Neth Heart J (2012) 20:332–335

DOI 10.1007/s12471-012-0285-7

ICIN

Idiopathic dilated cardiomyopathy: possible triggers

and treatment strategies
M. Hazebroek & R. Dennert & S. Heymans

Published online: 22 May 2012

# The Author(s) 2012. This article is published with open access at Springerlink.com

Abstract Despite recent advances in the management of Introduction

patients with heart failure, morbidity and mortality rates
remain high. Common causes of heart failure are ischae- Despite recent advances in the management of patients
mic heart disease, uncontrolled hypertension and valvular with heart failure, morbidity and mortality rates remain
disease. However, in up to 50 % of the cases its exact high. It is the only cardiovascular disease that has in-
cause remains initially unknown; this condition is called creased in prevalence over the last 20 years [1]. With
idiopathic dilated cardiomyopathy (DCM). Improved di- over 200,000 patients suffering from heart failure in the
agnostic methods, most notably the advancements in Netherlands, it continues to impose a great burden on the
molecular and immunohistological biopsy techniques health care system. Common causes of heart failure are
and genetic research, have endorsed a new era in the ischaemic heart disease, uncontrolled hypertension and
diagnosis and classification of patients with idiopathic valvular disease. However, in up to 50 % of the cases
DCM. These insights have led to novel aetiology-based its exact cause remains initially unknown; this condition
treatment strategies and improved outcome. The present is called idiopathic dilated cardiomyopathy (DCM) [2].
article will briefly discuss all causes of DCM with a Patients with idiopathic DCM are relatively young, ranging
special focus on inflammatory- and virus-mediated forms between 20 and 60 years, and often still in the prime of their
of DCM. lives. To discriminate different aetiologies of DCM, specific
diagnostic methods including serum markers, cardiac biopsies
Keywords Idiopathic dilated cardiomyopathy . and genetic screening are crucial to improve care and outcome
Possible triggers . Viral-mediated . Inflammatory mediated . in these patients.
Treatment strategies

Triggers of idiopathic dilated cardiomyopathy

M. Hazebroek : R. Dennert : S. Heymans
Department of Cardiology, CARIM,
DCM may be the consequence of a wide variety of causes,
University Hospital Maastricht,
Maastricht, the Netherlands including virus-mediated disease, immune dysregulation,
toxic and metabolic, inherited, and tachycardia-induced
S. Heymans conditions (Fig. 1) [2, 3]. We will briefly discuss all
Interuniversity Cardiology Institute of the Netherlands,
the possible triggers of DCM with a special focus on
Utrecht, the Netherlands
inflammatory- and virus-mediated forms of DCM.
S. Heymans (*)
Center for Heart Failure Research Cardiovascular Research Toxic and metabolic triggers
Institute Maastricht (CARIM), University Hospital Maastricht,
P. Debyelaan 25,
6229 HX Maastricht, the Netherlands Toxic cardiomyopathy results from toxic exposure of a
e-mail: s.heymans@maastrichtuniversity.nl variety of cardiotoxic agents, most notably alcohol and
Neth Heart J (2012) 20:332–335 333

idiopathic DCM patients. The most common mode of

inheritance is autosomal dominant transmission, al-
though less common forms including X-linked, autoso-
mal recessive and mitochondrial inheritance have also
been described. So far, 40 genes have been described
underlying inherited forms of idiopathic DCM. The
mutated genes predominantly encode two major sub-
groups: cytoskeletal and sarcomeric proteins. The cyto-
skeletal proteins include dystrophin, desmin, lamin A/C,
δ-sarcoglycan, β-sarcoglycan and metavinculin. In case of the
sarcomeric proteins they include β-myosin heavy chain,
myosin-binding protein C, actin, α-tropomyosin, and cardiac
troponin T and C. Furthermore, phospholamban, tafazzin and
the sodium-channel gene SCN5A have also been reported [3].
Fig. 1 Possible triggers of idiopathic dilated cardiomyopathy With the upcoming awareness of the importance of a
patient’s genetic background and the increasing numbers
of mutated genes found, genetic testing for idiopathic
chemotherapeutic drugs. Metabolic cardiomyopathies can DCM is becoming more common in clinical practice. In
be caused by a wide spectrum of pathological metabolic turn, this is an opportunity to unravel the molecular com-
conditions (Table 1) [4]. plexity of inherited DCM and develop possible disease-
modifying therapies in the future.
Tachycardia-induced cardiomyopathy
Virus infection
Tachycardia-induced cardiomyopathy (TIC) is caused by
sustained rapid ventricular rates and is one of the well- Virus infection may cause acute and chronic myocardi-
known forms of reversible myocardial diseases after the tis, and viral persistence has been linked to the devel-
normalisation of heart rate. It may follow any type of opment of ‘idiopathic’ DCM. Until the 1990s, the most
chronic cardiac arrhythmia: supraventricular tachyar- frequently reported viruses in patients in the developed
rhythmias, ventricular tachycardia, and frequent prema- countries were adenoviruses and enteroviruses. Recently,
ture ventricular complexes. The diagnosis of TIC remains parvovirus B19 (B19V) and human herpes virus-6 are
difficult since cardiomyopathy and tachycardia are often increasingly found in a significant percentage of patients
identified simultaneously [5]. In up to 70 % of the cases, diagnosed with both acute and chronic cardiomyopathy.
a tachycardia is the symptom and not the cause of an While up to 50 % of young adults and up to 90 % of
underlying cardiomyopathy. the elderly have been infected with these cardiotropic
viruses, only an ‘unlucky few’ develop cardiac sequelae
Inherited triggers [6].
Endomyocardial biopsies (EMB) are the golden stan-
A gene mutation may be the cause of DCM in up to 30 % of dard for the diagnosis of virus presence and inflammation
the cases [3], therefore cardiogenetic screening is crucial in in the heart. In the acute phase the living virus actively

Table 1 Classification of toxic

and metabolic cardiomyopathies Infiltrative Amyloidosis (primary, familial autosomal dominant, senile, secondary forms)
Gaucher disease, Hurler’s disease and Hunter’s disease
Storage Haemochromatosis, Anderson-Fabry disease, glycogen storage disease (Pompe),
Niemann-Pick disease
Nutritional deficiencies Beriberi (thiamine), pellagra, scurvy, selenium, carnitine, nutritional disorder
such as kwasiorkor
Endocrine Diabetes mellitus, hyperthyroidism, hypothyriodism, hyperparathyroidism,
pheochromocytoma
Toxicity Alcohol, drugs (cocaine, catecholamines, lithium, phenothiazines, methysergide),
heavy metals (cobalt, lead, arsenic) and chemical agents
Consequence of cancer Anthracyclines (doxorubicin, daunorubicin), cyclophosphamide and radiation
therapy
334 Neth Heart J (2012) 20:332–335

replicates within the myocardium, causing damage to car- is performed by measuring atrial natriuretic factor, sol-
diomyocytes and endothelial cells, in turn triggering the uble interleukin-2 and neopterin levels.
innate immune response. In most patients, this leads to
viral clearance with subsequent adequate downregulation
of the immune response resulting in a healthy recovered Treatment strategies for idiopathic DCM
heart. However, in some patients the immune response is
insufficient and clearance of the virus is not achieved. The goals of treatment in patients with idiopathic DCM
This may lead to viral persistence, causing progressive are to improve survival, slow disease progression, min-
myocyte damage which may ultimately progress to biven- imise risk factors, and alleviate symptoms. A standard
tricular dilatation with cardiac failure [6]. Therefore, a heart failure regimen with lifestyle modifications should
certain genetic background appears to be a prerequisite be initiated in all patients with this cardiac disease,
to developing clinical symptoms of myocarditis and/or including ACE inhibitors, angiotensin-II receptor antag-
progression to virus-induced DCM. This is illustrated by onists, beta-blockers, diuretics, aldosterone antagonists,
viral proteases which may cleave dystrophin, a cytosolic and digitalis. In some select patients known with
protein which is also affected in patients with Duchenne rhythm disturbances and/or increased risk of sudden
muscular dystrophy, leading to progression of heart failure cardiac death, resynchronisation therapy combined with
symptoms in these patients. an implantable cardioverter device should be considered
to reduce morbidity and mortality.
Immunological triggers Besides standard heart failure therapy, determination of
the aetiology of idiopathic DCM is essential to initiate
The role of viral infections in autoimmune disease has been treatment strategies if possible. In some cases, the specific
a topic of interest for over a century. There are two general condition can be addressed, such as alcohol abuse and
mechanisms by which viruses may induce autoimmunity. chemotherapy, to prevent disease progression. Catheter
Firstly, by providing or presenting the disease-initiating ablation should be considered in idiopathic DCM patients
antigen inducing the innate immune response, and secondly with frequent monomorphic PVCs (>10 % of QRS com-
by direct myocardial involvement of immune-mediated plexes), sustained rapid supraventricular tachyarrhythmias
inflammatory damage. or ventricular tachycardias.
While viral clearance by the innate immune response In case of a previously unknown inflammatory heart
may improve clinical outcome, detrimental secondary disease, distinction between virus-positive and virus-
effects may be triggered after the primary infection. negative inflammatory DCM, performed with EMB, is
Primed T-cells detect viral antigens and destroy infected crucial. Currently, sparse studies have investigated the role
cardiomyocytes through Fas/Fas ligand, TNF-alpha, cy- of antiviral therapy in an inflammatory DCM with viral
tokine and perforin pathways. In addition, some host presence. Recently, a pilot study with high-dose intravenous
myocardial cellular antigens may share epitopic similar- immunoglobulin (2 g/kg), known to especially eliminate the
ities (molecular mimicry) with viral antigens, and may most frequently found B19V in cardiac biopsies, has dem-
therefore induce an autoimmune response that can sus- onstrated favourable effects on both cardiac function as well
tain the inflammatory response even after initial viral as virus elimination in virus-positive inflammatory DCM
elimination. This autoimmune response induces a chronic patients [8]. Therefore, a randomised, double-blind, placebo-
inflammatory phase leading to immune-mediated myocyte controlled study has been initiated in patients with unex-
damage. plained heart failure related to a significant B19V myocardial
Secondly, besides a primary virus trigger for immune persistence (>200 copies/μg DNA).
dysregulation, also organ-specific and systemic immune- In the case of virus-negative inflammatory DCM
mediated diseases such as Wegener granulomatosis, patients, a randomised controlled trial has recently dem-
Churg-Strauss syndrome or sarcoidosis are known to directly onstrated the beneficial effects of immunosuppressive
affect the heart. Cardiac involvement is one of the therapy on myocardial function [9]. Patients received
complications that substantially contribute to mortality either prednisone and aziathioprine for 6 months (43
and morbidity in patients with systemic inflammatory patients) or placebo (42 patients) in addition to conven-
diseases. In addition, increased serum markers for im- tional heart failure therapy for 6 months. Although other
mune activation and autoantibodies (i.e. α/β-myosin studies have also investigated the effects of immunosup-
heavy chain, myosin light chain, troponin) may be pression in autoimmune-mediated inflammatory DCM
detected in patients with autoimmune-mediated inflam- (diagnosed by human leucocyte antigens or circulation auto-
matory disease [7]. General screening for this immune antibodies), only Frustaci et al. confirmed the absence of
dysregulation with subsequent increased serum markers cardiotropic viruses in endomyocardial biopsies within his
Neth Heart J (2012) 20:332–335 335

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