dilated cardiomyopathy: diagnostic work-up, pathogenesis
TRANSCRIPT
1
Dilated cardiomyopathy: diagnostic
work-up, pathogenesis, prognosis and
treatment
PhD thesis
Kaspar Broch
Department of Cardiology
Oslo University Hospital, Rikshospitalet
and
Faculty of Medicine
University of Oslo
Oslo, Norway
© Kaspar Broch, 2016 Series of dissertations submitted to the Faculty of Medicine, University of Oslo ISBN 978-82-8333-161-5 ISSN 1501-8962 All rights reserved. No part of this publication may be reproduced or transmitted, in any form or by any means, without permission. Cover: Hanne Baadsgaard Utigard Printed in Norway: 07 Media AS – www.07.no
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ACKNOWLEDGEMENTS
My work on the current thesis was performed at the cardiology ward at Oslo University
Hospital, Rikshospitalet from October 2008 to June 2015, intercepted by two brief leaves of
absence following the births of my two youngest children. During the first five years, I held a
teaching position at the University of Oslo, alternating between teaching eager-to-learn
medical students and fretting at slow patient recruitment. For the next six months, I received a
scholarship from the grant provided by Inger and John Fredriksen, to whom I am grateful.
Foremost, I would like to thank my principle supervisor, Professor Lars Gullestad, whose
door is (literally) always open, and whose enthusiasm I have relied heavily upon when
progress has been slow or a manuscript has been rejected. He was the one who talked me into
taking on this thesis, arguing that the data collection would be done in a matter of months, and
he was the one who comforted me when this turned out to be as far from the truth as possible.
(“But you are going to end up with a unique material and a large body of science to your
name!”)
I would also like to thank my co-supervisor, Professor Svend Aakhus. When Lars’ unbridled
enthusiasm and sometimes unrealistic expectations have had me crawling the walls of my
shared (and, to the despair of my colleagues, severely disorganised and overcrowded) office,
Svend has had a soothing effect with his cool, no-nonsense realism. Unlike Lars, Svend is a
creature for details. Thus, as Lars provided ideas and pointed me in the general direction,
Svend corrected my spelling mistakes and faulty statistics and above all tried to teach me how
to perform state-of-the-art echocardiography.
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The staff at the cardiology department has my gratitude for their patience and positive attitude
whenever I came sauntering in to make their days longer and more difficult by recruiting
patients for my project, requiring additional exams and extending the patients’ stay. In
particular, I would like to thank secretary Anne Hegna for helping me organise the many
diagnostic tests my patients went through, and nurse Maj-Britt Skaale for her invaluable
contribution to data collection and interpretation. In general, a positive attitude towards
research (and researchers!) permeates the walls of the department. The previous head of
department, Dr Lars Aaberge, and his successor Professor Thor Edvardsen have no doubt
inherited this mindset from their predecessors, but the cost-effectiveness demands of modern
medicine makes it no mean task to maintain it, and I am grateful to them for providing a
research friendly environment.
I extend my thanks to study nurses Rita Skårdal and Wenche Stueflotten for their contribution
to the organisation of patient follow-up, blood sampling and storage, and for their general
hospitality and smiling faces. I admire them for remembering my patients by name and family
anecdotes, when all I could remember was the patient’s left ventricular end diastolic diameter.
Whereas research nowadays is usually performed within a scientific environment, it is at
times lonely work. Many a day I have spent in front of the computer, reading other scientists’
work or despairing at my own. Luckily, I have been blessed with a number of good
companions to share my fate, among whom I count Christian Eek, Jan Otto Beitnes, Mette
Elise Estensen, Gabor Kunzt, Lene Anette Rustad, Wasim Zahid and Klaus Murbræch as
good friends. Expert sonographers Johanna Andreassen and Richard Massey have contributed
greatly to making my days brighter and my echocardiographic images less cloudy.
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My home, obviously, is where my heart is, and it is with my good wife Line and my three
children Marie, Erling and Tiril. Their love means the world to me, and without their support,
I could not have written this thesis. Line has had to put up with my despair at a perceived lack
of scientific progression, my irritation with obtuse reviewers and my coming home late and
staying away from home in order to perform research and provide some hard earned extra
income. She has done so with patience and grace, and for that, I am forever thankful.
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Innhold
ACKNOWLEDGEMENTS ................................................................................................................................ 2
Innhold ................................................................................................................................................................. 5
LIST OF PAPERS ............................................................................................................................................... 6
1 INTRODUCTION ...................................................................................................................................... 7
1.1 Heart failure .................................................................................................................................... 7
1.2 Dilated cardiomyopathy ............................................................................................................ 8
1.2.1 Definition ................................................................................................................................ 9
1.2.2 Aetiology .............................................................................................................................. 10
1.2.3 Pathogenesis ...................................................................................................................... 12
1.2.4 Prognosis in dilated cardiomyopathy ...................................................................... 16
1.2.5 Treatment ........................................................................................................................... 17
2 AIMS OF THE THESIS ........................................................................................................................ 19
3 PATIENTS AND METHODS .............................................................................................................. 20
3.1 Patient population, paper I, II and III ................................................................................. 20
3.2 Patient population, paper IV ................................................................................................. 23
3.3 Study Procedures papers I through III .............................................................................. 23
3.4 Study procedures, paper IV ................................................................................................... 24
3.5 Imaging .......................................................................................................................................... 24
3.5.1 Echocardiography ............................................................................................................ 24
3.5.2 Magnetic resonance imaging ....................................................................................... 24
3.5.3 Image analysis ................................................................................................................... 26
3.6 Measurement of peak oxygen consumption ................................................................... 26
3.7 Right-sided heart catheterisation ....................................................................................... 27
3.8 Viral genome detection ........................................................................................................... 27
3.9 Conventional and electron microscopy ............................................................................ 28
3.10 Blood sampling and laboratory analysis .......................................................................... 28
3.11 Statistics ........................................................................................................................................ 29
4 SUMMARY OF RESULTS: .................................................................................................................. 30
4.1 Paper I ............................................................................................................................................ 30
4.2 Paper II .......................................................................................................................................... 31
4.3 Paper III ......................................................................................................................................... 32
4.4 Paper IV ......................................................................................................................................... 34
5 DISCUSSION ........................................................................................................................................... 35
6 CONCLUDING REMARKS .................................................................................................................. 44
6
LIST OF PAPERS
1. Broch K, Andreassen AK, Hopp E, Leren TP, Scott H, Müller F, Aakhus S, Gullestad
L. Results of comprehensive diagnostic work-up in “idiopathic” dilated
cardiomyopathy (Submitted to Open Heart)
2. Broch K, Andreassen AK, Ueland T, Michelsen AE, Stueflotten W, Aukrust P,
Aakhus S, Gullestad L. Soluble ST2 reflects hemodynamic stress in non-ischemic
heart failure. Int J Heart Fail
3. Broch K, Murbræch K, Andreassen AK, Hopp E, Aakhus S, Gullestad L.
Contemporary Outcome in Patients with Idiopathic Dilated Cardiomyopathy. Am J
Cardiol (accepted)
4. Broch K, Askevold ET, Gjertsen E, Ueland T, Yndestad A, Godang K, Stueflotten W,
Andreassen J, Svendsmark R, Smith HJ, Aakhus S, Aukrust P, Gullestad L. The effect
of rosuvastatin on inflammation, matrix turnover and left ventricular remodeling in
dilated cardiomyopathy: a randomized, controlled trial. PLoS One 2014; 9: e89732.
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1 INTRODUCTION
1.1 Heart failure
Heart failure is a syndrome characterised by an impaired ability of the heart to fill or eject
blood.1 Heart failure may lead to symptoms of inadequate tissue perfusion, such as fatigue and
lethargy (so-called “forward failure”), or congestion, including shortness of breath and
peripheral oedema (often referred to as “backward failure”). All disorders affecting the
structural and/or functional integrity of the heart, such as valvular, coronary or myocardial
disease, can commence heart failure. Heart failure may also be precipitated by diseases
affecting the heart indirectly, such as hypertension, pericardial disease or pulmonary disease.
Many of the conditions that may cause heart failure are to some extent reversible. However,
once the burden of disease exceeds the compensatory capacity of the heart, the condition often
progresses toward a common end stage.1 The process whereby the myocardium undergoes
structural changes in the face of perturbed loading conditions or myocardial disease is known
as (adverse) remodelling.2,3 The pathophysiology behind this progressive deterioration is
incompletely understood. Haemodynamic stress,4 neurocrine activation,5 and inflammation,6,7
all contribute to the ventricular dilation,8 loss of contractile elements9 and changes in the
extracellular matrix composition10 observed in advanced heart failure.
Heart failure is a leading cause of morbidity and mortality in the Western world, affecting 2-3
% of the adult population.11,12 As the population ages, the prevalence is expected to increase
over the next 20 years.11 Current clinical guidelines12,13 take a generic approach to heart
failure, paying little attention to inter individual differences in aetiology and pathophysiology.
8
This may partly be because the biology of the failing heart is incompletely understood, and
partly because there is a lack of treatment strategies targeting many of the processes involved.
1.2 Dilated cardiomyopathy
Dilated cardiomyopathy is characterised by left ventricular dilation and dysfunction in the
absence of coronary disease, valvular disease or hypertension.14 Approximately 10 % of heart
failure cases are due to dilated cardiomyopathy.15
Figure 1 Dilated cardiomyopathy
Echocardiographic apical 4-chamber image of one of the patients in the study, demonstrating
the typical enlargement and ballooning of the left ventricle (LV).
9
1.2.1 Definition
By the European Society of Cardiology (ESC)’s definition above, dilated cardiomyopathy is
primarily a diagnosis based on phenotype, rather than aetiology (Figure 1). Accordingly, the
ESC lists a whole array of potential causes of dilated cardiomyopathy, with widely differing
pathogenic mechanisms. The American Heart Association (AHA) and the American College
of Cardiology (ACC) have proposed a different classification of cardiomyopathies. In their
guidelines, cardiomyopathies are firstly designated as either “primary” (i.e. predominantly
involving the heart) or “secondary” to some systemic disease, and secondarily whether they
are of a genetic, acquired or mixed aetiology.16 Although this latter classification of
cardiomyopathies is attractive in the way that it pivots around the underlying pathogenesis of
the disease, it poses several problems.17 Firstly, from a clinician’s point of view, the
diagnostic work-up of a patient begins with the clinical appearance. Thus, a diagnostic system
based on phenotype is operational when deciding what to do next in the diagnostic process.
Secondly, most patients with dilated cardiomyopathy present with symptoms of heart failure,
and as stated above, recommendations for treatment in heart failure do not take into account
individual differences in aetiology or pathophysiology. Thirdly, one might argue that the
categorisation of cardiomyopathies based on underlying causes is premature. Today, in the
majority of patients with a dilated, dysfunctional left ventricle, in the absence of ischaemia
and valvular or hypertensive disease, no particular cause is found, and the patients end up
with a diagnosis of “idiopathic” dilated cardiomyopathy.18 For the above reasons, I adhere to
the European definition of dilated cardiomyopathy in the following.
10
1.2.2 Aetiology
Dilated cardiomyopathy probably represents the end-stage phenotype of almost any kind of
global insult to the myocardium, coronary heart disease and altered loading conditions
excluded. Accordingly, the list of potential causes is long. The most common causes are listed
in Table 1. However, in most patients, no particular aetiology is uncovered, and they are
diagnosed with “idiopathic” dilated cardiomyopathy.
Table 1 Causes of dilated cardiomyopathy
Hereditary Monogenic, mitochondrial Myocarditis Viral, sarcoidosis, Kawasaki disease, eosinophilic Tachycardiomyopathy Atrial fibrillation, atrial tachycardia Pregnancy Peripartum cardiomyopathy Endocrine Thyroid disease, acromegaly Metabolic Haemochromatosis, amyloidosis, inborn errors of metabolism Nutritional Deficiencies (thiamine, niacin, selenium, carnitine, vitamin C, kwashiorkor) Toxic Cytostatics, alcohol, recreational drugs, heavy metals
Causes of dilated cardiomyopathy. The list is not exhaustive. Modified from Elliott et al14 and Maron et
al16
There are two prevailing theories regarding potential causes of idiopathic dilated
cardiomyopathy. One holds that a proportion of the cases are secondary to myocardial
inflammation, possibly subsequent to a (sub clinical) viral myocarditis.19,20 The other holds
that most cases of dilated cardiomyopathy are hereditary, but that their genetic nature is hard
to detect clinically due to incomplete penetrance and variable expressivity.
The former theory is supported by several observations. In murine models, viral myocarditis
subsequently develops into dilated cardiomyopathy.21 The same development is observed in
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some, but not all, human patients who have suffered from severe myocarditis. Moreover, viral
nucleic acids are detectable in the myocardium of a substantial number of patients with dilated
cardiomyopathy,22,23 and their presence may be associated with a poor prognosis.24 It has been
proposed that in genetically disposed individuals, viral myocardial infection either remains
unresolved or leads to an immunologic overreaction, and that the persistent inflammation
begets left ventricular remodelling and heart failure.20
On the other hand, recent studies have indicated that as many as 50 % of patients with
idiopathic dilated cardiomyopathy have familiar disease.25,26 Mutations in many different
genes have been shown to cause dilated cardiomyopathy, most commonly with an autosomal
dominant pattern of inheritance.25 Due to incomplete penetrance25,26 and variable
phenotypes25-27 within families with dilated cardiomyopathy, the hereditary nature of the
disease might easily escape detection. Current genetic screening tests are not in widespread
use, and are directed towards the known genetic causes of dilated cardiomyopathy only. The
mutations causing dilated cardiomyopathy that have been described so far, account for only a
minority of the cases thought to be hereditary on the basis of their familiar occurrence.26
We do not know why certain individuals with a given mutation develop clinical
cardiomyopathy, while other carriers remain healthy or develop signs of the disease only
detectable on specific examination. Neither do we know why it usually takes years to develop
clinical disease,27 although the primary defect is inborn. It has been proposed that mechanical
stress throughout life causes the development of DCM in individuals with a predisposing
genetic variant.27,28
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1.2.3 Pathogenesis
Irrespective of the nature of the initiating pathogenic stimulus, the body responds to a
compromised cardiac pump function with a number of compensatory mechanisms. These
include neurohormonal activation, characterised by an increased activity of the renin-
angiotensin-aldosterone axis, an elevated circulating concentration of catecholamines, and an
increased sympathetic activity. In the heart, the wall stress induces the production and release
of natriuretic peptides.
1.2.3.1 Left ventricular remodelling
The myocardium responds to the added strain by a process known as remodelling,8 whereby
the macroscopic and ultrastructural architecture of the heart changes towards a dilated
cardiomyopathy phenotype. On the macroscopic level, the left ventricle undergoes eccentric
hypertrophy and dilation.29 A gradual replacement fibrosis often occurs, whereby functional
cardiomyocytes undergo apoptosis30 or necrosis to be replaced by fibroblasts and extracellular
matrix.31 The extracellular matrix itself undergoes several changes. Extracellular collagen
deposition is increased,32 and at the same time, there is accelerated degradation of
extracellular proteins, resulting in an increased matrix turnover.10,33 This is mirrored in the
circulation by an increased concentration of collagen by-products and metalloproteinases.34
On the ultrastructural level, the protein composition of the myocyte is altered.35
Cardiomyocyte calcium handling is impaired,36 and with a return to a foetal gene expression
program, there is isoform switching of sarcomeric proteins and modified metabolism.37
1.2.3.2 Inflammation in dilated cardiomyopathy
There is a large body of evidence indicating that inflammation is involved in the pathogenesis
of heart failure.6 Circulating levels of pro-inflammatory cytokines are elevated in heart
failure38 irrespective of aetiology.39 Moreover, there is an association between the level of
13
inflammatory activity and prognosis in patients with recent-onset dilated cardiomyopathy.40
Auto-antibodies to key cardiac epitopes are at the core of certain forms of heart failure in
murine models,41 and induction of inflammation may lead to overt heart failure in
experimental settings.42,43 Accordingly, immunomodulation has been considered a promising
treatment concept in heart failure.44 A few, small studies have demonstrated a favourable
effect of anti-inflammatory treatment with intravenous immunoglobulin,45 immunoglobulin
adsorption46 and pentoxifylline47,48 in patients with dilated cardiomyopathy. However, the
results of major trials,49-51 especially those investigating anti TNF therapy,52,53 have been
disappointing.
One reason for the lack of effect of anti-inflammatory treatment may be that patients with
heart failure constitute such a heterogeneous population. Although circumstantial evidence
suggests that many of these patients would benefit from immunosuppressive treatment, some
patients may not. Indeed, it has been showed that in patients with virally infected
myocardium, boosting the immune system with interferon leads to improved outcome.54 Thus,
it may be that in this particular subgroup of patients with DCM, treatment with
immunosuppressive agents is detrimental. This heterogeneity may have acted as a confounder
in previous trials.
1.2.3.3 The role of ST2
ST2 is a receptor in the Interleukin (IL)-1 family. Discovered in 1989,55,56 it was long
considered an orphan receptor. In 2005, however, ST2 was shown to bind IL-33.57 The
binding of IL-33 to the membrane bound ST2 receptor induces a downstream cascade,
ultimately activating nuclear factor κB58,59 (Figure 2). Soluble ST2 (sST2) is a truncated
receptor that lacks the transmembrane/ intracellular domains of membrane bound ST2.60 It
arises by alternative splicing and is released into the circulation, where it acts as a decoy
14
receptor for IL-33. ST2 has been detected in many human tissues.61 ST2 is inducible in
cardiac tissue,62 and is expressed in endothelial cells and vascular smooth muscle cells.63
15
Figure 2 ST2 signalling
IL33/ST2-signalling. IL-33 binds to the ST2 receptor complex consisting of membrane bound ST2L and
the IL1RAcP. This leads to the recruitment of MyD88 and IRAK4. The latter autophosphorylates to
initiate a cascade of intracellular kinases that ultimately leads to activation of NFκB and MAPKs. This
again leads to transcription of inflammatory cytokines and regulation of cell proliferation. Soluble ST2
(sST2) sequesters IL33, preventing its interaction with the IL1RL1 receptor complex. Modified from
Broch et al64
16
IκB, Inhibitor of nuclear factor κB; IKK, Inhibitor of nuclear factor κB kinases; IL1RAcP, Interleukin-1
receptor accessory protein, IL33, Interleukin-33; IRAK4, Interleukin-1 receptor associated kinase 4;
MAPK, mitogen activated protein kinase; MyD88, Myeloid differentiation primary response gene 88;
sST2, soluble ST2; ST2L, membrane bound ST2; TRAF6, TNF receptor associated factor 6.
Not surprisingly, given its similarity to the IL-1 system, IL-33/ST2 signalling plays a role in
inflammatory diseases,65-68 where it seems to be pivotal to certain immune responses
involving TH2 helper cells.57,65,69,70 On the other hand, in 2002 Weinberg and colleagues
found that ST2 was up regulated in cardiomyocytes subjected to mechanical stress, and that
levels of circulating sST2 increased substantially after myocardial infarction.62 Subsequently,
the IL33/ST2 axis has been shown to protect against maladaptive hypertrophy and fibrosis
secondary to aortic banding,71 and against hypoxia-induced apoptosis.72 Serum concentrations
of sST2 are elevated in cardiac disease and are associated with mortality in acute coronary
syndromes.73-75 In heart failure, ST2 levels correlate with markers of disease severity, such as
left ventricular ejection fraction,76-78 New York Heart Association functional class77 and left
ventricular filling pressure.76 More importantly, sST2 has been shown to be an independent
predictor of outcome in patients with heart failure.64
1.2.4 Prognosis in dilated cardiomyopathy
Outcome in dilated cardiomyopathy depends on the aetiology. In the idiopathic form of the
disease, the prognosis is generally better than in patients with ischaemic heart failure.18,79
Five year mortality is substantial, however, ranging from more than 50 % in early reports80 to
approximately 25 % in recent reports.79,81 Survival differs due to various inclusion criteria in
different trials. In addition, there has probably been a real improvement in outcome as
treatment for heart failure has advanced over the last decades with the introduction of drugs
17
inhibiting major neuroendocrine axes and the use of devices to resynchronise left ventricular
contraction and treat ventricular arrhythmias.82,83
1.2.5 Treatment
The recommended therapy for dilated cardiomyopathy does not differ from that advocated for
heart failure in general, where inhibitors of the major neuroendocrine axes are the mainstay of
treatment.84 Several large studies have shown that in mixed heart failure populations (i.e.
including patients with non-ischaemic as well as ischaemic heart failure), treatment with
angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin II receptor blockers
(ARBs) confers a survival benefit.85,86 Likewise, there are several, large studies to show that
beta receptor antagonists (beta blockers) improve the outcome in patients with heart failure
and dilated cardiomyopathy,87-89 and that aldosterone antagonists provide an added survival
benefit in patients with heart failure who remain symptomatic after the up-titration of drugs
inhibiting the renin-angiotensin and sympathetic neurohormonal axes.90,91 Furthermore,
implantable cardioversion defibrillators (ICDs) reduce the number of sudden deaths in high-
risk patients with dilated cardiomyopathy,79,81 and cardiac resynchronisation therapy (CRT)
have been shown to improve outcome in patients with dilated cardiomyopathy and wide QRS
complexes.92-94
Statins reduce the number of cardiovascular events in patients with, or at risk of developing,
coronary disease.95,96 Statins are inhibitors of 3-hydroxy 3-methylglutaryl coenzyme A
reductase, the rate-limiting enzyme in cholesterol synthesis, and effectively reduce serum
cholesterol levels. It is hotly debated whether the cardioprotective effects of statins are due to
cholesterol reduction only. Statins also possess anti-inflammatory and matrix stabilizing
properties,97 and the relative risk reduction observed in statin trials has been independent of
18
baseline cholesterol levels.95 Also, the effect on clinical endpoints is associated with a
treatment-induced reduction in the C-reactive protein serum concentration.98 Whereas the two
major trials assessing the effect of statins in heart failure failed to show a positive effect on
the clinical outcome,99,100 several small, randomised trials have shown that treatment with a
statin could lead to improved left ventricular function and a reduction in markers of
inflammation in patients with dilated cardiomyopathy .101-104
19
2 AIMS OF THE THESIS
We aimed to explore the yield of a comprehensive baseline diagnostic evaluation, the
pathogenesis, the prognosis, and treatment options in patients with dilated cardiomyopathy.
From the outset, we hypothesised that dilated cardiomyopathy results from an environmental
insult in a genetically disposed individual, whereby inappropriate inflammation and metabolic
derangement ultimately lead to myocardial remodelling and ensuing heart failure. In this
thesis, we wanted to answer the following questions:
1) What are the causes of initially unexplained dilated cardiomyopathy, and what are the
diagnostic and therapeutic yields of an extensive diagnostic work-up?
2) What are the determinants of the novel biomarker ST2 in patients with dilated
cardiomyopathy, and are sST2 levels associated with outcome in these patients?
3) What is the prognosis in patients with dilated cardiomyopathy treated according to
contemporary, evidence based guidelines, and what are the determinants of left ventricular
remodelling and cardiovascular events and mortality in this population?
4) Can the hydroxymethylglutaryl-CoA reductase inhibitor rosuvastatin contribute to reverse
left ventricular remodelling in patients with dilated cardiomyopathy through effects on
inflammation and matrix remodelling?
20
3 PATIENTS AND METHODS
The first three papers derive from a prospective cohort study performed at our tertiary care
university hospital. The fourth paper, on rosuvastatin for dilated cardiomyopathy, describes a
randomised, controlled trial dubbed the EVRICA study (“Effect of rosuvastatin on left
Ventricular Remodeling and inflammatory markers in Idiopathic dilated Cardiomyopathy”)
This trial was initiated before the above-mentioned cohort study was designed. We recruited
some of the patients enrolled in the latter study from the cohort population, but many were
included at Oslo University Hospital before recruitment to the cohort study had started, and
some were enrolled at Drammen Hospital, Vestre Viken Hospital Trust, Drammen and St
Olav’s Hospital, Trondheim University Hospital, Trondheim.
Both studies comply with the Declaration of Helsinki and were approved by the Regional
Committee for Medical and Health Research Ethics (REK Sør-Øst). All patients provided
written, informed consent.
3.1 Patient population, paper I, II and III
For the cohort study, we included consecutive patients aged 18 or above with a referral
diagnosis of dilated cardiomyopathy, or with signs or symptoms that turned out to be caused
by non-ischaemic, non-valvular, and non-congenital heart failure. Inclusion criteria were an
end diastolic left ventricular internal diameter ≥ 6.5 cm and a left ventricular ejection fraction
< 40 %. Exclusion criteria were
ischaemic, hypertensive or valvular aetiology as judged by patient history, physical
examination, echocardiography and coronary angiography
21
other known or suspected causes of heart failure, such as myocarditis, metabolic
disease, toxins, radiotherapy or poorly controlled tachycardia
inotropic or mechanical support at admittance
implantable cardiac devices
severe concomitant disease such as infections, connective tissue disease, pulmonary
disease, cancer, serious psychiatric disease, life threatening ventricular arrhythmias,
severe kidney failure or severe hepatic failure
referral specifically for heart transplantation
From the 13th of October 2008 to the 16th of November 2012, a total of 265 patients admitted
to our tertiary care cardiology department were evaluated for participation, of whom 169 were
excluded from and 102 included in the study cohort. Figure 3 is a flow-chart depicting patient
selection, inclusion and follow-up.
22
Figure 3 Patient selection and follow-up
Some patients had several reasons for exclusion from participation
Known or
suspected cause of
dilated
cardiomyopathy*
(n = 37)
Patients screened
for participation
(n = 265)
Ischaemic
heart failure
(n = 9) Primary
valvular
heart disease
(n = 8)
LVEF above 40 %
or left ventricular
internal diameter
below 6.5 cm / 3.3
cm indexed
(n = 29)
Compliance
deemed poor
(n = 12)
Referred
specifically
for heart
transplant
evaluation
(n = 36)
Included
(n = 102)
Not included for
administrative
reasons (n = 5)
Intra cardiac
device
(n = 54)
Unwilling to
participate
(n = 3)
Required
mechanical or
inotropic support
(n = 17) Reduced life
expectancy due to
non-cardiac
disease (n = 7)
Transplanted or on
LVAD (n = 3)
Lost to short term
follow-up (n = 2)
Follow-up after 13
months (n = 95)
Transplanted
(n = 6), dead due
to worsening heart
failure (n = 2),
dead due to other
reasons (n = 2)
Alive and transplant-free after
median follow-up 3.5 (2.2 – 4.4)
years (n = 89)
Follow-up after 6
months (n = 97)
Lost to short term
follow-up (n = 4)
23
3.2 Patient population, paper IV
For the EVRICA trial, patients aged 18 to 80 years were eligible. In brief, the inclusion
criteria were symptomatic heart failure, a left ventricular ejection fraction < 40 % and no
current use of statins or indication for statins. Criteria for exclusion included decompensated
heart failure; heart failure of ischaemic aetiology; haemodynamically significant valvular
disease not considered secondary to ventricular dilation; recent or planned surgical procedures
or operations; significant concomitant disease such as infection, severe pulmonary disease or
connective tissue disease; acute or chronic liver disease; or contraindications to statin therapy
defined as hypersensitivity to any statin, alanine transaminase ≥ 2 times the upper limit of
normal, serum creatinine ≥ 2 mg/dL, an unexplained creatine kinase ≥ 3 times the upper limit
of normal, current or planned pregnancy, or breast feeding. According to the study protocol,
we aimed to include all together 75 patients, but due to slow recruitment and a low number of
dropouts, the recruitment was stopped after the enrolment of 72 patients. The trial flow chart
and population characteristics are presented in paper IV.
3.3 Study Procedures papers I through III
At baseline, participants underwent physical examination; blood tests including screening for
known monogenic causes of dilated cardiomyopathy; echocardiography; cardiac magnetic
resonance imaging; exercise testing with measurement of peak oxygen uptake; and right-sided
cardiac catheterisation with endomyocardial biopsy. After 6 months, physical examination,
blood tests and echocardiography were repeated. One year after inclusion, a second follow-up
was performed including physical examination, blood tests, echocardiography, exercise
testing with measurement of peak oxygen uptake, and magnetic resonance imaging.
24
3.4 Study procedures, paper IV
Paper 4 describes a multicentre, randomised, double blind, placebo-controlled trial designed
to assess the effect of rosuvastatin on left ventricular function in patients with DCM. It was
conducted at three sites in Norway. At baseline, all participants underwent physical
examination, blood tests, echocardiography and, unless contraindicated, cardiac magnetic
resonance imaging. Patients were then randomised in a 1:1 fashion to receive 10 mg of
rosuvastatin or matching placebo once a day in a double blind fashion. Physical examination,
blood tests, echocardiography and cardiac magnetic resonance imaging were repeated after six
months of intervention.
3.5 Imaging
3.5.1 Echocardiography
Echocardiography was performed mainly with Vivid 7, and in a few instances E9, ultrasound
scanners (GE Vingmed Ultrasound, Horten, Norway). We examined the patients in the lateral
recumbent position after > 5 minutes of rest. Three heartbeats were recorded with each
registration. Cine loops comprising ultrasound raw data were digitally stored and later
analysed off line using Echo-Pac (GE Vingmed). 2D parameters and conventional Doppler
parameters were measured according to current recommendations.105,106 Valvular
regurgitations were graded as mild, moderate or severe by visual assessment.107 Left
ventricular ejection fraction (LVEF) was measured by Simpson’s biplane method.105
3.5.2 Magnetic resonance imaging
Magnetic resonance imaging was performed with Siemens 1.5 tesla scanners (Siemens
Avanto and Siemens Sonata; Siemens Medical Systems, Erlangen, Germany). Left ventricular
25
long and short axis images were acquired using a prospectively ECG-triggered, segmented,
balanced steady-state free precession gradient-echo cine sequence with minimum echo and
repetition times, 6 mm slice thickness, 4 mm short-axis interslice gap, a spatial resolution of
1.9 mm x 1.3 mm, and a temporal resolution of 30-35ms. The endocardial borders were traced
manually using a PACS workstation (Sectra Medical Systems AB, Linköping, Sweden). Left
and right ventricular volumes and ejection fractions were calculated by short axis slice
summation. In the cohort study participants, images with late gadolinium enhancement (LGE)
were acquired 10 to 20 minutes after intravenous injection of 0.2 mmol/kg of gadoterat
meglumine (Guerbet, Villepinte, France) unless contraindicated due to a reduced glomerular
filtration rate. The total volume of late myocardial enhancement was quantified from visual
analysis of short axis slices covering both ventricles (Figure 4).
Figure 4 Cardiac magnetic resonance imaging with late Gadolinium enhancement
The image shows typical, mid-wall late enhancement (arrow) reflecting the septal fibrosis often seen in
patients with dilated cardiomyopathy
26
3.5.3 Image analysis
All image analysis was performed off-line. The analyses were performed in a blinded manner
and without knowledge of the results of the other image modalities. For the cohort study, the
echocardiograms were analysed by two researchers, Klaus Murbræch and Kaspar Broch.
Individual exams were de-identified and randomised, and image analysis was performed
blinded to patient characteristics and to whether the exam was performed at baseline or
follow-up. Repeatability was excellent, with an intra-observer intraclass correlation
coefficient for left ventricular ejection fraction of 0.95 (95 % confidence interval 0.93 – 0.97),
and an inter observer coefficient of 0.93 (0.89 – 0.95).
3.6 Measurement of peak oxygen consumption
Maximal, upright, symptom-limited exercise testing was performed using an electrically
braked bicycle ergo meter at a constant cadence of 60 rpm. The test employed an
individualised, stepwise protocol, with the load incrementally increased every minute. Based
on the patient’s age, gender, size, physical shape and symptoms, an expected maximum load
was estimated for each patient, and the test was designed to reach this load after
approximately 10 minutes. The test was discontinued at patient exhaustion (defined as an
inability to keep the pedalling rate steady at 60 rpm) or at the occurrence of arrhythmia, chest
pain, dizziness or other symptoms causing severe patient discomfort.
Simultaneous gas exchange and haemodynamic monitoring was performed on a Cardiovit CS-
200 unit (Schiller, Baar, Switzerland) using a Ganshorn PowerCube gas analyser (Ganshorn,
Niederlauer, Germany). Peak VO2 was defined as the VO2 achieved at maximum load at the
27
end of the exercise. Heart rate was recorded continuously by 12 lead electrocardiography, and
blood pressure was recorded at regular intervals throughout the test with a semi-automated
recorder. Perceived exertion was rated using the Borg’s RPE scale.108
3.7 Right-sided heart catheterisation
We performed right-sided heart catheterisation using a Swan–Ganz pulmonary artery
thermodilution catheter (Baxter Health Care Corp, Santa Ana, CA). Patients were not required
to fast. The following pressures were recorded: right atrial mean pressure, systolic pulmonary
artery pressure, mean pulmonary artery pressure, and mean pulmonary capillary wedge
pressure. The wedge position was verified by observing the typical changes in waveforms,
and by fluoroscopy. We measured cardiac output by the thermodilution technique, and cardiac
index was calculated by dividing cardiac output with body surface area. Septal right
ventricular endomyocardial biopsies were obtained for viral RNA/DNA detection, and
conventional and electron microscopy. In addition, for each patient two biopsies were snap
frozen and stored for future analyses.
3.8 Viral genome detection
We extracted total nucleic acid from the endomyocardial biopsy specimens and performed
real-time polymerase chain reaction assays for the detection of Enteroviruses (including
Coxsackievirus and Echovirus), Adenovirus, Human Parvovirus B19, Epstein-Barr virus,
Cytomegalovirus, and Human herpes virus 6 as described elsewhere.109
28
3.9 Conventional and electron microscopy
We fixed endomyocardial specimens with formalin, embedded the specimens in paraffin, and
sliced them into 5-μm sections. They were then stained with haematoxylin and eosin as well
as haematoxylin phloxine saffron and Congo stains for light microscopic examination.
In addition, we fixed biopsy fragments with glutaraldehyde and examined by electron
microscopy.
3.10 Blood sampling and laboratory analysis
Peripheral blood samples were obtained in the non-fasting state and collected in glass tubes
containing ethylenediamine tetraacetic acid, immediately centrifuged and analysed by routine
laboratory methods. We determined concentrations of N-terminal pro-B-type natriuretic
peptide by an electrochemiluminescence immunoassay (Roche proBNP II, Roche
Diagnostics, Basel, Switzerland). Levels of C-reactive protein were determined on a
MODULAR Analytical platform, P800 module (Roche Diagnostics) using a particle-
enhanced immunoturbidimetric assay (Tina-Quant CRP Gen.3, Roche Diagnostics).
Plasma for the measurement of sST2 was stored at –80ºC and thawed once for analysis.
Soluble ST2 was measured with the Presage® ST2 Assay (Critical Diagnostics, San Diego,
CA) as described by Dieplinger et al.110 Soluble tumour necrosis factor receptor type 1,
osteoprotegerin, soluble glycoprotein 130, matrix metalloproteinase-9 and monocyte
chemotactic protein-1/CCL2 were analysed by enzyme immunoassays obtained from R&D
Systems (Minneapolis, MN). Procollagen type I and III N-terminal pro-peptides were
analysed by radioimmunoassays (UniQ PINP RIA and UniQ PIIINP RIA, Orion Diagnostica,
Espoo, Finland). Von Willebrand factor was determined by an enzyme immunoassay as
29
previously reported.111 Inter-and intra-assay coefficients of variation were < 10 % for all
biochemical analyses.
3.11 Statistics
All statistical analyses were performed in IBM SPSS for Windows (IBM Corp., Armonk, NY,
USA) Values are presented as mean ± standard deviation, median (interquartile range) or no
(%) as appropriate. Baseline characteristics stratified by sST2 tertiles were analysed using one
way ANOVA for symmetric, continuous variables, Kruskal-Wallis test for asymmetric
continuous variables, and χ2 test for categorical variables. Temporal changes were assessed
with dependent Student’s t-tests or analysis of variance (ANOVA) for normally distributed
parameters, or by Wilcoxon’s or Friedman’s test for categorical parameters. Associations
between baseline characteristics and sST2, and between baseline parameters and left
ventricular ejection fraction at follow-up, were assessed by bivariate and multiple linear
regression. Associations between baseline values and the time to death or transplantation were
assessed by Cox regression. Skewed parameters were log transformed prior to analyses.
Differences in numerical outcome variables between patients treated with rosuvastatin and
patients treated with placebo were analysed using analysis of covariance (ANCOVA),
adjusting for baseline values.112 The number of adverse events was compared across treatment
groups by Poisson regression. All end point analyses were performed according to the
intention-to-treat principle.
30
4 SUMMARY OF RESULTS:
4.1 Paper I
In paper 1, we show that there are but modest diagnostic and therapeutic yields of performing
an extensive diagnostic work-up in patients with no suspected cause of dilated
cardiomyopathy based on patient history, clinical examination, coronary angiography and
echocardiography. Out of 102 patients with “idiopathic” dilated cardiomyopathy, only 15
received an aetiology-specific diagnosis based on genetic screening, magnetic resonance
imaging, and endomyocardial biopsies (Table 2).
Table 2 Diagnostic yield and therapeutic consequences of additional testing in “idiopathic”
dilated cardiomyopathy
Diagnostic test Diagnostic yield Therapeutic consequences
Cardiac MRI Two patients diagnosed with non-compaction cardiomyopathy
Oral anticoagulation initiated and ICDs implanted
MRI with gadolinium contrast Two patients diagnosed with cardiomyopathy in association with systemic inflammatory disease
Appropriate immunosuppressant therapy initiated
Right-sided cardiac catheterisation
None No direct therapeutic consequences. Haemodynamic data can be used to optimise diuretic treatment
Endomyocardial biopsy Two patients diagnosed with cardiac sarcoidosis* and ATTR-amyloidosis, respectively
Patient with sarcoidosis treated with prednisone
Exercise test with measurement of peak oxygen consumption
None Ventricular arrhythmia prompted ICD implantation in two patients. Peak oxygen consumption one of several parameters used in stratification for heart transplantation.
Twenty-four hour electrocardiogram
None No direct consequences. Detection of non-sustained ventricular tachycardia strengthens the case for ICD implantation
Genetic screening Ten patients diagnosed with possible disease-causing mutations
Finding prompted ICD implantation in one patient. Allowed for family screening.
* This patient was also diagnosed on cardiac MRI with late gadolinium enhancement. MRI = magnetic
resonance imaging; ICD = implantable cardioverter-defibrillator
31
4.2 Paper II
In this paper, we demonstrate that levels of circulating, soluble ST2 are associated with the
level of haemodynamic stress, but not with potential aetiological factors in patients with
dilated cardiomyopathy (Figure 5).
40 60 80 100 1202
3
4
5
6
r = 0.55p < 0.001
Heart rate (beats per minute)
ln(s
ST
2)
0 10 20 302
3
4
5
6
r = 0.44p < 0.001
Right atrial pressure (mmHg)
ln(s
ST
2)
0 10 20 30 40 502
3
4
5
6
r = -0.43p < 0.001
Left ventricular ejection fraction (%)
ln(s
ST
2)
A B
C D
0 10 20 30 40 502
3
4
5
6
r = 0.36p < 0.001
Pulmonary capillary wedge pressure
ln(s
ST
2)
Figure 5 Associations between sST2 and haemodynamic variables
Scatter plots illustrating the association between log-transformed soluble ST2 (ln(sST2) and heart rate
(panel A), right atrial pressure (panel B), left ventricular ejection fraction (panel C) and pulmonary
capillary wedge pressure (panel D). All p-values < 0.001. Adapted from Broch et al.113
32
4.3 Paper III
Symptomatic and left ventricular improvement occurred within a year in a large proportion of
patients referred to our tertiary care centre due to dilated cardiomyopathy. Moreover, we
found that their medium to long-term prognosis was favourable. A short duration of
symptoms and a relatively preserved left ventricular volume were predictors of a reasonably
good left ventricular function after one year. Determinants of the improvement in left
ventricular ejection fraction are presented in Figure 6. A small subgroup of patients with
particularly severe heart failure went on to receive cardiac allografts or died from progressive
heart failure.
33
Monogenic aetiology
Yes N
o
-20
0
20
40
60p = 0.67
Ch
an
ge
in
LV
EF
Viral persistence
Yes N
o
-20
0
20
40
60p = 0.84
Ch
an
ge
in
LV
EF
Atrial fibrillation
Yes N
o
-20
0
20
40
60p = 0.09
Ch
an
ge
in
LV
EF
Late Gadolinium enhancement
Yes N
o
-20
0
20
40
60 p = 0.22
Ch
an
ge
in
LV
EF
Duration of heart failure
Above
med
ian
Bel
ow m
edia
n
-20
0
20
40
60 p < 0.001
Ch
an
ge
in
LV
EF
Left ventricular end diastolic volume
Above
med
ian
Bel
ow m
edia
n
-20
0
20
40
60 p = 0.10
Ch
an
ge
in
LV
EF
A B
C D
E F
Figure 6 Determinants of left ventricular functional improvement
The improvement in left ventricular ejection fraction is independent of the presence of a monogenic
aetiology (A), viral persistence (B), atrial fibrillation (C) or late Gadolinium enhancement (D), but
improved significantly more in patients with a duration of symptoms below median (F). There was a
trend towards a more pronounced improvement in patients with a severely dilated ventricle from the
outset (E), but these patients had a worse left ventricular ejection fraction to start with. Boxes: 25 – 75
percentiles, whiskers 2.5 – 97.5 percentiles.
34
4.4 Paper IV
Paper IV shows that rosuvastatin does not contribute to left ventricular improvement in well-
treated, stable patients with symptomatic heart failure due to dilated cardiomyopathy. Neither
does rosuvastatin affect the serum levels of markers of inflammation or matrix remodelling in
this population (Figure 7).
Rosuvastatin Placebo
-20
-10
0
10
20
30
40p = 0.94
LVEF
Perc
en
tag
e p
oin
ts
Rosuvastatin Placebo
-6
-4
-2
0
2 p < 0.001
LDL
mm
ol/l
Figure 7 Changes in left ventricular ejection fraction and LDL cholesterol
The left panel illustrates the change in left ventricular ejection fraction (LVEF) stratified by treatment
allocation. There was no difference in the change in LVEF between the two groups as analysed by an
independent group t-test (p = 0.94). The right panel illustrates the change in LDL cholesterol stratified by
treatment allocation. The fall in LDL cholesterol occurred in patients allocated to rosuvastatin (p for
difference < 0.001). Boxes: 25-75 percentiles; whiskers: 10-90 percentiles. Modified from Broch et al.114
35
5 DISCUSSION
In this thesis, we show that the clinical value of diagnostic evaluation beyond careful history
taking, physical examination, routine blood sampling, echocardiography and coronary
angiography is limited in patients with “idiopathic” dilated cardiomyopathy. Serum levels of
sST2 seem to reflect the level of haemodynamic stress, rather than aetiological factors, in
these patients. Moreover, their short- and medium term prognosis is favourable, and
substantially better than some previous reports have indicated. Statins do not have a place in
the routine treatment of patients with dilated cardiomyopathy.
We took care to include patients with a definite dilated cardiomyopathy only. Current
guidelines define dilated cardiomyopathy as left ventricular dilation and dysfunction in the
absence of coronary disease, valvular disease or hypertension,14,16 but the degree of left
ventricular dysfunction and dilation required to make the diagnosis is not specified. There is
no consensus on what is the ideal cut-point for discerning dilated cardiomyopathy from
normal hearts.25,115 The upper limit of the normal left ventricular diameter (defined as the
average + 2 standard deviations) is 5.8 cm in males and 5.2 cm in females, corresponding to
3.0 and 3.1 cm/1.73 m2, respectively.116 To err on the safe side, in the cohort study we used
3.2 cm/m2 or, in very large patients (who were not included in the above reference materials),
an absolute value of 6.5 cm.
Several important randomised trials, starting with the ground-breaking SOLVD
investigations,85 have used an LVEF cut-point of 35 %. This is also true of the more recent
“device trials” such as DEFINITE. However, a number of major trials, including CIBIS117, the
cardiomyopathy-specific MDC87 trial, CHARM-Alternative118 and recently PARADIGM-
HF119 have used 40 % as a cut-off. Moreover, current guidelines use 40 % as a cut-point for
36
recommending pharmacological intervention.84 We therefore chose a cut-off of 40 % for left
ventricular ejection fraction when designing the EVRICA trial as well as the cohort study.
An in-depth medical assessment may serve many purposes. First and foremost, we examine
our patients in order to deliver correct therapy. If the aetiology is known, causal therapy may
be provided. A thorough evaluation may also yield prognostic information that can be
important for deciding whether to supply prophylactic therapies such as ICDs, how closely to
monitor the patients, and how to inform the patients and their kin. On another level, a
meticulous diagnostic work-up may help care providers better to understand disease
pathophysiology, and ultimately help devise new treatment/follow-up strategies. This latter
purpose is best served when the examinations are performed in a controlled study setting.
“Dilated cardiomyopathy” is a morphologically based diagnosis that covers myocardial
diseases of widely different aetiologies. However, most cases are labelled “idiopathic”,
meaning that the potential for cause-directed therapy remains unexploited. Many methods
have been used for diagnostic investigation of patients with dilated cardiomyopathy.
However, to our knowledge, the value of each of these methods has not been systematically
explored. We assessed the diagnostic and therapeutic yield of a comprehensive, multi-
modality work-up in dilated cardiomyopathy. The results could impact diagnostic strategies
for a relatively common disease. However, despite a “state of the art” diagnostic evaluation,
extensive testing did not reveal the cause of the heart failure in but a minority of our patients.
Naturally, this does not mean that the other patients do not have a cause for their myocardial
dysfunction, but rather serves to point out that our understanding of the aetiology in dilated
cardiomyopathy remains inadequate.
37
Genetic testing holds the promise to revolutionise the field of cardiology. In the case of
monogenic diseases, such as some cases of familial dilated cardiomyopathy, the approach
should theoretically be straight forward. However, in reality, there are several difficulties with
genetic testing as of today. One problem is that the distinction between a disease-causing
mutation and an innocent polymorphism can be difficult to make. As de novo mutations are
frequent and penetrance often incomplete, family history cannot necessarily be relied upon to
ascertain the pathophysiological importance of a particular mutation. In some cases, as in
early truncation of the protein in question, an assumption of clinical significance can be made
with some certainty. In other cases, prediction programs can be used. We used, and compared,
two such prediction programs, PolyPhen2 (http://genetics.bwh.harvard.edu/pph2/) and SIFT
(http://sift.jcvi.org/). As evident from Table 3 in our article no 1, there is not complete
agreement between the predictions made by these programs, and the results must be
interpreted with care.
On the other hand, unless an exploratory whole genome analysis is performed, the genetic
tests are restricted to genes already known to be involved in the pathogenesis of dilated
cardiomyopathy. Thus, mutations affecting genes that are not known to affect cardiac function
will not be discovered by the tests in use. Some of our patients had quite an impressive family
history including several family members with early onset heart failure, yet negative results
on genetic screening. This considered the proportion of our patients with monogenic aetiology
is probably underestimated.
None of our patients had primary myocarditis as defined by the Dallas criteria.120 However,
the sensitivity of these criteria for detecting myocarditis has been questioned,121,122 and more
subtle inflammation may have been present in a substantial proportion of our patients. We
38
found late enhancement, potentially representing fibrosis123 or areas of inflammation,124 in
approximately one third of our patients. This finding has been shown to herald an adverse
prognosis in patients with dilated cardiomyopathy.123,125,126 However, we did not find late
enhancement to be of prognostic importance in our patients. On the same note, viral
persistence was present in a sixth of our patients, but was not associated with outcome.
Previous studies have produced conflicting results regarding the clinical significance of
biopsy-proven myocardial viral persistence.24,127-129 Moreover, in the few studies to look for
traces of viral genome in the myocardium of patients free from heart failure, there has been a
similar prevalence of “viral persistence” in subjects without heart failure as in patients with
heart failure,130,131 calling into question the aetiological association between viral persistence
and dilated cardiomyopathy. Our results suggest that endomyocardial biopsy should be
performed in patients with dilated cardiomyopathy only when a specific aetiology is
suspected, or when the suspicion of primary inflammatory disease has been raised by
magnetic resonance imaging with Gadolinium late enhancement.
An important part of the diagnostic evaluation in patients with heart failure is cardiac
imaging. Whereas magnetic resonance imaging is widely regarded as the “gold standard” for
determining cardiac dimensions and volumes,132-135 echocardiography is the primary tool
when assessing most patients with cardiac disease. Echocardiography enables a
comprehensive evaluation of haemodynamic features as well as cardiac structure, is readily
available, relatively cheap, and can be used bedside. On the other hand, the use of gadolinium
contrast in magnetic resonance imaging allows for the identification of myocardial disease not
detectable by echocardiography, such as inflammation, subtle scarring and fibrosis.
39
I have mainly relied on echocardiography when describing the patient population in this
thesis. First, all of the patients were examined with echocardiography, whereas for various
reasons magnetic resonance imaging was not performed in some patients at baseline. At
follow-up, magnetic resonance imaging could not be done in a substantial portion of our
patients due to the large number of implantable intracardiac devices. Moreover, some of the
shortcomings of echocardiography, such as the limited resolution and tendency to
underestimate intracardiac volumes, can be overcome by the use of new equipment and
careful image acquisition and analysis. Figure 8 demonstrates the very high agreement
between echocardiography and magnetic resonance imaging in our patients.
40
0 200 400 600 8000
200
400
600
800
Y = 1.07 -3.4r = 0.91 (p<0.001)
LVEDV by Echo
LV
ED
V b
y M
RI
0 20 40 60 800
20
40
60
80
Y = 1.02 x + 1.8r = 0.88 (p<0.001)
LVEF by Echo
LV
EF
by
MR
IA
B
Figure 8 Left ventricular end diastolic volume and ejection fraction
Panel A depicts left ventricular end diastolic volume (LVEDV) and panel B left ventricular
ejection fraction (LVEF) by echocardiography and magnetic resonance imaging. The data
from baseline and follow-up are pooled. The Pearson correlation coefficients between results
obtained by magnetic resonance imaging and results obtained by echocardiography were 0.91
(p < 0.001) for LVEDV and 0.88 (p < 0.001) for LVEF.
41
The aetiology in dilated cardiomyopathy is heterogeneous, and the pathophysiology is
complex. There is a growing understanding that the “one treatment fits all” paradigm that
exists today should probably yield to individually tailored treatment. Biomarkers hold the
promise to help pinpoint patient-specific pathophysiological pathways and guide treatment.
Soluble ST2 is a cardiac biomarker that has been approved by the Food and Drug
Administration, and some regard it as “ready for prime time”. We believe that it is crucial to
know what a biomarker actually reflects, before it is used extensively in clinical practice.
Soluble ST2 is secreted by cardiomyocytes subjected to mechanical stress, but the source of
the elevated serum levels measured in patients with heart failure remains unsettled. Our
results show that the level of haemodynamic deterioration, more specifically right atrial
pressure and resting heart rate, are important determinants of sST2 levels. These findings,
when viewed in the light of basic science reports suggesting that the sST2 in heart failure is
not primarily released by cardiomyocytes,76,136 imply that sST2 may be a marker of
congestion, rather than myocardial disease. This fact possibly limits its potential usefulness as
a therapeutic target.
Outcome in the heart failure population at large has improved with the introduction of
treatment targeted at neurohormonal activation, malignant arrhythmias and dyssynchrony, but
remains dismal.11,84 On the other hand, there are several reports of rapid and sustained
improvement in patients with dilated cardiomyopathy, especially in patients with a short
duration of symptoms. In the late 1990ies, McNamara and colleagues observed a seemingly
impressive effect of intravenous immunoglobulin in patients with recent-onset dilated
cardiomyopathy.137 However, from the controlled trial that followed, it was apparent that the
improvement in left ventricular ejection fraction occurred independently of treatment
assignment: There was as large an improvement in controls as in patients assigned to active
42
treatment.51 Moreover, the overall survival rate in the subsequent IMAC trial was surprisingly
high.138 Since then, there has been a growing awareness of the fact that a large proportion of
patients presenting with “idiopathic” dilated cardiomyopathy and a short duration of
symptoms experience substantial symptomatic and left ventricular improvement.139
Judging from reports over the last three decades, there has been an unequivocal, and quite
impressive, improvement in the long-term survival of patients with dilated cardiomyopathy
with time. This improvement is probably, at least in part, due to the beneficial effect of
current, evidence based pharmacological treatment. Our very good results concerning median-
to-long-term, heart transplant-free survival must be viewed in the light of the very tight
adherence to recommended therapy in our population. On the other hand, this fact raises the
bar for the introduction of new therapeutic interventions: A new drug would have to not only
facilitate myocardial function, it would have to do so on top of the already substantial
improvement in left ventricular ejection fraction and survival conferred by existing therapy.
On this background, a new therapeutic intervention would probably have to target some of the
pathways that are not addressed by current, guideline-recommended therapy, such as
inflammation or ultrastructural remodelling.
The anti-inflammatory effect of statins has been widely studied, and a recent meta-analysis
concluded that statins can improve left ventricular ejection fraction in patients with heart
failure.140 The pleiotropic effects of statins are, however, not universally acknowledged.141
Our results suggest that statins do not affect ejection fraction, markers of inflammation or
matrix turnover in patients with dilated cardiomyopathy. We believe that this trial provides an
important contribution to the scientific evidence pertaining to the pleiotropic effects of statins,
and specifically call into question the clinical relevance of these effects.
43
Limitations
We present data from a well-characterised, extensively examined, prospective cohort
subjected to meticulous follow-up and little loss of data. However, the number of patients was
limited, and the inclusion criteria were strict, making broad generalisations to the entire
population of patients with dilated cardiomyopathy difficult. On the other hand, as the
diagnosis “dilated cardiomyopathy” covers such a heterogeneous disease, as far as both
aetiology and clinical manifestations are concerned, a very fastidious characterisation and
reporting of the actual sample at hand is required for the results to be reproducible.
Contraindications, technical difficulties and a very few complications precluded some
diagnostic test from being performed or analysed. We cannot exclude the possibility that a
few more aetiological diagnoses could have been made had every diagnostic option been
exhausted in every patient. The battery of genetic tests was limited, and did not include
primers for titin, truncations of which are known to be a common cause of dilated
cardiomyopathy.142 For administrative reasons, we were unable to perform
immunohistochemistry on biopsy specimens. Immunohistochemistry is more sensitive than
conventional light microscopic examination with regard to detecting subtle inflammation,40
and might have been useful to identify sub-clinical myocarditis.
The EVRICA trial was small, but the results were unequivocal, and unlikely to change
substantially with a larger number of subjects. Nonetheless, the study was underpowered to
detect small, but potentially relevant changes in inflammatory activity, extracellular matrix
remodelling and left ventricular function.
44
6 CONCLUDING REMARKS
In this thesis, my co-authors and I have shed new light on the value of comprehensive
aetiological evaluation, the involvement of a putative pathogenic pathway, the prognosis and
aspects of treatment in dilated cardiomyopathy. More specifically, we show that:
1) The clinical value of diagnostic evaluation beyond careful history taking, physical
examination, routine blood sampling, echocardiography and coronary angiography is modest
in patients with “idiopathic” dilated cardiomyopathy.
2) Serum levels of sST2 seem to reflect the level of haemodynamic stress, rather than
aetiological factors, in these patients.
3) With contemporary, evidenced based therapy, a majority of patients experience left
ventricular reverse remodelling along with a substantial and clinically significant symptomatic
and functional improvement. A short duration of symptoms on presentation is associated with
LV functional improvement, suggesting that patients with DCM should receive a complete
diagnostic work-up and evidence-based therapy as soon as possible. Their short- and medium
term prognosis is favourable, but a minority of patients presenting with particularly severe HF
subsequently die from HF or need orthotopic heart transplantation.
4) Statins do not contribute to reverse left ventricular remodelling in patients with dilated
cardiomyopathy, and should not have a place in the routine treatment of these patients.
45
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