Novel Cardiomyopathies
Arrhythmogenic right ventricular cardiomyopathy (ARVC), formerly known as right ventricular dysplasia, was found at post-mortem to be a major cause of sudden death in the young [1]. The striking feature is the prevalent involvement of the right ventricular myocardium, with fibro-fatty replacement and parchment-like thinning as well as aneurysms of the free wall [2]. Cardiac dysfunction is mostly characterized by ventricular arrhythmias with left bundle branch block morphology, indicating right ventricular origin [3]. Ventricular arrhythmogenicity is precipitated by effort, thus explaining why this myocardial disorder is reported as the most frequent cause of sudden death in athletes [4]. A similar cardiomyopathy was reported in cats [5] and dogs [6]. The myocardial disappearance is progressive. Genetically determined dystrophy, myocarditis and myocyte apoptosis, have been postulated to play a role in the cell loss [3, 7] . Why healing occurs through fatty tissue replacement it remains intriguing. In nearly 50% of cases the disease is inherited with an autosomal dominant pattern, variable penetrance and polymorphic phenotype; certainly, ARVC is not a congenital heart disease due to a myocardial maldevelopment (ie dysplasia), since the myocardial disappearance occurs late during childhood [8]. Naxos disease is a recessive form of ARVC with high penetrance, associated with palmoplantar keratosis and wholly hair [9]. A similar phenotype expression is shown by other cardiocutaneous disease like Carvajal syndrome [10].

Another novel disease is primary restrictive cardiomyopathy [11]. Diastolic ventricular filling is impaired, whereas systolic function is usually preserved. Congestive heart failure may be so severe as to require cardiac transplantation [12]. The ventricles are of normal size, whereas the atria are remarkably dilated as to indicate the difficulty to empty during diastole because of ventricular myocardium stiffness. The ventricular diastolic impairment is the consequence neither of endocardial thickening like in eosinophilic obliterative cardiomyopathy nor of amyloid extracellular deposits. Myocardial disarray and interstitial fibrosis are the striking features at histology [13].

A third novel entity is non-compacted myocardium where the heart is featured by coarse trabeculations of the ventricular myocardium with so deep intrertrabecular spaces that the endocardium almost reaches the epicardium [14]. This human heart resemble the heart of animals without epicardial coronary arteries where the myocardial blood supply comes directly from the cavities through sinusoids. The defect is ascribable to an arrested development, with lack of compaction following embryonic myocardium undermining [15].

Update of WHO Classification
The discovery of new entities, not contemplated in the 1980 WHO classification, fostered the need to update the classification. Primary restrictive and arrhythmogenic right ventricular cardiomyopathies were added within the list [16] (Table 1).

Table 1 - Cardiomyopathy Classifications: 1980 versus 1995

1980	1995
Dilated	Dilated
Hypertrophic	Hypertrophic
Restrictive	Restrictive
	Arrhythmogenic right ventricular

A new definition of cardiomyopathy was put forward ("disease of the myocardium associated with cardiac dysfunction") considering that the previous ("heart muscle disease of unknown etiology") was aged in the light of genetic discoveries (Table 2).

Table 2 - Cardiomyopathy Definition: 1980 versus 1995

1980	1995
CARDIOMYOPATHY	CARDIOMYOPATHY
Heart muscle disease of unknown cause	Disease of the myocardium associated with cardiac dysfunction
SPECIFIC HEART MUSCLE DISEASE	SPECIFIC CARDIOMYOPATHY
Heart muscle disease of known cause or associated with disorders of other systems	Heart muscle disease associated with specific cardiac or systemic disorders

Non-compacted myocardium was also listed among the non-classified cardiomyopathies, together with mitochondrial cardiomyopathies and endocardial fibroelastosis.

Specific heart muscle diseases associated with cardiac or systemic disorders, like amyloids and haemochromatosis, are now named specific cardiomyopathies.

Myocarditis, mostly ignored in the early 1980 classification [17], is included within specific cardiomyopathies with the name "inflammatory cardiomyopathy". Ischemic, valvular and hypertensive diseases are also regarded as specific cardiomyopathies, when the severity of myocardial dysfunction largely exceeds the extent of the basic defect.

No question that the introduction of a unified terminology and the recognition of new entities are to be considered steps forward. A major concern has been arisen on the opportunity to extend the concept of cardiomyopathies to dysfunctioning myocardium due to coronary artery, valvular and hypertensive disease, in which the damage to the myocardium traditionally has been considered secondary [18].

Understanding the Etiology of Cardiomyopathies
The extraordinary advances accomplished in the last two decades in molecular genetics have allowed the identification of the gene defects in many monogenic hereditary cardiomyopathies, inherited according to the Mendelian law.

Hypertrophic cardiomyopathy was discovered to be a "sarcomeric" disase in so far as most mutations were found in genes encoding sarcomeric proteins (β-myosin heavy chain, α-tropomyosin, myosin binding – protein C, troponin T, C, I), thus accounting for impairment of force generation [19]. The same familial idiopathic restrictive cardiomyopathy was found to be a sarcomeric disease due to mutation of troponin I [20].

On the opposite, in familial forms of dilated cardiomyopathy the mutated genes are those coding cytoskeletal proteins, related to force transmission: dystrophin, cardiac actin, desmin, δ-sarcoglycan [21].

In ARVC as well as in cardiocutaneous syndromes genes encoding cell junction proteins, like plakoglobin [22], desmoplakin [23, 24] and plakophilin [25], were found to show causative missense mutations or deletions.

Remodelling of gap junctions, presumably because of abnormal linkage between the mechanical junctions and the cytoskeleton, was also demonstrated, probably enhancing the arrhythmogenic risk [26].

As far as inflammatory cardiomyopathy, the introduction of molecular biology techniques as routine diagnostic procedures, like PCR and RT-PCR, allowed the identification of viral genome in nearly 50% of biopsy proven myocarditis as well as the discovery of new cardiotropic viruses, like adeno- and parvoviruses [27]. These findings entail important implications in the choice of pharmacological therapy, whether antiviral or immunosuppressive [28].

Future Perspectives
The new definition of cardiomyopathy is based on the concept of myocardial disease associated with cardiac dysfunction [16]. If we accept that the term dysfunction should include not only depressed contractility and impaired relaxation, but also conduction and rhythm disturbances as well as enhanced myocardial arrhythmogenicity, then we have to realize that myocardial electrical diseases do exist in the absence of structural abnormalities: long and short QT syndromes [29, 30] , Brugada syndrome [31] and cathecolaminergic polymorphic ventricular tachycardia [32] in which the defect is ascribable to ion channel disorders. These defects are invisible even at ultrastructural levels through electron microscopy, nonetheless the function of the myocyte is abnormal. These disturbances should be considered cardiomyopathies too [18].

A genomic-postgenomic classification of inherited cardiomyopathies may be postulated by taking into account the underlying gene mutations and the encoded defective proteins and then distinguishing cytoskeleton, sarcomeric and ion channel cardiomyopathies [33] (Table 3).

Table 3 - A Genomic/Post-genomic Classification of Inherited Cardiomyopathies

Cytoskeletal cardiomyopathy ("cytoskeletalopathy")	Dilated cardiomyopathy, Arrhythmogenic right ventricular cardiomyopathy, Cardiocutaneous syndromes
Sarcomeric cardiomyopathy ("sarcomyopathy")	Hypertrophic and restrictive cardiomyopathy
Ion channel cardiomyopathy ("channelopathy")	Long and short QT syndromes, Brugada syndrome, Catecholaminergic polymorphic VT

What was considered for years as idiopathic ("unknown"), and as such at the base of the early classification, was largely elucidated by the finding of a genetic background or a viral etiology.

Proteomics, with the employment of microarrays for the study of myocyte biology and protein expression, as well as investigation of cytokine overexpression in inflammatory cardiomyopathies [34], will be of great help to understand the pathogenesis of the disease and to pursue other possible therapeutic targets.

Molecular biology and genetics are becoming a routine tool for the pathologist and the gold standard for the diagnosis of infective or genetic disease. They should not be limited to in vivo studies, but also used for achieving a definitive diagnosis at autopsy in cases of sudden death "sine materia" [35].

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