Idiopathic dilated cardiomyopathy: possible triggers and treatment strategies

Toxic cardiomyopathy results from toxic exposure of a variety of cardiotoxic agents, most notably alcohol and chemotherapeutic drugs. Metabolic cardiomyopathies can be caused by a wide spectrum of pathological metabolic conditions (Table 1) [4].

Tachycardia-induced cardiomyopathy (TIC) is caused by sustained rapid ventricular rates and is one of the well-known forms of reversible myocardial diseases after the normalisation of heart rate. It may follow any type of chronic cardiac arrhythmia: supraventricular tachyarrhythmias, ventricular tachycardia, and frequent premature ventricular complexes. The diagnosis of TIC remains difficult since cardiomyopathy and tachycardia are often identified simultaneously [5]. In up to 70 % of the cases, a tachycardia is the symptom and not the cause of an underlying cardiomyopathy.

A gene mutation may be the cause of DCM in up to 30 % of the cases [3], therefore cardiogenetic screening is crucial in idiopathic DCM patients. The most common mode of inheritance is autosomal dominant transmission, although less common forms including X-linked, autosomal 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 subgroups: cytoskeletal and sarcomeric proteins. The cytoskeletal 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].

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 DCM is becoming more common in clinical practice. In turn, this is an opportunity to unravel the molecular complexity of inherited DCM and develop possible disease-modifying therapies in the future.

Virus infection may cause acute and chronic myocarditis, and viral persistence has been linked to the development of ‘idiopathic’ DCM. Until the 1990s, the most frequently reported viruses in patients in the developed countries were adenoviruses and enteroviruses. Recently, parvovirus B19 (B19V) and human herpes virus-6 are increasingly found in a significant percentage of patients diagnosed with both acute and chronic cardiomyopathy. While up to 50 % of young adults and up to 90 % of the elderly have been infected with these cardiotropic viruses, only an ‘unlucky few’ develop cardiac sequelae [6].

Endomyocardial biopsies (EMB) are the golden standard for the diagnosis of virus presence and inflammation in the heart. In the acute phase the living virus actively replicates within the myocardium, causing damage to cardiomyocytes and endothelial cells, in turn triggering the innate immune response. In most patients, this leads to viral clearance with subsequent adequate downregulation of the immune response resulting in a healthy recovered heart. However, in some patients the immune response is insufficient and clearance of the virus is not achieved. This may lead to viral persistence, causing progressive myocyte damage which may ultimately progress to biventricular dilatation with cardiac failure [6]. Therefore, a certain genetic background appears to be a prerequisite to developing clinical symptoms of myocarditis and/or progression to virus-induced DCM. This is illustrated by viral proteases which may cleave dystrophin, a cytosolic protein which is also affected in patients with Duchenne muscular dystrophy, leading to progression of heart failure symptoms in these patients.

The role of viral infections in autoimmune disease has been a topic of interest for over a century. There are two general mechanisms by which viruses may induce autoimmunity. Firstly, by providing or presenting the disease-initiating antigen inducing the innate immune response, and secondly by direct myocardial involvement of immune-mediated inflammatory damage.

While viral clearance by the innate immune response may improve clinical outcome, detrimental secondary effects may be triggered after the primary infection. Primed T-cells detect viral antigens and destroy infected cardiomyocytes through Fas/Fas ligand, TNF-alpha, cytokine and perforin pathways. In addition, some host myocardial cellular antigens may share epitopic similarities (molecular mimicry) with viral antigens, and may therefore induce an autoimmune response that can sustain the inflammatory response even after initial viral elimination. This autoimmune response induces a chronic inflammatory phase leading to immune-mediated myocyte damage.

Secondly, besides a primary virus trigger for immune dysregulation, also organ-specific and systemic immune-mediated diseases such as Wegener granulomatosis, Churg-Strauss syndrome or sarcoidosis are known to directly affect the heart. Cardiac involvement is one of the complications that substantially contribute to mortality and morbidity in patients with systemic inflammatory diseases. In addition, increased serum markers for immune activation and autoantibodies (i.e. α/β-myosin heavy chain, myosin light chain, troponin) may be detected in patients with autoimmune-mediated inflammatory disease [7]. General screening for this immune dysregulation with subsequent increased serum markers is performed by measuring atrial natriuretic factor, soluble interleukin-2 and neopterin levels.