Primary myopathies and the heart

Abstract

Myopathies are frequently not confined to the skeletal muscles but also involve other organs or tissues. One of the most frequently affected organ in addition to the skeletal muscle is the heart (cardiac involvement, CI). CI manifests as impulse generation or conduction defects, focal or diffuse myocardial thickening, dilation of the cardiac cavities, relaxation abnormality, hypertrophic, dilated, restrictive cardiomyopathy, apical form of hypertrophic cardiomyopathy, noncompaction, Takotsubo phenomenon, secondary valve insufficiency, intra-cardiac thrombus formation, or heart failure with systolic or diastolic dysfunction. CI occurs in dystrophinopathies, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy, limb girdle muscular dystrophies, laminopathies, congenital muscular dystrophies, myotonic dystrophies, congenital myopathies, metabolic myopathies, desminopathies, myofibrillar myopathy, Barth syndrome, McLeod syndrome, Senger's syndrome, and Bethlem myopathy. Patients with myopathy should be cardiologically investigated as soon as their neurological diagnosis is established, since supportive cardiac therapy is available, which markedly influences prognosis and outcome of CI in these patients.

• Neuromuscular disorders
• genetics
• electromyography
• muscle
• heart
• electrocardiography
• echocardiography

One of the organs most frequently affected in addition to the skeletal muscle in myopathies is the heart (cardiac involvement, CI) 1. Since the first recognition of muscular dystrophies in the second half of the 19^th century CI has been described in various other primary myopathies and is even the dominant feature in some of them (Table I) 2. CI in myopathies comprises impulse generation or impulse propagation defects, myocardial abnormalities, secondary valve insufficiency, intracardial thrombus formation, or heart failure with systolic or diastolic dysfunction (Table II). Early recognition of CI is warranted, since appropriate, supportive treatment greatly influences management and thus outcome and prognosis of these patients.

Table I.  Primary myopathies with cardiac involvement.

Type of myopathy	MI	GL	G/GP	Reference
Dystrophinopathies	Xr	Xq21	Dystrophin	8
Emery-Dreifuss MD	Xr	Xq28	Emerin	13
	ad	1q11–23	Lamin A/C	9
Facioscapulohumeral MD	ad	4q35	Tandem repeat deletion	13
Limb-girdle MD 1B	ad	1q11-q23	Lamin A/C	10
Limb-girdle MD 1C	ad	3p25	Caveolin-3	17
Limb-girdle MD 2B	ar	2p13.3	Dysferlin	22
Limb-girdle MD 2C	ar	13q12	γ-Sarcoglycan	20
Limb-girdle MD 2D	ar	17q12-q21.33	α-Sarcoglycan	16, 20
Limb-girdle MD 2E	ar	4q12	β-Sarcoglycan	20
Limb-girdle MD 2F	ar	5q33–34	δ-Sarcoglycan	16
Limb-girdle MD 2I	ar	19q13.3	Fukutin related protein	18
Fukuyama congenital MD	ar	9q31–33	Fukutin	27
Merosin deficient congenital MD	ar	6q2	Laminin α2	29
Rigid spine syndrome	ar	1p36	Selenoprotein N1	30
Myotonic dystrophy type 1	ad	19q13.3	MDPK	16
Myotonic dystrophy type 2	ad	3q	Zinc-finger protein 9	42
Nemaline myopathy	ar, ad	1q42.1	α-Actin	46
	ar	1q21–23	α-Tropomyosin	45
	ar	2q21.2–22	Nebulin	33
Central core disease	ad	19q13.1	Ryanodine receptor.	109
Centronuclear myopathy	ad	19p13.2	Dynamin 2	52
Desminopathy (granulofilamentous)	ad	2q35	Desmin	109
Myofibrillar myopathy	ad	10q22.3–23.2	Cypher/ZASP	55, 56
Distal myopathy and rimmed vacuoles	ar	9p1-q1	GNE (IBM2)	58
Glycogenosis IIa (Pompe)	ar	17q23	α-Glucosidase	60
Glycogenosis IIb (Danon)	Xd	Xq24	LAMP-2	67
Glycogenosis III (Forbes)	ar	1p21	Debrancher enzyme	67
Glycogenosis IV (Andersen)	ar	uk	Branching enzyme	61
Glycogenosis VII (Tarui)	ar	1cen-q32	Phosphofructokinase	62
Glycogenosis IX	Xr	Xq13	Phosphoglycerate kinase	63
Primary carnitine deficiency	ar	5q31	OCTN2 (SLC22A5)	70
CACT deficiency	ar	3p21.31	CACT	69
CPT2 deficiency	ar	1p32	CPT2	69
VLCAD	uk	17p	Acyl-Co-A dehydrogenase	75
Respiratory chain disorders	mi, ad, ar	mtDNA	Respiratory chain complexes,	54
		nDNA	tRNAs, rRNAs
Myoadenylat-deaminase deficiency	ar	5q31	Myoadenylat-deaminase	83
Barth syndrome	Xr	Xq28	Taffazin	86
Bethlem myopathy	ad	21q22.3	Collagen VI α1 + 2-subunit	90
	ad	2q37	Collagen VI α3-subunit	90
McLeod syndrome	Xr	Xp21.1	Kell Antigen	95
Senger's syndrome	ar	4q35	ANT1	84
Rippling muscle disease	ad	3p25	Caveolin-3	96

MI: mode of inheritance, GL: gene location, G/GP: gene/gene product, MD: muscular dystrophy, CACT: carnitin/acyl-carnitin translocator, CPT2: carnitin-palmitoyl-transferase 2, VLCAD: very-long chain acyl-CoA dehydrogenase deficiency, ad: autosomal dominant, ar: autosomal recessive, mi: maternally inherited, Xr: X-chromosomal recessive, Xd: X-chromosomal dominant, uk: unknown, MDPK: muscular dystrophy phosphokinase, ZASP: Z-band alternatively spliced PDZ-motif containing protein, GNE: UDP-GlcNAc2-epimerase, LAMP2: Lysosomal associated protein 2, OCTN: organic cation/carnitine transporter, ANT1: adenine nucleotide translocator.

Table II.  Cardiac abnormalities in primary myopathies.

Abnormality	Definition
Impaired impulse generation or conduction	Predefined electrocardiographic abnormalities
Focal or diffuse myocardial thickening	Posterior wall and septum >11mm
Dilation of the cardiac cavities	Left atrium: >40mm, left ventricle: >58mm in diastole
Impaired relaxation	E/A-ratio <1
Hypertrophic cardiomyopathy	Coronary angiography normal, posterior or septal wall thickness >15mm, FS >25%
Dilated cardiomoypathy	Normal coronary angiography, FS <25%, LVEDD >60mm
Restrictive cardiomyopathy	Normal systolic function, enlarged atria, deceleration time <150ms
Apical hypertrophic cardiomyopathy	Apical hypertrophy, apical aneurysm on MRI
Left-ventricular hypertrabeculation	>3 coarse trabeculations apically to the papillary muscles, interventricular spaces perfused from the ventricular side
Takotsubo phenomenon	Angina, normal coronary angiography, hypokinesia of the apex and anterior and posterior wall, apical ballooning, initially ST-elevation and QT-prolongation, afterwards negative T for weeks or months
Secondary valve insufficiency	Aortic or mitral insufficiency from dilation of the cardiac cavities
Intracardiac thrombus formation	From atrial fibrillation, severe dilation, PFO-closure, closure of the left atrial appendage
Heart failure (clinical diagnosis)	Systolic dysfunction (fractional shortening <30%) Diastolic dysfunction (a) classic (E/A-ratio <1), b) restrictive (tall E-wave, deceleration time <150ms), c) pseudonormalisation (in case of concomitant systolic dysfunction)

FS: fractional shortening, PFO: patent foramen ovale, LVEDD: left ventricular enddiastolic diameter, MRI: magnetic resonance imaging.

Diagnosing myopathies

The diagnosis of myopathies relies upon a comprehensive individual and family history, clinical neurologic examination, blood chemical investigations at rest or during exercise, nerve conduction studies and electromyography, muscle biopsy with histological, immunehistological or biochemical investigations, and genetic studies. Special attention should be directed towards the family history, particularly if other family members are also affected and present with the same or different manifestations.

Symptoms patients with myopathy report comprise those attributable to the skeletal muscle and those attributable to extra-cardiac manifestations. Symptoms of muscle affection are easy fatigability, exercise intolerance, spontaneous or induced muscle cramps, muscle aching after slight exercise, myalgias, muscle stiffness, double vision, drooping eyelid, fasciculations, transient or fixed weakness and wasting of limb, trunc, or facial muscles, scapular winging, dysphagia, dysarthria, gait disturbance, difficulties to get up from a chair or the floor, difficulties to carry the head, falls, or dark urine.

Signs of muscle affection on clinical neurologic examination include double vision, ptosis, ophthalmoparesis, myopathic face, tongue atrophy, focal or generalized transient or fixed, symmetrical or asymmetrical weakness, scapular winging, reduced tendon reflexes, muscle hypotonia, clinical myotonia, fasciculations, myokymia, pseudohypertrophy (calves, masseter, tongue), a positive Gower sign, gait disturbance (waddling gait, steppage gait), joint contractures, thorax deformities, or spinal deformities.

Cardiac manifestations of myopathies

CI in myopathies manifests as impulse generation or conduction abnormalities, myocardial abnormalities, secondary valve insufficiencies, or thrombogenic states. There are no pathognomonic electrocardiographic (ECG) abnormalities typical for CI in myopathies. All types of blocking, bradycardious or tachycardious supraventricular or ventricular ECG abnormalities can be observed. However, particular patterns are more frequent with the one than the other disorder. Atrio-ventricular (AV) block I can be found in two thirds of the patients with myotonic dystrophy type I. Atrial fibrillation occurs in almost all patients with laminopathies and in many of those with mitochondrial disorders. Complete AV-block is a frequent cardiac feature of Emery-Dreifuss muscular dystrophy (EDMD). Myocardial manifestations of CI are listed in Table III, 3. In case of dilation of the cardiac cavities dilation of the anulus may result in secondary valve insufficiency. Atrial fibrillation and severe dilation may be associated with hypercoagulability.

Table III.  Myopathies associated with hypertrophic, dilative, restrictive cardiomyopathy or with LVHT.

Disorder	Reference
Associated with hypertrophic cardiomyopathy
Becker muscular dystrophy	110
Laminopathy	12
Limb girdle muscular dystrophy	111
Myotonic dystrophy 1	33
Nemaline myopathy	47, 83
Multicore myopathy	112
Cytoplasmic body myopathy	108
Desminopathy	113
Myofibrillar myopathy	57
Glycogenosis II (M. Pompe)	114
Danon's disease	65
VLCAD	74, 75
LCHAD	74
Mitochondrial disorders	115
Senger's disease	85
Rigid spine syndrome	30
Associated with dilative cardiomyopathy
Dystrophinopathies	8
Laminopathies	10
Limb girdle muscular dystrophies	18, 25
FCMD	28
Nemaline myopathy	48
Centronuclear myopathy	52
Congenital fiber type dysproportion	50
Desminopathy	113
Glycogenosis type IV	116
Mitochondrial disorders	77
Barth syndrome	117
Myofibrillar myopathy	55
Primary carnitin deficiency	72
Associated with restrictive cardiomyopathy
Laminopathies	10, 11
Desmin myopathy	54
Myofibrillar myopathy	57
Multicore myopathy	118
Distal myopathy with rimmed vacuoles	119
Mitochondrial disorder	120
Eosinophilia-myalgia syndrome	121
Associated with LVHT
Myotonic dystrophy I	37
Dystrophinopathies	122
Barth syndrome	86
Mitochondrial disorders	3
Zaspopathy	56
Dystrobrevinopathies	123
Myoadenylate-deaminase deficiency	3
Glycogenosis type II (M. Pompe)	(unpublished)
Laminopathies	3
Friedreich ataxia	(unpublished)

VLCAD: very-long-chain acyl-CoA dehydrogenase deficiency, LCHAD: long-chain 3-hydroxy acetyl-CoA dehydrogenase deficiency, FCMD: Fukuyama type congenital muscular dystrophy, CMT:.

Frequency of CI

The prevalence of CI in various myopathies is listed in Table IV. It is highest in Barth syndrome, laminopathies, and dystrophinopathies 4–6. Bundle branch block can be found in one third and decreased systolic function in 22% of the patients with myotonic dystrophy I. Death is due to cardiac dysfunction in 10% of the DMD-patients.

Table IV.  Frequency of cardiac involvement in primary myopathies.

Disorder	CI (%)	Reference
Barth syndrome	90	89
Laminopathies	80	11
Dystrophinopathies	75–90	4
Myotonic dystrophy 1	77	124
Limb girdle muscular dystrophy 2I	55	19
DMD/BMD carrier	50	4
Sarcoglycanopathies	20	16
Myotonic dystrophy 2	19	5
Distal myopathy with rimmed vacuoles	18	58
Facioscapulohumeral muscular dystrophy	12	6

Assessment of cardiac involvement

To diagnose and monitor CI in myopathies, the same cardiac methods and techniques are applied as for diagnosing cardiac disease of other causes. Diagnosing CI in myopathies requires a comprehensive cardiac investigation, including history, clinical cardiologic examination, surface ECG, ambulatory 24h-ECG, and echocardiography (Figure 1). Patients with myopathy should undergo these basic cardiac investigations as soon as the neurological diagnosis has been established. If these investigations provide evidence for an impulse generation or conduction abnormality without clarifying its origin further invasive electrophysiological investigations are indicated (Figure 1). If the basic cardiologic investigations provide evidence of a myocardial affection more sophisticated methods for its assessment may be applied, such as cardiac magnetic resonance imaging (MRI), stress echocardiography, tissue Doppler imaging, cardiac PET, myocardial scintigraphy with Tc-99m methoxy-isobutyl-isonitrile, I-123-β-methyl-p-iodophenylpentadecanoic acid or I-123 meta-idobenzyl-guanidine or myocardial biopsy. To exclude coronary heart disease as the cause of the cardiac abnormalities or to confirm an additional vascular pathology coronary angiography or SPECT may be necessary (Figure 1). Particularly, if the onset of the neurological manifestations follows the onset of CI, CI may be easily overlooked or misinterpreted. Subclinical CI in dystrophinopathies may be detected only upon cardiac MRI 7, tissue Doppler imaging, or cardiac positron emission tomography (PET). After decease autopsy of the heart is obligatory (Figure 2).

Figure 1.  Flow-chart according to which patients with myopathies can be assessed for cardiac involvement

Figure 2.  Cardiac autopsy specimen of a patient with suspected encephalomyopathy shows marked left ventricular hypertrabeculation distally to the papillary muscles

Myopathies with cardiac involvement

There is growing evidence that the prevalence of CI in myopathies is higher than previously thought (Table IV). In addition to muscular dystrophies, CI has been reported in metabolic myopathies, congenital myopathies, disorders of the contractile proteins, and some unclassified myopathies. CI usually increases with age and may precede, follow, or accompany the onset of skeletal muscle disease.

Muscular dystrophies

Dystrophinopathies

Dystrophinopathies are X-linked disorders due to deletions, insertions, or point mutations in the dystrophin gene on chromosome Xq21 (Table I). Clinically, they manifest as DMD (out-of–frame mutation) or BMD (in-frame mutation). DMD is characterized by general weakness and wasting, with onset in the pelvic girdle and progression towards the distal and respiratory muscles. BMD has a similar phenotype, but with later onset and much slower progression and only late involvement of the respiratory muscles.

CI is an important feature of DMD, BMD patients and carriers, and comprises supraventricular or ventricular arrhythmias, abnormal Q-waves, ST-segment depression, prolonged QT-interval, hypertrophy signs, regional wall motion abnormalities, dilation, dilated cardiomyopathy (Table III), secondary valve insufficiency, or heart failure with systolic or diastolic dysfunction 8, necessitating heart transplantation in selected cases. Most of these abnormalities are attributed to replacement of cardiomyocytes by connective tissue or fat, as assessed by gadolinium-enhanced cardiac MRI. In several DMD cases, reduction of the coronary vasodilated reserve, possibly due to involvement of the vascular smooth muscle, has been described. In two patients BMD was associated with isolated LVHT. In the early stages of the disease CI may be subclinical and only detected by instrumental investigations, such as cardiac MRI or MRI tagging. In single patients CI may worsen during general anesthesia. Besides these cardiac manifestations, there is some evidence for hypercoagulability in dystrophinopathies. Generally, the genotype/phenotype correlation for CI in dystrophinopathies is poor.

Both, DMD and BMD female carriers may be symptomatic from the mutation. The degree of CI in female carriers is, according to the Lyon-hypothesis, depended on the amount of X-chromosome inactivation. Accordingly, DMD-carriers can be asymptomatic or severely affected and can even develop dilation or heart failure, necessitating biventricular pacing or even heart transplantation (Table IV).

X-linked Emery-Dreifuss muscular dystrophy (XL-EDMD)

XL-EDMD is characterized by slowly progressive muscle weakness and wasting with humero-peroneal distribution and early onset contractures of the elbow joints, Achilles tendons, and posterior-cervical muscles 9. XL-EDMD is due to a mutation in the Emerin gene on chromosome Xq28 (Table I). Emerin is a type II inner nuclear membrane protein, which regulates the flux of β-catenin, a transcription co-activator. Wild-type emerin restricts access of β-catenin to the nucleus, whereas mutated emerin dominantly stimulates β-catenin activity.

CI in XL-EDMD includes conduction defects, such as sinus bradycardia, AV-block I, or may cause sudden death without prior symptoms, unless treated with an early inserted pacemaker. In single cases heart failure, necessitating heart transplantation may occur. In a study on 18 XL-EDMD patients 10 required a pacemaker for bradyarrhythmias. Atrial fibrillation or flutter developed in 11 of them and atrial standstill in 5 of the 11. In single cases decreased accumulation of I-123 meta-idobenzyl-guanidine may predict left ventricular dysfunction. CI may precede the skeletal muscle affection by years.

Laminopathies

Laminopathies are due to mutations in the lamin A/C gene on chromosome 1q11–23 (Table I), which encodes for lamin A/C, a component of the nuclear envelope. Lamins A and C are two different proteins produced by alternative splicing from the same gene. Lamin A/C mutations manifest at least as seven different disorders in the skeletal muscle, myocardium, peripheral nerve, or adipose tissue (Table V) 10. These include autosomal dominant EDMD (AD-EDMD), limb girdle muscular dystrophy (LGMD) 1B, characterized by proximal muscle weakness and wasting, AV-block, and dilated cardiomyopathy (Table III) 10, familial partial lipodystrophy, dilated cardiomyopathy with conduction system disease, autosomal recessive type 2 Charcot-Marie-Tooth disease, Hutchinson-Gilford progeria, and mandibulo-sacral dysplasia.

Table V.  Phenotypic heterogeneity of mutations causing myopathy with cardiac involvement.

Mutated protein	Phenotypes
Dystrophin	DMD, BMD, XL-dilated cardiomyopathy
Lamin A/C	LGMD1B, autosomal dominant EDMD, familial partial lipodystrophy, dilated cardiomyopathy with conduction system disease, autosomal recessive type 2 Charcot Marie Tooth disease, Hutchinson-Gilford progeria, mandibulo-sacral dysplasia
Taffazin	Barth syndrome, X-linked endocardial fibroelastosis, X-linked fatal infantile dilated cardiomyopathy, familial isolated noncompaction of left ventricular myocardium
ANT1	CPEO, FSH, Senger's syndrome
Caveolin-3	LGMD1C, rippling muscle disease, sporadic and familial forms of hyper-CK-emia, distal myopathy
Dysferlin	LGMD2B, Miyoshi myopathy
Titin	LGMD2J, tibial muscular dystrophy Udd, congenital muscular dystrophy 1G
Ryanodine receptor	Autosomal dominant and recessive central core disease, malignant hyperthermia
Fukutin-related protein	LGMD2I, congenital muscular dystrophy with secondary merosin deficiency
α-Actin	Nemaline myopathy, actin-myopathy
Collagen type VI subunit α2	Bethlem myopathy, Ullrich syndrome
Selenoprotein N1	Desmin myopathy with Mallory bodies, multiminicore disease with external ophthalmoplegia, rigid spine syndrome

CI in laminopathies is characterized by conduction system or rhythm disturbances, such as supraventricular arrhythmias (sinustachycardia, atrial fibrillation, atrial tachycardia, or atrial standstill), AV-block, or ventricular arrhythmias, which occur early during the disease course, followed by dilation, dilated cardiomyopathy (Table III), restrictive cardiomyopathy (Table III), or systolic dysfunction 10, 11. Cardiac abnormalities may precede the onset of the skeletal muscle weakness by years 12. Rhythm abnormalities may be life threatening and often responsible for sudden cardiac death 10. CI in AD-EDMD occurs in adulthood and comprises bradycardia, AV-block I, atrial tachycardia, atrial fibrillation, or ventricular conduction blocks, ventricular arrhythmias, non-dilated cardiomyopathy, dilated cardiomyopathy (Table III), or restrictive cardiomyopathy (Table III) 11. In single cases the heart may be subclinically affected and CI only detected upon tissue Doppler imaging or cardiac MRI. CI in LGMD1B may require implantation of an implantable cardioverter defibrillator (ICD) or, in single cases, heart transplantation 10, 12. In a family of 72 members with quadriceps myopathy due to a lamin A/C mutation, CI was found in 15%. Two thirds of the patients had dilated cardiomyopathy or ventricular arrhythmias, three quarters had bundle branch block, but all had atrial fibrillation.

Facioscapulohumeral muscular dystrophy (FSH)

FSH affects the facial, shoulder girdle, and, sometimes the peroneal muscles. Some cases with minor facial involvement but predominant affection of the limbs may mimic scapulo-peroneal syndrome. In addition to the muscle, the retina or the ears (sensorineural hearing loss) may be affected. FSH is caused by a deletion of an integral number of 3.3kb tandem repeats from the subtelomeric region on chromosome 4q35.

There is controversy concerning CI in FSH. Previous studies found no or hardly any clinically significant cardiac disease in FSH 13. More recent studies, however, provide increasing evidence that the conduction system and the myocardium are clinically or subclinically affected at least in some patients with FSH. In a multi-center study on 83 FSH patients, of whom, 62 were without cardiovascular risk factors, 10 developed clinical or subclinical CI (12%) 6. Five reported frequent palpitations as the equivalent of supraventricular paroxysmal tachycardia and 5 had asymptomatic supraventricular tachycardia 6. In a study on 24 patients with FSH the systo-diastolic variation of the integrated backscatter signal was reduced and the QT-dispersion increased 14. In 9 patients ventricular late potentials were recorded. QT and QTc-dispersion were inversely related to the integrated backscatter signal of the septum and posterior wall. In none of these patients CI manifested clinically 14. Studies on single cases or small case series additionally found sinus node dysfunction, manifesting as transient P-wave inversion, prolonged P-P-interval, or tall P-waves, premature atrial contractions, supraventricular arrhythmias, AV-block, intraventricular conduction delay, tall T-waves, ST-elevation, long-QT syndrome, ventricular tachycardia, or reduced Tl-201 uptake on scintigraphy 15. In single cases myocardial thickening has been described 15. Rarely, intractable heart failure may be the cause of death in FSH.

Limb girdle muscular dystrophies (LGMD)

LGMDs are a genetically heterogeneous group of autosomal dominant (6 entities) or autosomal recessive (10 entities) myopathies, clinically characterized by weakness and wasting of the shoulder and pelvic girdle muscles, calf hypertrophy and reduced tendon reflexes. Some patients are severely affected and resemble DMD (β-sarcoglycanopathy). The phenotype is due to mutations in genes, which encode for muscle membrane bound sarcoglycanes or the proteins such as myotilin, lamin A/C, caveolin-3, calpain, dysferlin, telethonin, E3-ubiquitine ligase, fukutin-related protein, or titin (Table I). Caveolin-3 is the muscle-specific product of the caveolin gene family and integral membrane component of caveolae 17. Mutations in the caveolin-3 gene underlie not only LGMD1C but also rippling muscle disease, sporadic and familial forms of hyper-CK-emia, and distal myopathy (Table V) 17. A caveolin-3 mutation may cause all four distinct phenotypes within the same family 17. In all these patients the caveolin-3 expression in the myocardium was reduced to 60% of normal 17.

CI in LGMDs comprise incomplete right bundle branch block, tall R-waves in V1-2, left anterior hemiblock, shortened QT-interval, ST-segment elevation, abnormal Q-waves 16, reduction of the coronary vasodilated reserve, dilation of the cardiac cavities, dilated cardiomyopathy (Table III) 18, wall motion abnormalities, or heart failure 19, requiring heart transplantation in selected cases 18. A mutation in one of the sarcoglycan genes may disrupt the entire sarcoglycan complex in both the skeletal and cardiac muscle 20. Furthermore, there are indications that disruption of the sarcospan/sarcoglycan complex in vascular smooth muscles perturbates vascular function and may promote the development of cardiomyopathy 21. In a patient with dysferlinopathy (LGMD2B) echocardiography revealed left ventricular dilation and diffuse hypokinesia 22. LGMD2B may also go along with severe ECG abnormalities and subclinical affection of the right ventricular myocardium, as assessed by tissue Doppler-imaging 23. A study on 10 patients with γ-sarcoglycanopathy reported ECG abnormalities and myocardial relaxation abnormalities in four of them 23. In a study on 6 patients with LGMD2E half presented with CI and one of them with dilated cardiomyopathy. CI has been also reported in 8 of 9 patients with LGMD2I 24, manifesting as reduced systolic function, dilation of the cardiac cavities, or even dilated cardiomyopathy (Table III) 25. Overall, CI is assumed to occur in up to 20% of the patients with sarcoglycanopathies (Table IV) 16.

Congenital muscular dystrophies

Congenital muscular dystrophies (CMD) constitute a clinically and genetically heterogeneous group of autosomal recessive myopathies, characterized by marked weakness, generalized hypotonia, joint contractures, and dystrophic changes on muscle biopsy, manifesting in early infancy. Mutations in the laminin α2 (LAMA2), fukutin (FCMD), integrin α7, O-mannose β-1,2-N-acetylglucosaminyl transferase, O-mannosyl transferase 1, fukutin-related protein, selenoprotein N1 (SEPM1), like-glykosyl-transferase, or collagen (COLA2, COLA3) genes have been identified as causative 26. According to histological findings they are subdivided into merosin-positive and merosin-negative forms. The function of most of these genes is unknown. For fukutin, however, there are indications that it is involved in the glycozilation of α-dystroglycan 27, 28.

CI has been predominantly reported in the Fukuyama type congenital muscular dystrophy (FCMD). The most frequently reported cardiac abnormalities in these patients are myocardial fibrosis or heart failure. In a study on 34 patients with FCMD 47% had a fractional shortening (FS) of <28% or reduced mean velocity of the circumferential fiber shortening. The FS decreased with age. Dilated cardiomyopathy requiring heart transplantation may be a rare feature of FCMD 28. Five patients died from heart failure. In a study on 10 merosin-positive patients with non-specified CMD three showed reduced systolic function and one dilation of the cardiac cavities. In a study on 42 patients with merosin-positive CMD left ventricular function was decreased. Among 6 children with merosin-negative CMD (LAMA2) one presented with cardiomyopathy and heart failure. In another study on six merosin-deficient children (LAMA2) two presented with dilated cardiomyopathy (Table III) 29. Cardiac abnormalities reported together with rigid spine syndrome (SEPM1) were, incomplete left bundle branch block, complete AV-block, heart failure, or a sinus venous defect (Table III) 30.

Myotonic dystrophy type 1 (MD1)

MD1 is an autosomal dominant multi-system disorder, usually involving the skeletal muscle, brain, heart, eyes, intestines, or endocrinium 31. Clinically, MD1 presents with myotonia, diffuse weakness and wasting, frontal baldness, diabetes, megacolon, cataracts, or infertility. MD1 is caused by an expanding trinucleotid CTG-repeat in the 3′ prime untranslated region of a serine-threonine kinase gene on chromosome 19q13.3 (Table I) 31. The mutation results in nuclear entrapment of mutant RNAs, which extensively interact with RNA-binding proteins in ribonuclear inclusions 32.

The most frequent cardiac abnormalities in MD1 are impulse generation or propagation defects, like AV-block I in 64%, prolonged QT-interval, QRS-prolongation in 32%, Torsades de pointes, myocardial thickening 33, or heart failure 34. There are also altered electro-anatomic patterns in the right cardiac chambers of MD1 patients as confirmed by electro-anatomic mapping 35. The most common sustained arrhythmia is reported to be atrial flutter. In a study on 37 patients the PQ-interval increased with age. In a study on 79 MD1 patients the QRS duration increased with disease progression 36. There is some evidence that the smooth muscle of the coronary arteries is affected. In single cases myocardial thickening and LVHT have been reported 37. Decreased systolic or diastolic function can be found in 22 and 30% of the patients respectively. Subclinical CI may be documented by reduced myocardial velocities on tissue Doppler echocardiography 38, which may also indicate early left ventricular systolic or diastolic dysfunction. There are also indications that there is parasympathetic autonomic dysfunction in some of these patients 39. The genotype/phenotype correlation between the CTG-repeat expansion and CI is generally poor 40. Factors other than the CTG-expansion size appear to determine severity and progression of CI in MD1 41.

Myotonic dystrophy type 2 (MD2)

MD2 is an autosomal dominantly inherited myopathy, which presents with clinical features similar to MD1. Contrary to MD1, the MD2 phenotype is less severe, presents additionally with pseudohypertrophy of the calves, hyperhidrosis, or, less frequently than MD1, with dementia, hypersomnia, diabetes, or hypogonadism. MD2 is due to mutations in the ZNF9 gene on chromosome 3q21 and shows anticipation less frequently than MD1.

Cardiac abnormalities described in MD2 include sinus-bradycardia, supraventricular tachycardia, atrial fibrillation, supraventricular bigeminia, abnormal T-waves, right bundle branch block, ventricular ectopy, sustained monomorphic ventricular tachycardia, heart failure, or myocardial infarction 42. Atrial flutter may be provoked by electrophysiologic examination. Ventricular arrhythmias may necessitate implantation of an ICD or may cause sudden cardiac death. In a study on 379 DM2 patients CI was detected in 19% of them (Table IV) 43.

Congenital (protein aggregation) myopathies

So far, congenital myopathies were diagnosed upon structural abnormalities on enzyme histochemistry, immunehistochemistry, or electron microscopy 44. With the elucidation of the underlying genetic defects the morphological classification of congenital myopathies has changed to the concept of protein aggregation myopathies, comprising disorders due to mutations in genes encoding for desmin, αB-crystallin, selenoprotein, myotilin, actin, myosin, tropomyosin, troponin T, nebulin, dynamin, myotubularin, cypher, or the ryanodine receptor 44. Since this new heuristic classification is still not fully established the old morphological classification is still in general use.

Nemaline myopathy

Nemaline myopathy is a rare, genetically heterogeneous, autosomal dominant or recessive myopathy, characterized by severe, generalized weakness and hypotonia from birth or infancy 45, 46. Nemaline myopathy is due to mutations in the α-actin, α-tropomyosin, β-tropomyosin, slow troponin T, or nebulin gene (Table I).

CI in nemaline myopathy comprises myocardial thickening, hypertrophic cardiomyopathy (Table III), dilation of the cardiac cavities, or heart failure 47. Hypertrophic cardiomyopathy has been recently described for the first time in a 2-year-old child carrying an α-actin mutation 47. A patient with nemaline myopathy also developed dilated cardiomyopathy (Table III), requiring heart transplantation 48. Additionally, myocardial relaxation may be impaired and may result in diastolic dysfunction 49. In a report on two patients with congenital fiber-type dysproportion myopathy atrial fibrillation, AV-block, dilation of the cardiac cavities, and heart failure, necessitating heart transplantation, were described. Another patient presented with dilated cardiomyopathy and complete AV-block (Table III) 50.

Central core disease

Central core disease is due to mutations in the ryanodine receptor gene and clinically characterized by general hypotonia, muscle cramps and predominantly proximal lower limb weakness at birth 51. Also congenital dislocation of the hip, pes cavus, pes planus, shortening of the Achilles tendon, extensive lumbar lordosis or kyphoscoliosis may be present. Most cases, however, are only mildly disabled. CI in central core disease presents with myocardial dilation, or heart failure, necessitating heart transplantation in single cases 52.

Centronuclear myopathy

Centronuclear myopathy is a rare congenital myopathy due to mutations in the dynamin 2 gene on chromosome 19p13.2 (Table I) 52. Rarely CI has been described, manifesting as myocardial thickening, dilated cardiomyopathy (Table III), heart failure, or sudden cardiac death 52. A single patient required heart transplantation so far 52.

Desmin myopathy

Desmin is the main intermediate filament protein in the skeletal muscle and myocardium and important as part of the cytoskeleton 53. The desmin filament lattice surrounds the Z-discs, interconnects them to each other, interlinks myofibrils, and links the contractile apparatus to the sarcolemma, cytoskeleton, cytoplasmic organelles, and the nucleus 53. In mildly affected cases, distal limb and axial weakness, and, in severely affected patients, general weakness are the predominant neurological abnormalities 54. Histologically, desmin myopathy 2 is characterized by abnormal aggregates of desmin-type intermediate filaments in the skeletal, cardiac, or rarely, the intestinal smooth muscle 54. Desminopathy due to mutations in the desmin gene present with progressive weakness of the limb muscles and desmin-reactive granular aggregates in myofibers. Lack of desmin results in susceptibility of myofibers and cardiomyocytes to damage 53.

CI in desmin myopathy comprises ECG abnormalities, such as atrial flutter, AV-block, or ventricular tachycardia. Additionally, there may be myocardial thickening, dilation, or heart failure with systolic or diastolic dysfunction 1. In some cases, predominantly right ventricular dysfunction has been described 1. Generally, it is assumed that rather the absence of an intact desmin filament system than the accumulation of the protein is responsible for skeletal muscle and cardiac abnormalities.

Myofibrillar myopathy

Myofibrillar myopathy is morphologically characterized by desintegration of the Z-disk and myofibrils, followed by abnormal accumulation of various proteins 55. Myofibrillar myopathy is genetically heterogeneous due to mutations in the Z-disk-related proteins desmin, αB-crystallin, myotilin, myotubularin (myotubular myopathy), LMNA, myosin heavy chain IIa (myopathy with contractures, ophthalmoplegia and rimmed vacuoles, also termed inclusion body myopathy 3), or selenoprotein N1 (multiminicore disease with external ophthalmoplegia) 55. Recently, myofibrillar myopathy due to mutations in the Z-band alternatively spliced PDZ motif-containing protein (cypher/ZASP (Z-band alternatively spliced PDZ-motif containing protein), zaspopathy) has been reported 56. In a study on 54 patients with myofibrillar myopathy Z-band alternatively spliced PDZ-motif containing protein mutations were detected in 11 55.

CI in myofibrillar myopathy includes dilated cardiomyopathy or LVHT 55, 56. In a Qatary family with myofibrillar myopathy one presented with restrictive cardiomyopathy, one with hypertrophic cardiomyopathy necessitating heart transplantation, and one with complete heart block necessitating implantation of a pacemaker 57.

Distal myopathies

Distal myopathy with rimmed vacuoles (hereditary inclusion body myopathy 2)

Distal myopathy with rimmed vacuoles has been recently shown to be the same disorder as hereditary inclusion body myopathy and is due to mutations in the tile UDP-GlcNAc2-epimerase gene, which encodes for a bifunctional protein with activities of the UDP-GlcNAc2-epimerase and the ManNAc-kinase 58. The UDP-GlcNAc2-epimerase catalyzes the rate-limiting step in the sialic acid biosynthesis and ManNAc-kinase catalyzes the next step. CI occurs in 18% of the patients (Table IV) amd often manifests as sudden cardiac death (58). CI has not been described in Myoshi myopathy (dysferlin), tibial muscular dystrophy (titin), or autosomal dominant distal myopathy also known as hyaline myopathy or myosin storage disease (myosin heavy chain 7).

Metabolic myopathies

Glycogenoses

Glycogenoses are a heterogeneous group of system disorders, due to impaired activity of enzymes involved in the glucose metabolism. Clinically, these patients present with proximal weakness, hypotonia (floppy infant), fatigue, respiratory failure, seizures, cardiac or liver involvement. Histologically, glycogenoses show intracellular glycogen accumulations. Depending on the affected enzyme, 11 different types have been described so far 59.

CI has been described in glycogenosis type IIa (M. Pompe), IIb (Danon's disease) III (Forbes disease), IV (McArdle's disease), VII (M. Tarui), and glycogenosis type IX so far. Most well known is CI in type II glycogenosis (acid-α glucosidase-deficiency, Pompe's disease) manifesting as premature ectopic beats, severe myocardial thickening, or sudden death 60. In type III glycogenosis ECG abnormalities can be observed in up to 90% of the patients. Myocardial thickening occurs in up to 20% of these cases. In a family with type IV glycogenosis myocardial thickening, heart failure, and heart transplantation were reported 61. In a patient with Tarui's disease CI manifested as anginal chest pain for years, myocardial thickening, and abnormal myocardial texture 62. In two infants with type IX glycogenosis large QRS complexes, short PQ-interval and myocardial thickening were reported 63.

Danon's disease, a lysosomal glycogen storage disease, is characterized by mental retardation, vacuolar myopathy with mild general weakness, and fatal hypertrophic cardiomyopathy in males before 20 years 64. Single patients may additionally present with Wolff-Parkinson-White syndrome 65. Females are without CNS or PNS abnormalities but may develop cardiomyopathy in adulthood 66. Danon's disease is due to mutations in the lysosomal associated protein 2 (LAMP-2) gene on chromosome Xq25-q25, which encodes for a lysosome-associated glycoprotein 67. Typically, autophagic vacuoles accumulate in the myocardium and skeletal muscle. On immunehistochemistry LAMP2 is completely absent in these patients 67. Autophagic vacuoles are likely to be causal for the depressed contractile function resulting in an attenuated left ventricular pump reserve. Severe cardiac muscle involvement may lead to early death already at infancy 66.

Fatty acid oxidation disorders

Mitochondrial β-oxidation of long-chain fatty acids provides energy for heart and muscle during prolonged aerobic exercise and for hepatic ketogenesis during long-term fasting 68. Oxidation of long-chain fatty acids may be disturbed at various enzymatic levels. To gain access to the β-oxidation enzymes, long-chain fatty acids need to be transferred via the inner mitochondrial membrane 68. The shuttle is dependent on various enzymes and carnitine. Carnitine is essential for esterification of long-chain fatty acids. Carnitine is transported into the intermembrane space via the organic cation/carnitine transporter. Carnitine is conjugated with long-chain fatty acids by the carnitine palmitoyl transferase 1 (CPT1). Long-chain fatty acids are transferred across the inner plasma membrane by the carnitine-acylcarnitine translocase (CACT), and conjugated back to coenzyme A for subsequent β-oxidation by the carnitine palmitoyl transferase 2 (CPT2). The clinical presentation of fatty acid oxidation disorders varies significantly according to the underlying enzymatic defect 69. They may present as isolated cardiomyopathy, myopathy, or hepatopathy 70.

Deficiency of the organic cation/carnitine transporter, which has been recently localized to mitochondria 71, or carnitine uptake defect cause primary carnitine deficiency (PCD). PCD is characterized by increased loss of carnitine to the urine and decreased carnitine accumulation in various tissues. Plasma carnitine levels are very low 72. Patients may present with neonatal metabolic acidosis, hypoketotic hypoglycemia, hepatic encephalopathy, epilepsy, recurrent infections, hepatomegaly, hyperammonemia, skeletal myopathy, and hypertrophic or dilated cardiomyopathy with lipid accumulation 70, 71. Most of the disease manifestations of PCD respond well to carnitine supplementation. Defects in the liver isoform of CPT1 present with recurrent attacks of fasting hypoketotic hypoglycemia. The heart and the skeletal muscles, which express a genetically distinct form of CPT1, are usually unaffected. These patients can have elevated levels of plasma carnitine. CACT deficiency presents in most cases in the neonatal period with hypoglycemia, hyperammonemia, cardiomyopathy, or arrhythmias leading to cardiac arrest. Plasma carnitine levels are extremely low. Patients with the myopathic form of CPT2 deficiency present with muscle pain, cramps, rhabdomyolysis or myoglobinuria triggered by prolonged exercise. In these patients in-vivo oxidation of long-chain fatty acids is severely impaired during prolonged low-intensity exercise 73. More severe variants of CPT2 deficiency present in the neonatal period together with multiple congenital anomalies. Among 107 patients with inherited fatty acid oxidation disorders arrhythmias were recorded in 22% 68.

Very-long chain acetyl CoA dehydrogenase deficiency and long chain 3-hydroxy-acetyl CoA dehydrogenase deficiency, are also disorders of the mitochondrial long-chain fatty-acid oxidation, and may present with hypoketotic hypoglycemia, rhabdomyolysis, exercise-induced episodes of intense generalized muscle pain, weakness, or myoglobinuria 74. A frequent cardiac manifestation of very-long chain acetyl CoA dehydrogenase deficiency and long-chain 3-hydroxy acetyl-CoA dehydrogenase deficiency is hypertrophic cardiomyopathy (Table III) 74, 75.

Respiratory chain disorders (RDCs)

Respiratory chain disorders are a group of genotypically or phenotypically heterogeneous disorders, which are associated with impaired function of the respiratory chain, Krebs cycle, β-oxidation, transport proteins, assembly proteins or structural proteins. The most frequent and important of these are disorders due to abnormal respiratory chain function, leading to insufficient ATP production via the oxidative phosphorylation system. RCDs are predominantly multisystem diseases with great phenotypic variability, why they are easily overlooked or misdiagnosed for years. RCDs are due to mutations in mitochondrial desoxy-ribonucleic acid (mtDNA) or nuclear DNA (nDNA) located genes, encoding for components of the respiratory chain complexes I-V, t-RNAs, or rRNAs 76.

Most respiratory chain disorders are multi-system diseases affecting a variety of organs or tissues, including the heart. However, CI may also occur isolated, even as the presenting feature. CI in respiratory chain disorders comprises ECG abnormalities, focal or diffuse myocardial thickening, hypertrophic cardiomyopathy 77, dilation of the cardiac cavities, dilated cardiomyopathy 77, LVHT (Figure 3) 78 or heart failure 79, 80. Heart failure may also respond to biventricular pacing 81. Intractable heart failure requires heart transplantation in a growing number of patients 82.

Figure 3.  Echocardiographic parasternal short-axis view of a patient with MELAS syndrome shows extensive hypertrabeculation of the lateral and posterior wall

Myoadenylate deaminase (MADA) deficiency

MADA deficiency is characterized by childhood onset muscle cramps, stiffness, post-exercise myalgia, or weakness. Myocardial thickening seems to be a rare cardiac manifestation of MADA deficiency 83. In a single case MADA deficiency manifested as recurrent muscle cramps and exercise intolerance and was associated with myocardial thickening and LVHT 3.

CI has not been reported in glycogenosis type X (muscle phosphoglycerate mutase), glycogenosis type XI, enolase deficiency (β-enolase), or carnitine palmitoyl-transferase deficiency 1 (CPT1) so far.

Unclassified myopathies

Senger's syndrome

Senger's syndrome is an autosomal recessive condition, characterized by congenital heart defects, and morphologically abnormal mitochondria of the skeletal muscle, lactacidosis, and cataracts 84. Senger's syndrome is due to depletion of the adenine nucleotide translocator, presumably following a yet unidentified adenine nucleotide translocator-specific transcriptional or translational error. Interestingly, the gene encoding for the adenine nucleotide translocator is not only involved in the pathogenesis of Senger's syndrome but also that of autosomal dominant chronic progressive external ophthalmoplegia (CPEO) and FSH, in the latter by its depression through the subtelomeric deletion of certain tandem repeats on chromosome 4q35 84. In single cases Senger's syndrome is associated with hypertrophic cardiomyopathy 85.

Barth syndrome

Barth syndrome is a rare X-linked recessive disorder of infancy characterized by myopathy, cardiomyopathy, cyclic neutropenia, short stature, low cholesterol, and mitochondrial abnormalities 86. Barth syndrome is due to mutations in the taffazine gene on chromosome Xq28. In addition to Barth syndrome taffazin mutations are also responsible for X-linked endocardial fibroelastosis, X-linked fatal infantile dilated cardiomyopathy (CMD3A), or familial isolated noncompaction of left ventricular myocardium (Table V) 87. The exact function of taffazine is unknown but there are indications that it is directly involved in the metabolism of cardiolipin localized in the inner mitochondrial membrane 88. Cardiolipin not only plays a role in the maintenance of the membrane potential and architecture but also provides essential structural and functional support to proteins involved in mitochondrial bioenergetics 88.

CI in Barth syndrome comprises endocardial fibroelastosis, increased number of mitochondria in cardiomyocytes 86, myocardial thickening in the majority of the cases, or LVHT 86. In a study on 34 patients with Barth syndrome 90%, had cardiomyopathy and 50% LVHT (Table IV) 89. Ventricular arrhythmias were found in 43% of the cases 89. Ventricular arrhythmias appear to be a dominant feature of CI, which often require the implantation of an ICD 89.

Bethlem myopathy (Ullrich syndrome)

Bethlem myopathy is an autosomal dominant, early onset, slowly progressive limb-girdle myopathy with contractures of the fingers, the elbow and the Achilles tendon 90. The disease is due to mutations in each of the three type VI collagen subunit genes. The interaction of type VI and type IV collagen within the basal lamina provides a possible molecular mechanism for the pathogenesis of this disorder 13, 91.

Usually, the heart is not severely affected in Bethlem myopathy 92. In a study on 50 patients with Bethlem myopathy CI was found in none of them 92. Only in single cases myocardial thickening has been described 13.

McLeod syndrome

McLeod syndrome is a multi-system disorder including the CNS (chorea, epilepsy), the PNS (axonal polyneuropathy), and the blood cells (acanthocytosis of the erythrocytes). Mild myopathy is also a common manifestation in most cases 93. Rarely, life-threatening rhabdomyolysis may occur 93. Often, patients present with mild, asymptomatic hyperCK-emia 94. The absence of the Kell Kx membrane protein seems to be causative 95. CI has been rarely observed and is described as progressive heart disease in these patients 95.

CI has not been described so far in oculo-pharyngeal muscular dystrophy (polyA-binding protein), epidermiolysis bullosa simplex (plectin), Schwartz-Jampel syndrome (perlecan), or Brody disease (calcium ATPase). In a single patient rippling muscle disease (caveolin-3) was associated with arrhythmias and cardiomyopathy 96.

Therapy of cardiac abnormalities in primary myopathies

General

Therapy of cardiac abnormalities due to CI in primary myopathies is not at variance to therapy of cardiac disease due to other causes. If atrial fibrillation is tachycardious, digitalis, amiodarone or β-blockers should be added. Electrical cardioversion may be tried, if atrial fibrillation lasts <1 year and if the left atrial diameter is <50mm. In case of bradycardia, intractable to drugs, or AV-block III, a pacemaker is indicated. In case of severe ventricular arrhythmias, an ICD may be required. Supraventricular re-entry tachycardia may be treated by high-frequency catheter ablation. In cases of intracardiac thrombus formation, anticoagulation is essential. Systolic dysfunction may be treated with high-dose angiotensin-converting enzyme inhibitors (ACEI), diuretics, or in case of tachycardia, β-blockers in low dosages. Diastolic dysfunction may respond to ACEI as well. Intractable heart failure may necessitate implantation of a biventricular pacemaker, or even heart transplantation.

Diagnosis-sensitive

In respiratory chain disorders all drugs should be discontinued, which could impair the respiratory chain function, such as acetyl-salicylic acid, valproic acid, barbiturates, biguanides, tetracyclines, chloramphenicol, zidovudin, some local anesthetics, or phenothiazines 97. In single DMD patients with end stage cardiac dysfunction continuous intravenous infusion of milrinone or dobutamine resulted in long-term improvement of cardiac function for up to 30 months 98. In a retrospective study on 111 DMD patients, of whom 48 received steroids, the decline in cardiac function was significantly lower as compared to those not receiving steroids 99, 100. In a study on 62 DMD patients and 7 BMD patients ACEI or β-blockers were given after the first abnormal echocardiography in these patients 101. β-blockers were added if there was no ventricular remodeling upon ACEI after three months 101. In a study on 25 DMD patients, 2 with FCMD and one with EDMD application of the β-blocker carvedilol resulted in significant improvement of left ventricular systolic function, whereas ACEI were ineffective. Recent studies have also shown that ACEI have a beneficial effect directly on muscle force in patients with myopathy 102. L-carnitine is not only beneficial to extracardiac manifestations of PCD, but also beneficial to hypertrophic or dilated cardiomyopathy 71. A beneficial effect in patients with CPT1, CPT2, and CACT was reported for a low-fat diet supplemented with medium chain triglycerides, which are metabolized by mitochondria independently from carnitine, carnitine supplements, or avoidance of fasting and sustained exercise 103. Hypertrophic cardiomyopathy in patients with Pompe's disease responds well to enzyme replacement therapy with recombinant human acid-α-glucosidase 104. Particularly, the QT-interval decreases and hypertrophy signs decline 105. Also left ventricular function improves 104. The earlier affected subjects receive this therapy, the better their outcome. Aerobic conditioning in eight patients with McArdle's disease increased the cardiac output in 15% of these patients 106.

Experimental approaches

The tri-block poloxamers, specifically poloxamer 188 (P188), are able to stabilize the membranes of dystrophic myocardium in animal models and may offer a new therapeutic approach for cardiac disease in DMD 107. There are also indications, at least in a mouse model, that L-carnitine together with activators of the peroxisome proliferator-activated receptors resolve lipotoxic, hypertrophic cardiomyopathy in PCD 72. In juvenile visceral steatosis mice, an animal model of PCD, low lipid diet markedly attenuated the development of hypertrophic cardiomyopathy 108.

Conclusion

CI in primary myopathies occurs more frequently than previously thought. Because of the high prevalence of CI, patients with myopathies should be cardiologically investigated as soon as their neurological diagnosis is established, since sufficient cardiac therapy improves CI in these patients and since management of these patients and disease course are strongly influenced by the degree of CI. Future studies should be directed towards the detection of subclinical CI, if early treatment of CI in the subclinical stage improves the outcome of these patients, if prophylactic cardiac therapy attenuates progression of CI, and if CI develops or becomes symptomatic with progression of the muscular manifestations in myopathies, in which CI has not been described so far.