardiomyopathies, i.e. those associated with known cardiac or systemic processes. ‘Unclassifi ed 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_.

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 defi ned as: a dilated cardiomyopathy in a patient with a history of myocardial infarction or evidence of clinically signifi cant (≥70% narrowing of a major epicardial artery) coronary artery disease resulting in remodelling of the left ven-tricle 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 infarc-tion and in a smaller percentage of patients experiencing an inferior wall infarcinfarc-tion 5 6_.

The pathogenesis of idiopathic dilated cardiomyopathy is uncertain with speculations on familial and genetic factors, chronic viral infection or an abnormal immunological re-sponse7_{. 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 unclassifi ed cardiomyopathy 2_.

Valvular cardiomyopathy occurs in the presence of a valvular abnormality (mostly mi-tral/aortic valve regurgitation) when the systolic function is depressed out of proportion to the increase in wall stress.

Table 1

World Health Organization Classifi cations of Cardiomyopathies (adapted from Richard-son P, Circulation 1996;93:841-2)

WHO Classifi cation

A. Functional Classifi cation of cardiomypathy

1. Dilated cardiomyopathy 2. Hypertrophic cardiomyopathy 3. Restrictive cardiomyopathy

4. Arrhythmogenic right ventricular cardiomyopathy 5. Unclassifi ed cardiomyopathies

B. Specifi c cardiomyopathies

1. Ischemic cardiomyopathy 2. Valvular cardiomyopathy 3. Hypertensive cardiomyopathy 4. Infl ammatory cardiomyopathy – Idiopathic

– Autoimmune – Infectious

5. Metabolic cardiomyopathy – Endocrine

– Familial storage diseases and infi ltrations – Defi ciency

– Amyloid

6. General system disease – Connective tissue disorders – Infi ltrations and granulomas 7. Muscular dystrophies 8. Neuromuscular disorders 9. Sensitivity and toxic reactions 10. Peripartal cardiomyopathy

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In addition to the above mentioned causes of dilated cardiomyopathy, virtually all spe-cifi c WHO classifi ed 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 signifi cantly. 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, myofi bril disarray and often marked hypertrophy of the myocardium. The pathophysiological consequences may consist of dy-namic left ventricular outfl ow 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_.

Restrictive cardiomyopathy

Restrictive cardiomyopathy is either an idiopathic or systemic myocardial disorder charac-terized by restrictive fi lling of the ventricles, reduced (or normal) left ventricular and right ventricular volumes and normal or nearly normal systolic (left ventricular and right ven-tricular) function. Abnormal ventricular diastolic compliance and impaired ventricular fi ll-ing 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-infi ltrative or infi ltrative (interstitial: e.g. amyloidosis, sarcoidosis /cellular:hemochro-matosis) and occurs with or without ventricular obliteration 18_.

Arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an unusual car-diomyopathy that predominantly, but not exclusively, affects the right ventricle. ARVD/C is characterized pathologically by fi brofatty 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 (fi brofatty}

in-fi ltration, 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 fail-ure 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 Unit-ed States of America suffer from heart failure relatUnit-ed 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 treat-ment 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

Diabetes mellitus Myocardial fibrosis Abnormal metabolism Micro angiopathy Hemostatic disorders Endothelial dysfunction Coronary Artery Disease Heart Failure Hypertension Dislipidaemia Diabetic cardiomyopathy Comorbidities

+

Figure 1

Potential mechanism linking diabetes mellitus to heart failure

Diabetes mellitus is associated with multiple pathophysiological changes in the cardiovascular system. The con-sequences 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 fi brosis and abnormal myocardial metabolism – and the, with diabetes associated, comorbidities – dyslipidaemia and hyper-tension – may induce a more potent, progressive form of heart failure in diabetics.

(adapted from Bauters, Cardiovascular Diabetology 2003;2:1-16)

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decade (Figure 2) 29_{. 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 hospi-talizations 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 con-temporary 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 in-creased load (due to loss of myocytes/inin-creased 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 elon-gation of the cardiac myocytes) through which the stroke volume remains intact despite

a reduced ejection fraction (left ventricular remodeling) 36_{. However, this provides only a}

short-term benefi t. 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 signifi cant contribution to the patho-genesis and progression of heart failure related symptoms.

Within this simplifi ed model many processes take place. Ventricular remodeling fi rst 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 fi brosis, myocyte slippage (dissolution}

of the collagen struts holding the individual myocytes together) and growth of the intersti-tial 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 fi brosis and myocyte hypertrophy, along with the altered cyto-skeletal structure within the cardiomyocyte 42 43_{. Besides the process of hypertrophy and}

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)

1 3 6 13 28 2 5 9 17 31 0 5 10 15 20 25 30 35 wom en m en Av er a ge a nnu a l i n ci denc e p er 1000 45-54 55-64 65-74 75-84 85-94 Age Rate per 1000: Age Men Women 35-64 3 2 65-94 11 9

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 subse-quent 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 in-creased 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 in-creasing 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 ↓ Neurohumoral activation Myocardial growth response ↑ Cardiac energy expenditure ↑ Myocardial hypertrophy Apoptosis Cell elongation Remodeling Myocyte necrosis

Myocardial cell death

↑Load, Stretch

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fi brosis, 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 fi ber shortening and dilatation of the mitral annulus with subsequent mitral regurgitation. In addition to these mechanical aspects, neuroendocrine factors (including angiotensin II, norepineph-rine 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 as-sociated with clinical signs of heart failure. The clinical symptoms appear to be related to compensatory mechanisms such as an activated renin-angiotensin system, increased sym-pathetic 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-threaten-ing ventricular arrhythmias 51_.

Prognosis

The long-term prognosis associated with chronic heart failure is still poor despite improve-ments 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_.

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 ma-lignant ventricular arrhythmias although vascular events (myocardial infarction, stroke) and/or thrombo-embolic events may also cause a sudden death (Table 2) 58-60_{. The}

per-centage 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 benefi t most from different therapeutic approaches (chapter 2). In contrast, patients who survive

Left ventricular dysfunction

Cardiac output ↓

Sympathetic tone ↑

Renin-angiotensin system ↑

Cytokine activation Increased pre -load

Increased after-load

Vasoconstriction Salt & water retention

Figure 4

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 resis-tance, sodium and water retention and the direct cardiac effects of these factors have adverse long-term implica-tions (Adapted from Crawford Cardiology, page 5/1.10)

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 fi brillation

Myocardial ischemia/infarction Myocardial fi brosis/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

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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 pathofysi-ological feature of cells and tissues isolated from failing hearts 67 68_{. Alteration in the}

func-tional expression of ion channels and transporters (specifi cally down-regulation of the I_to andI_k–currents Figure 6) may result in spatially and temporarily unstable repolarization predisposing to for example afterdepolarization-mediated triggered activity. After-depolariza-tions occur during phase 3 and early phase 4 of the transmembrane potential before re-polarization is completed (early after-dere-polarizations) or after rere-polarization 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 calcium-handling (activation of Na/Ca exchanger leading to transient inward current) by the sar-coplasmatic 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, fi brosis and remodel-ing, re-entrant mechanisms contribute signifi cantly 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}

mono-morphic 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 fi brosis), abnormal gap junction distribution and function and an increased path length 7273 74_{. Extracellular recordings during sinus}

rhythm from sites of ventricular tachycardia origin therefore demonstrate low-amplitude,

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}

pa-tients died from progressive pump failure than from sudden cardiac death (SCD).

MERIT -HF Study Group, The Lancet 1999; 353:2001-07

MERIT -HF NYHA II 64% 12 % NYHA III 26% 59% NYHA IV 56% 33% n = 163 n = 232 n = 27 SCD CHF Other 12 % 64% Figure 6

The action potential

The action potential is classically divided into fi ve 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 fi rst phase of the repolarization consisting of a rapid outward current of potas-sium ions (I_to = transient outward current). Phase 2 is the plateau phase (equilibrium between in-and outward current) consisting of calcium infl ux through L-type and T-type Ca channels and potassium effl ux (I_k = delayed rectifi er). Phase 3 The third phase of potassium effl ux (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 an-tegradely one way (B) and retrogradely the other (anan-tegradely blocked, C) way.

A

C B

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prolonged multi-component potentials 75_{. In arrhythmogenic right ventricular}

cardiomy-opathy the arrhythmia mechanism arises from the development of marked fi brofatty infi l-tration. Anatomical reentry causes ventricular tachycardia, also based on the phenomenon of viable myocytes embedded in fi brofatty tissue having poor intercellular communications

76_{. No single mechanism, but multiple factors contribute to the arrhythmogenicity in}

id-iopathic dilated cardiomyopathy. Subendocardial scarring and multiple patchy areas of fi brosis may act as sites for reentry. In addition, in more advanced stages of heart failure, the electrophysiological milieu changes through several mechanisms serving as modulat-ing factors (Table 3). The presence of elevated circulatmodulat-ing catecholamines (heterogeneity within the myocardium), electrolyte abnormalities (hypokalemia and hypomagnesemia), ventricular hypertrophy (depression of resting membrane potential, reduction in cell-to-cell coupling, interstitial fi brosis) 77_{and ventricular dilatation (mechano-electrical}

feed-back = stretch-activated ion channels lead to shortening of the action potential and re-fractoriness 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 pa-tients. 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

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}

arrhyth-mogenic 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.

Atrial fi brillation in heart failure

Atrial fi brillation and heart failure frequently co-exist. The prevalence of atrial fi brillation in-creases as the severity of heart failure inin-creases (Figure 8). The pathophysiological changes occurring in patients with heart failure and atrial fi brillation 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 pe-riods, increase automaticity and triggered activity and may promote extra-cellular matrix fi brosis83_{.The onset of atrial fi brillation and thus the loss of atrio-ventricular synchronicity}

results in impaired diastolic fi lling, 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.

Table 3

Underlying mechanisms of tachy-arrhythmias in heart failure (adapted from Kjekshus J, AJC 1990;65:42I-48I).

Arrhythmias in heart failure

Basic mechanisms Reentrant activity

Enhanced automaticity Delayed after depolarizations

Myocardial substrates Scar tissue

Aneurysm Hypertrophy Ventricular dilatation Ventricular dysfunction

Modulating factors Myocardial ischemia

Electrolyte defi cits

Myocardial release of cathecholamines Sympaticoadrenergic activation Myocardial stretch Antiarrhythmic drugs Inotropic drugs Diuretics Figure 8

Prevalence of atrial fi brillation 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}

Sur-vival 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}

Insufi ciencia 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}

4,2 10,1 14,4 15,4 25,8 28,9 49,8 0 10 20 30 40 50 60 I II-III III-IV IV

New York Heart Association Functional Class

Prev a lence of At ri a l F ibrill a ti o n ( % ) 1 2 3 4 5 6 7

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23 Management of arrhythmias in cardiomyopathies

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 Ar-rhythmia Suppression Trial (CAST) is placebo-controlled evaluating the effect of antiar-rhythmic therapy (encainide, fl ecainide, 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 contrib-uted 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 fi brillation with a low ejection fraction should be discouraged).

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 effec-tive 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 signifi cant reductions in resuscitated ventricular fi brillation 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 confi rmed 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 Insufi ciencia Cardiaca en Argentina (GESICA) trial reported a 28% reduction in mortality in patients with mostly non-isch-emic 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 ar-tery disease indeed confi rmed no survival benefi t of amiodarone in this group compared to placebo. In contrast, there was a trend towards a mortality reduction in the non-ischemic

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 fi brillation/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-ar-rhythmic 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).}

Surgery

The fi rst 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 ven-tricular 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 pa-tients who survived the procedure remained free of clinical ventricular tachycardia and 60-70% of patients did not require suppressive antiarrhythmic therapy 103_.

Radiofrequency catheter ablation

Drug treatment is often ineffective and implantable cardioverter defi brillators can termi-nate ventricular tachycardia, but cannot prevent them. Radiofrequency (RF) catheter abla-tion is the only antiarrhythmic therapy (with the excepabla-tion of the above menabla-tioned surgical techniques) that can potentially cure patients with drug-refractory incessant ventricular tachycardia or patients with frequently recurring ventricular tachycardia 104-106_{. The effi cacy}

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 electro-cardiographic 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 arrhythmo-genic right ventricular cadiomyopathy can also cause scar-related reentry. Dense fi brotic scar creates areas of anatomic conduction block and fi brosis between surviving myocyte

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bundles deceases cell- to-cell coupling. This distorts the path of propagation causing slow conduction, which promotes reentry72_{. These reentry circuits often contain a narrow}

isth-mus of abnormal conduction. The QRS complex is caused by propagation of the wavefront from the exit of the circuit to the surrounding myocardium (Figure 9). After leaving the exit of the isthmus, the circulating reentry wavefront may propagate through a broad path along the border of the scar (loop), back to the entrance of the isthmus. Electrograms recorded at the isthmus typically display an isolated potential preceding the QRS complex. Additionally, as a result of the conduction delay, those locally recorded electrograms are fragmented and demonstrate low amplitude. Successful ablation of a reentry circuit is achieved either by targeting an isthmus where the circuit can be interrupted with one or a small number of RF lesions, or by creating a line through a region containing the reentry circuit. Ablation of clinical reentry circuit isthmuses can be successful in >70% in postinfarc-tion patients 107108 109_{. However, identifi cation 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-volves defi ning the area of scar from its low amplitude sinus rhythm electrograms followed by a further delineation of the likely reentry circuit based on the QRS morphology of the ventricular tachycardia or on pace mapping110-112_{). Finally, a series of anatomically guided}

ablation lesions is placed through the abnormal region113_{. However, due to the signifi cant}

number of RF applications necessary, this technique may further depress LV function in already diseased hearts. This issue is further studied in chapter 5.

Implantable Cardioverter Defi brillator therapy

In 1980 Mirowski introduced the implantable cardioverter defi brillator (ICD)114_{. Although}

the ability of an ICD to convert ventricular arrhythmias was demonstrated, it was contro-versial whether this implied a meaningful increase in the patient’s life expectancy. Conse-quently, several randomized trials were initiated. A fi rst randomized study of 60 patients by Wever et al, demonstrated a signifi cant survival benefi t for ICD implantation versus antiarrhythmic drugs in postinfarct sudden death survivors115_{. The, Cardiac Arrest Study}

Hamburg (CASH) trial was the fi rst large-scale randomized controlled study comparing the effect of antiarrhythmic drugs versus ICD therapy on all-cause mortality in sudden car-diac death survivors116_{. The antiarrhythmic drugs used in the CASH trial were metoprolol,}

amiodarone and propafenone (the latter was stopped early due to high morta lity 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 com-pared to the amiodarone/metoprolol treated group. However this mortality reduction was statistically not signifi cant. Similarly the Canadian Implantable Defi brillator Study (CIDS) comparing amiodarone with ICD in survivors of sudden cardiac arrest or hemodynamically unstable ventricular arrhythmias117_{, reported a statistically non-signifi cant 20% relative risk}

reduction in all-cause mortality and 33% relative risk reduction in arrhythmic death. The Antiarrhythmics versus Implantable Defi brillators (AVID) trial was the fi rst large-scale randomized study confi rming a signifi cant survival benefi t 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 hemodynami-cally 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 <35% 119 120_{. The majority of patients had coronary artery}

disease and prior myocardial infarction, the impact of ICD therapy in patients with non-ischemic cardiomyopathy was therefore unknown.

Next, a series of trials investigated the prophylactic role of the ICD in postinfarction tients. The Multicenter Automatic Defi brillator Implantation Trial (MADIT) enrolled pa-tients after myocardial infarction with an ejection fraction < 35%, non-sustained

ventricu-Figure 9

Representation of a double-loop (fi gure-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 wave-front emerges from the exit. It returns to the common pathway by propagating through outer loops (see also text).

Entrance Site

Scar Exit Site

Outer Loop Common Pathway

Outer Loop

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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 fi rst to show that selected high risk patients could derive survival benefi t 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 fi rst during an electrophysiological study, pa-tients who failed to respond to drugs received an ICD. Over a 5-year follow-up, the papa-tients randomized to antiarrhythmic therapy experienced a 27% lower risk for arrhythmic death or cardiac arrest compared to the maximal conservative treated group. The improved sur-vival 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 Defi brillator 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}

result-ed in a 31% mortality rresult-eduction (comparresult-ed 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%.

Heart failure based on non-ischemic cardiomyopathy is also associated with a poor prog-nosis. Several prospective randomized clinical trials evaluated the potential benefi t of ICD therapy in patients with non-ischemic cardiomyopathy. The Amiodarone Versus Implant-able Cardioverter-Defi brillator Trial (AMIOVIRT) randomized patients with non-ischemic cardiomyopathy and asymptomatic non-sustained ventricular tachycardia to ICD versus amiodarone therapy125_{. There was no difference in mortality between both groups due}

to a very low overall mortality and a small number of patients enrolled in this study. The Defi brillators in Nonischemic Cadiomyopathy Treatment Evaluation (DEFINITE) random-ized patients with non-ischemic cardiomyopathy (ejection fraction ≤35%) and premature ventricular contractions (>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 signifi cance. The cardio-myopathy 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_.

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}

ventricu-lar ejection fraction (<35%), regardless of the underlying cause, were randomly assigned to ICD therapy, amiodarone therapy or placebo without any prior additional risk stratifi ca-tion. ICD therapy reduced the relative risk of death by 23% and amiodarone had no effect on mortality compared with placebo.

Cardiac Resynchronization Therapy

The concept of cardiac resynchronization therapy (CRT) for heart failure most likely emerged out of a variety of animal studies performed in the late 1980s. Most notable among these studies was the 1986 study of canine pacing in which Burkhoff et al noted that the left ventricular pressure decreased linearly as the QRS duration increased 129_{. In}

additional studies it was noted that there was a high prevalence of a prolonged QRS du-ration with a left bundle branch block confi gudu-ration in chronic heart failure patients 130_.

Following the Burkhoff study, Lattuca et al hypothesized that by simultaneous pacing of left and right ventricle a more synchronous ventricular activation plus a resultant more synchronous ventricular contraction pattern could be achieved131_{. The fi rst observational}

studies by Cazeau et al and Bakker et al demonstrated effi cacy132 133_{. Ever since, CRT has}

emerged as a vital new treatment option in heart failure patients.

Mechanism

Cardiac resynchronization therapy improves cardiac function in patients with heart failure and ventricular dyssynchrony through 3 different mechanisms. Yet, the relative contribu-tion of these 3 mechanisms to the success of CRT is currently unknown. First, atrio-ven-tricular sequential pacing allows for optimization of the atrio-venatrio-ven-tricular delay and thus in an activation sequence with an optimal left ventricular fi lling time to improve systolic performance. Secondly, CRT can reduce the left-bundle-branch block induced interven-tricular dyssynchrony between the right and left ventricle and lastly the intraveninterven-tricular dyssynchrony within the left ventricle. That is, dilated cardiomyopathy hearts with a left bundle branch block-type conduction delay display early activation of the septal wall, as-sociated with lateral wall pre-stretch. This is followed by a delayed lateral contraction at a higher stress and a further systolic stretch of the early-activated septum. Since the sep-tal myocardium is less able to withstand the stress developed later in systole it is pushed toward the right heart. Therefore, septal motion is termed paradoxic. Late-systolic septal stretch however worsens function. First, there is effectively a reduced cardiac output by

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the internal shuffl e 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, di-minishing systolic force development. Additionally, this may result in repolarization inho-mogeneity 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}

ef-fect 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 As-sociation functional class, quality of life and exercise capacity 144145 146_{as well as LV systolic}

performance 147148_{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 signifi cant decrease in morbidity, expressed as hospitalization rate/duration for de-compensated heart failure and a 51% relative reduction in death from progressive heart failure as compared to optimized medical therapy 149_{. Finally, CRT resulted in signifi cant}

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 ven-tricular tachy-arrhythmias153_{(see above), knowledge of potential effects of CRT on}

arrhyth-mogenicity is of major importance. Fish et al154_{described 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 transmu-ral 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 reduc-tion in ventricular arrhythmogenicity after CRT152 155-159_.155-157_{It 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 fi brillation. Several studies have demonstrated that CRT can be benefi cial in heart failure patients with concomitant atrial fi brillation in terms of improved symptoms, exercise capacity, systolic left ventricular function and survival.145 160-162_{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.

Clinical trials on resynchronization therapy

Numerous observational studies and a series of randomized controlled trials have been completed, demonstrating the safety, effi cacy and the long-term benefi cial effects of CRT in patients with chronic systolic heart failure and ventricular dyssynchrony. Early obser-vational 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}

fail-ure. The primary objective of the InSync Trial was to evaluate the safety and effectiveness of CRT in these patients. In this trial a signifi cant 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.

Since then, nearly 5000 patients have been evaluated in a randomized setting (Table 4). These randomized trials demonstrated statistically signifi cant 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}

Cardio-myopathy (MUSTIC) trial174_{was the fi rst randomized, controlled trial in which the}

trans-Table 4

Landmark randomized controlled trials of cardiac resynchronization therapy in heart fail-ure

Study Study design No of randomized

patients NYHA class Rhythm ICD

MIRACLE144 _Parallel-arm ₅₂₄ _{III, IV} _SR _No

MUSTIC SR174_Crossover ₅₈ _III _SR _No

MUSTIC AF161 _Crossover ₄₃ _III _AF _No

PATH CHF146 175 _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

PATH CHF II178 _Crossover ₈₉ _{III, IV} _SR _No

COMPANION179 _Parallel-arm ₁₅₂₀ _{III, IV} _SR _No

MIRACLE ICD II180 _Parallel-arm ₁₈₆ _II _SR _Yes

CARE HF181 ₈₀₀ _{III, IV} _SR _No

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venous approach for left ventricular lead placement was utilized. The MUSTIC study was distinctive since both the effi cacy of atrial-synchronized biventricular pacing (by evaluating patients in sinus rhythm only174_{) and of biventricular pacing alone (by evaluating patients}

in atrial fi brillation only161_{) were evaluated separately. The MUSTIC and the Pacing}

Thera-pies for Congestive Heart Failure (PATH-CHF175_{) studies had a cross-over design, whereas}

the Multicenter Insync RAndomized CLinical Evaluation (MIRACLE144_{) was the fi rst}

pro-spective, 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 signifi cantly improved quality-of-life score, 6-minute hall walk distance and NYHA class ranking. In addition, these patients required fewer hospitaliza-tions (50% reduction), a reduced length of stay and/or less intravenous medicahospitaliza-tions for the treatment of worsening heart failure. Subgroup analyses revealed a greater benefi t in ejection fraction and reverse remodeling in patients with non-ischemic as compared to pa-tients with ischemic cardiomyopathy. Greater benefi ts were also seen in papa-tients with less severe baseline mitral regurgitation.

The MIRACLE ICD177_{and the CONTAK CD}176_{trial had similar study designs, but with}

the prerequisite that eligible patients required an implantable cardioverter defi brillator (ICD). No pro-arrhythmia was observed and arrhythmia termination capabilities were not impaired. Both studies demonstrated that heart failure patients with an ICD indication benefi t as much from CRT as those without an indication for an ICD. The COmparison of Medical therapy, Pacing ANd defi brillatION in heart failure trial (COMPANION) was a 3-arm study (1:2:2 ratio) that evaluated the effect of medical therapy versus CRT versus CRT-ICD 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 signifi cant 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 signifi cantly 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% reduc-tion reported in Madit II, whereas the 50% reducreduc-tion provides evidence of the effi cacy of adjunctive defi brillator therapy in patients with nonischemic cardiomyopathy.

The CArdiac REsynchronization in Heart Failure (CARE-HF 181 182_{) study compared}

opti-mized medical therapy alone with optiopti-mized 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 com-plications and death (both sudden death and death from worsening heart failure) with similar benefi ts 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<0.002) was similar to that among patients who received both a CRT and an ICD device in the COM-PANION trial (0.64; 95% CI 0.48-0.86; p=0.003). From these hazard’s ratios, it can be

calculated that for every nine devices implanted, one death and three hospitalizations for major cardiovascular events are prevented. CARE-HF is the fi rst randomized controlled trial that establishes a signifi cant reduced risk of death in patients treated with CRT versus optimal medical therapy.

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 tri-als have established the effi cacy 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 signifi cant 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 benefi t from a combined device (CRT-D). As CRT has proven to be of great benefi t 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.

Tachyarrhythmias in structural heart disease Kiès, P.

Tachyarrhythmias in structural heart disease

Tachyarrhythmias in Structural Heart Disease

Philippine Kiès

Tachyarrhythmias in

Structural Heart Disease

PROEFSCHRIFT

ter verkrijging van

de graad van Doctor aan de Universiteit Leiden,

op gezag van de Rector Magnifi cus 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

Philippine Kiès

geboren te Ede

in 1975

Promotiecommissie

Voor mijn ouders

Aan Diederik

Table of Contents

1

Chapter

General introduction

Arrhythmias in Structural Heart Disease

10

11

General Introduction

Cardiomyopathies

12

13

Heart Failure

+

+

+

14

15

16

17

18

19

20

21

22

23

Management of arrhythmias in cardiomyopathies

24

25

26

27

Cardiac Resynchronization Therapy

28

29

30

31

Conclusion