Uncharted waters: rare and unclassified cardiomyopathies characterized on cardiac magnetic resonance imaging
Cardiac magnetic resonance imaging (CMR) has undergone considerable technology advances in recent years, so that it is now entering into mainstream cardiac imaging practice. In particular, CMR is proving to be a valuable imaging tool in the detection, morphological assessment and functional assessment of cardiomyopathies. Although our understanding of this broad group of heart disorders continues to expand, it is an evolving group of entities, with the rarer cardiomyopathies remaining poorly understood or even unclassified. In this review, we describe the clinical and pathophysiological aspects of several of the rare/unclassified cardiomyopathies and their appearance on CMR.
KeywordsHumans Magnetic resonance imaging Cardiomyopathies/diagnosis Ventricular dysfunction/classification
The prevalence of cardiomyopathy in the United States is approximately one in 5,439 or 0.02% of the population . Approximately 26,000 deaths per annum are attributed to cardiomyopathy, which follows coronary heart disease as the commonest cause of sudden death. Transthoracic echocardiography (TTE) is the mainstay imaging modality for cardiomyopathy assessment . Nevertheless, poor acoustic windows can make it difficult to optimally assess certain patients.
Several evolving technical developments have allowed cardiac magnetic resonance imaging (CMR) to enter mainstream cardiology imaging practice for cardiomyopathy assessment . Increasing magnet strengths and surface coil channels and rapid k-space sampling have resulted in faster scan times, placing CMR in a primary position in the work-up of many complex cardiomyopathies . Several consensus statements include CMR as a primary imaging technique in cardiomyopathy assessment [3, 5]. In this review, we outline the clinical and pathophysiological aspects of several of the rarer or unclassified cardiomyopathies and their appearances on CMR.
Classification of cardiomyopathy
In 2006 a re-classification of the cardiomyopathies was published, as our understanding of the importance of genetics in the pathophysiology of the cardiomyopathies became more central . This consensus report revised the definition of cardiomyopathy to include “mechanical or electrical dysfunction that usually exhibits inappropriate ventricular hypertrophy and dilatation due to a variety of causes that frequently are genetic”. Under this classification system, the division of cardiomyopathy was divided into primary and secondary causes. A more recent classification published by Elliott et al.  from the European society of cardiology working group on myocardial and pericardial diseases places an emphasis on phenotypic classification.
Examples of common and rare cardiomyopathies 
Familial, unknown gene
Familial, unknown gene
Familial, unknown gene
Familial, unknown gene
Familial, unknown gene
Sarcomeric protein mutations
Sarcomeric protein mutations (see HCM)
Intercalated disc protein mutations
Sarcomeric protein mutations
Left ventricular non-compaction
β myosin heavy chain
Troponin I (RCM ± HCM)
Cardiac myosin binding protein C
Muscle LIM protein
Essential light chain of myosin
Cardiac troponin 1
Transthyretin (RCM + neuropathy)
Apolipoprotein (RCM + neuropathy)
Essential myosin light chain
Cardiac ryanodine receptor (RyR2)
Regulatory myosin light chain
Transforming growth factor-β3 (TGFβ3)
α-myosin heavy chain
Glycogen storage disease
Muscle LIM protein
Glycogen storage disease (e.g. Pompe; PRKAG2, Forbes’, Danon)
Lysosomal storage disease (e.g. Anderson-Fabry, Hurler’s)
Mildly dilated CM
Disorders of fatty metabolism
Intercalated disc protein mutations (see ARVC)
Phosphorylase B kinase deficiency
Tako Tsubo cardiomyopathy
Infants of diabetic mothers
Eosinophilic (Churg Strauss syndrome)
Drugs (serotonin, methysergide, ergotamine)
Nutritional—thiamine, carntitine, selenium, hypophosphatemia, hypocalcemia
Carcinoid heart disease
Uncommon cardiomyopathies characterized by hypertrophy
Hypertrophic cardiomyopathy (HCM) is defined by the presence of increased ventricular wall thickness or mass without a loading condition such as hypertension or valvular disease .
Cardiac amyloidosis describes amyloid deposition in the heart, which may occur as part of systemic amyloidosis or as a localized process.
Systemic amyloidosis (SAA) is a complication of chronic inflammatory conditions, with renal disease being the predominant feature, presenting with proteinuria and renal failure. Cardiac involvement is rare . Systemic amyloidosis (SAL) is the most commonly diagnosed form of clinical amyloid. Multiorgan involvement is common and the heart is affected approximately 90% of the time. Diastolic heart failure with right heart failure is the most common mode of presentation . Hereditary systemic amyloidosis is due to deposition of amyloid fibrils derived from transthyretin, lysosome or apolipoprotein A-1. Clinical syndromes include cardiomyopathy, nephropathy or neuropathy. Senile systemic amyloidosis is caused by deposition of amyloid fibrils derived from normal wild type transthyretin and presents as a slowly progressive infiltrative amyloid cardiomyopathy .
Friedreich’s ataxia is the most common of the hereditary ataxia syndromes. Clinical features are secondary to a reduction in fraxetin synthesis associated with an unstable expansion of a GAA trinucleotide repeat . Patients are homozygous when a GAA expansion is present on two alleles, irrespective of the length of the expansion, and heterozygous when a GAA expansion is found on one allele and a point mutation on the other allele . The clinical hallmark is progressive ataxia, generally starting before 25 years of age, as well as dysarthria, sensory neuropathy, lower limb areflexia, extensor plantar response and weakness from degeneration of dorsal columns and pyramidal tracts . Skeletal abnormalities and glucose intolerance are also present to a variable degree. Cardiac involvement in Friedreich’s ataxia is a common finding and is characterized by increased thickness of the ventricular wall that is typically concentric and symmetrical, with a normal or small LV cavity and normal systolic function . The age of disease onset and the rate of clinical progression are variable and are influenced by the size of the GAA expansion in the smaller allele (GAA1) .
Noonan syndrome is characterized by short stature, typical facies and congenital heart defects. Noonan syndrome occurs in an autosomal dominant or sporadic inheritance. Male and females are equally affected . Its pathophysiology is not fully understood. Four disease-causing genes have been identified which are involved in the RAS/RAF/MEK/ERK signal transduction pathway. These are PTPN11, SOS1, RAF1 and KRAS [22, 23]. The cardinal features of Noonan syndrome are unusual facies including hypertelorism, down-slanting eyes, epicanthic folds, low-set posterior ears, micrognathia and a webbed neck . Short stature, chest deformity, bleeding diathesis and mental retardation are also cardinal features . The phenotype becomes less pronounced with increasing age .
Danon disease is a multisystemic, lysosomal, glycogen-storage disease with normal acid maltase . It is characterized by a triad of cardiomyopathy, skeletal myopathy and variable mental retardation with intracytoplasmic vacuoles containing autophagic material and glycogen in cardiac and skeletal muscle cells [30, 31]. Danon disease is an X-linked dominant disorder, though spontaneous mutations have also been reported. Males are usually more severely affected than females and also present at an earlier age. Age of presentation in males ranges from infancy to the second decade and affected males rarely survive beyond their 20 s and die secondary to an arrhythmia or congestive cardiac failure . Female carriers develop cardiomyopathy during adulthood, most commonly in the 4th or 5th decades. Both skeletal myopathy and mental retardation are less common in females . Wolff-Parkinson-White, increased serum creatinine kinase and ophthalmic abnormalities are also seen in Danon disease [31, 32]. Mutations in the lysosome-associated protein 2 (LAMP-2) have been identified as the causative gene . LAMP-2 is a heavily glycosated protein found inside the lysosomal membrane. Its deficiency results in excessive myocardial glycogen accumulation, which is responsible for the myocardial hypertrophy .
Piotrowska-Kownacka et al.  describe the CMR appearances of a patient with Danon disease. Subendocardial perfusion defects were visible in almost all segments on first-pass perfusion sequences. These were located predominantly in the lateral and anterior walls. Late gadolinium enhancement was seen in the subendocardium in the septal segments and transmurally in the anterior and lateral walls.
Uncommon cardiomyopathies characterized by dilation
Dilated cardiomyopathies (DCM) are characterized by dilatation of the cardiac chambers with impaired contraction of the ventricles. DCM in the familial from is usually related to cytoskeletal genetic mutations. Non-familial causes are numerous and include myocarditis and drug causes.
Peripartum cardiomyopathy (PPCM) is a rare cause of heart failure. It typically develops in the final month of pregnancy or within 5 months of delivery. Its aetiology appears multifactorial and complex. Several proposed theories for its aetiology exist, including a form of viral myocarditis, an abnormal immune response to pregnancy, an abnormal response to hameodynamic stress of pregnancy, increased myocyte apoptosis, cytokine–mediated myocardial inflammation, malnutrition, genetic factors, excessive prolactin production, abnormal hormone function and increased adrenergic tone .
This disparity in CMR reports is likely to be related to the numerous causes of peripartum cardiomyopathy. Baruteau et al.  divided peripartum cardiomyopathy into two distinct subgroups: (1) non-inflammatory cardiomyopathy secondary to malnutrition, genetics, excessive prolactin production, abnormal hormone function and increased adrenergic tone. The non-inflammatory cardiomyopathies do not appear to cause late gadolinium enhancement or T2 hypersignal; (2) inflammatory cardiomyopathy are secondary to viral myocarditis, abnormal immune responses in pregnancy, abnormal response to hemodynamic stress, increased myocyte apoptosis and cytokine-mediated inflammation. Inflammatory causes do appear to cause late gadolinium enhancement on CMR.
Duchenne (DMD) and Becker (BMD) muscular dystrophies are X-linked genetic disorders due to mutations in the dystrophin gene. The protein dystrophin is totally absent or dysfunctional in DMD and is reduced in expression or mildly dysfunctional in BMD. Duchenne muscular dystrophy is a more severe disorder and patients die of respiratory failure, generally surviving only until the 3rd decade. In contrast, BMD has a slower decline and patients may survive until the 6th decade. Cardiomyopathy is the main cause of death in BMD .
The incidence of cardiomyopathy in DMD is zero under the age of 10 years, one-third at 14 years, half at 18 years and 98% over 18 years .
Drug related dilated cardiomyopathies
Myocarditis is an inflammatory disease of the myocardium with a wide range of clinical presentations. It may be caused by a wide variety of infectious organisms, autoimmune disorders and drugs. It typically manifests in a previously healthy person and may result in rapidly progressive heart failure and arrhythmia. Acute myocarditis with established ventricular dysfunction can progress to dilated cardiomyopathy .
There are several case reports of ephedra-associated myocarditis [49, 50, 51]. Ephedra is a potent sympathomimetic agent with direct and indirect effects on adrenergic receptors. An adverse effect of adrenergic stimulation is myocyte toxicity . Naik et al.  described two men, aged 19 and 21 years respectively, who were admitted on separate occasions with dilated cardiomyopathy secondary to ephedra. Methamphetamine is a sympathomimetic agent that causes sympathetic stimulation by excessive release of noradrenaline and blockade of re-uptake at the sympathetic synaptic receptors. Several case reports have documented reversible dilated cardiomyopathy secondary to methamphetamine use [53, 54]. A case report by Lopez et al.  evaluated the CMR appearances in a patient presenting with cardiomyopathy secondary to methamphetamine. CMR demonstrated a reduced ejection fraction of 37% but no evidence of LGE, indicating no acute myocardial inflammation. The patient improved following treatment and repeat CMR showed improved ejection fraction to 64%. In our institution, we have recently encountered a patient with mephedrone-associated myocarditis. Mephedrone is a cathinone derivative that is purchasable legally on the Internet or in ‘head-shops’. This substance bears similar pharmacological and structural similarities to amphetamine. This is also referred to as ‘meow’, ‘meph’, ‘rush’ and ‘roxy’. People presenting to hospital after taking mephedrone describe a number of cardiovascular signs, agitation and sometimes a drug-induced psychosis . At least four deaths in the UK in March 2010 and a further 18 deaths in England and seven in Scotland have been attributed to cathiniones .
Uncommon cardiomyopathies characterized by restriction
Restrictive cardiomyopathies demsontrate ventricular diastolic dysfunction, and typically bilateral atrial enlargement with relatively normal ventricular end-diastolic volume and systolic function.
Systemic sclerosis (SSc) is a connective tissue disorder of unknown aetiology characterized by diffuse vascular lesions, fibrosis of the skin and other organs, including the heart, kidneys and lungs. Excess collagen deposition is a characteristic feature of systemic sclerosis. Systemic sclerosis is divided into five forms: diffuse, limited, transitory, systemic scleroderma sine scleroderma and malignant scleroderma. The principal forms are diffuse and limited systemic scleroses . Diffuse systemic sclerosis is characterised by Raynaud phenomenon that precedes the development of skin changes by one year . There is generalised skin fibrosis of the chest and limbs, skin hyperpigmentation or hypopigmentation There is early involvement of the lungs, kidneys, gastrointestinal tract and the heart. Limited systemic slcerosis is characterized by sclerotic changes of the hands, feet, face and forearms. There is telangictasia of the skin, cutaneous calcification and late involvement of the lungs with late development of pulmonary hypertension. Diffuse systemic sclerosis occurs equally in males and females. Limited systemic sclerosis has a female predominance. Sytemic scleroderma sine scleroderma is characterised by involvement of the internal organs alone with no external signs . Diastolic dysfunction may occur before any clinical sign or symptom of the disease, in both diffuse and limited forms of the disorder [60, 61].
Idiopathic hypereosinophilic syndrome (HES) is characterized by peripheral eosinophilia and multiorgan dysfunction in the absence of known causes of hypereosinophilia. The heart is frequently involved and there are three stages of eosinophilia-related cardiac damage. Stage one is an acute necrotic stage, which is usually clinically silent. An intermediate stage follows that is characterized by thrombus formation. This leads to the third stage, which is a fibrotic stage resulting in endomyocardial fibrosis and restrictive cardiomyopathy .
Metastatic disease to the heart and pericardium is rare but is more common than primary cardiac tumours . Cardiac metastases are associated with a poor prognosis. The most common tumours to metastasize to the cardiac structures are lung, lymphoma, breast, esophagus and melanoma [69, 70]. Bronchogenic carcinoma is the most common malignancy to spread to the cardiac structures and adenocarcinoma is the most common histological type . Metastatic disease from bronchogenic carcinoma to the heart may be via direct spread, lymphatic or haematogenous spread. Intrapericardial extension of tumour into the pericardium and left atrium should be suspected when there is obliteration of the superior pulmonary vein .
Involvement of the heart and pericardium is usually a late manifestation of lymphoma. Cardiac involvement occurs in 16% of patients with Hodgkin’s disease and 18% of patients with non-Hodgkin lymphoma. Metastases are usually firm, focal nodules, which can be found in the walls of all cardiac chambers and in the pericardium . Breast cancer may spread via direct extension. Enhancement of the pericardium or pericardial nodularity is suggestive but not definitive of malignant involvement .
In melanoma, autopsy reports have shown myocardial tissue replaced by extensive nodular deposits appearing as pigmented epicardial ‘black’ implants. This black macroscopic appearance gave rise to the term ‘charcoal heart’ .
Cardiomyopathies that are unclassified
This group of unclassified cardiomyopathies includes left ventricular noncompation and Takotsubo cardiomyopathy.
Left ventricular non-compaction
Left ventricular non-compaction (LVNC) is a myocardial disorder characterized by prominent and excessive trabeculations and deep intratrabecular recesses. These recesses communicate with the ventricular cavity rather than the coronary circulation . Chin et al.  were the first group to use the term LVNC in their review of eight cases in 1990. Left ventricular non-compaction is postulated to arise from an abnormality of the normal myocardial maturation process. The early fetal myocardium has deep recesses between loosely interwoven fibres, which communicate with the ventricular cavity. The trabeculations provide oxygenation exchange by creating a larger surface for direct exchange diffusion from the cardiac lumen. In the 5th–8th weeks of fetal life, the coronary circulation develops. obviating the need for direct exchange transfusion and in a normal fetus the loosely interwoven fibres undergo compaction . The severity of LVNC will depend on the timing of the arrest in the myocardial maturation and compaction process. Compaction moves from base to apex, from epicardium to endocardium and from the septal to the lateral wall. This process of maturation explains why the apex and midventricular lateral segments are more commonly involved in LVNC . Histology demonstrates that ventricular endothelium lines the recesses and is in continuity with the ventricular cavity . Other histopathological characteristics include focal ischemic necrosis within the trabeculations and endocardial layer, compensatory hypertrophy of the myocardium, interstitial fibrosis and scarring reflecting focal replacement fibrosis .
Familial LVNC can be transmitted as an autosomal dominant trait with incomplete penetrance and less commonly as an autosomal recessive trait and X-linked inheritance are seen. Genetic mutations in the G4.5 and α-dystrobrevin are seen in a minority of patients with LVNC [80, 84]. Non-compaction has been reported in association with neuromuscular disorders including Barth syndrome (also G4.5 genetic mutation), muscular and myotonic dystrophies, Pompe’s disease, mitochondrial and various other genetic disorders . It is also seen in association with other congenital cardiac defects, ventricular septal defects being the most frequent. Further congenital defects include subaortic obstruction, bicuspid aortic valves, coarctation of the aorta, Ebstein’s anomaly, valvular pulmonary stenosis, Tetralogy of Fallot and pulmonary atresia [86, 87].
LVNC can present as fetal hydrops, neonatal heart failure and with ventricular fibrillation in its most severe form . Cardiac failure is the most prevalent finding and complication in all studies of LVNC [78, 88]. Arrhythmias and thromboembolic events are more common in the adult population. In the study by Oechslin et al. , 11 thromboembolic events were seen in eight patients (24%), one stroke, six episodes of transient ischaemic attacks, one mesenteric infarction and three episodes of pulmonary embolism. Ventricular tachycardia were seen in 14 patients (41%).
Echocardiography has previously been the mainstay imaging modality in the diagnosis of LVNC. Diagnostic criteria for LVNC on echocardiography have become confusing, some studies suggesting using a two layered myocardium with a non–compacted to compacted ratio of more than 2:1 (end systolic value) and colour Doppler flow within the trabeculations . Other studies suggest using more than two thickened trabeculations as a diagnostic criteria.
CMR is increasingly performed for confirmation of the diagnosis and also to evaluate for complications related to the disorder. It has the advantage over echocardiography of optimal apical and lateral wall visualization, which are the most commonly involved segments . Appearances can be variable with three basic features described by Dursun et al. ; extensive spongiform transformation of the left ventricular myocardium, trabeculations of the ventricular wall with deep recesses of the ventricular cavity and a dysplastic appearance of the myocardium with thinned myocardium and excessive trabeculations.
Fibrosis may be observed in LVNC on CMR, which correlates with histological findings (Fig. 11c). Delayed enhancement is usually found in a subendocardial distribution. Delayed enhancement can also be found in some compacted normal segments indicating that fibrosis is also present in these normal appearing areas .
Takotsubo cardiomyopathy (TTC) is also referred to as apical ballooning syndrome and stress cardiomyopathy. It was first described in Japan almost twenty years ago . The diagnosis is based upon transient akinesia or dyskinesia of the LV apical, mid or basal segments extending beyond a single coronary vascular distribution; absence of angiographic evidence of acute plaque rupture or obstructive coronary artery disease; new ECG abnormalities or elevated troponin; no recent head trauma, intracranial bleeding, hypertrophic cardiomyopathy or phaeochromocytoma . Takotsubo may also be accompanied by acute chest pain that when accompanied with ECG changes and cardiac enzyme rises explains why many patients are initially misdiagnosed with acute coronary syndrome.
The pathogenesis behind TTC has not been fully elucidated. Coronary spasm, coronary emboli with spontaneous fibrinolysis, abnormalities in the coronary microvascular function and regional myocarditis are some suggested etiologies. Numerous studies have linked it with catecholamine excess [94, 95]. One study described TTC in nine patients immediately following intravenous administration of epinephrine or dobutamine . Both emotional and physical stresses are commonly seen as a precursor to TTC. Plasma catecholamine and neuropeptide levels in patients with TTC induced by emotional stress are markedly elevated compared with patients with myocardial infarction . Endocardial biopsies of patients with TTC support excessive catecholamine exposure characterized by contraction bands, increased interstitial fibrosis and regional accumulation of inflammatory cells .
Eitel et al.  have highlighted the discriminating ability of CMR in patients presenting with acute chest pain syndromes. Late gadolinium enhancement (LGE) was seen in patients with myocardial infarctions and myocarditis, but not in patients with TTC (Fig. 12c). One study has demonstrated LGE in patients with TTC, though the LGE was of lower signal intensity than seen in myocardial infarction or myocarditis and the extent of tissue involvement was minimal .
Eitel et al.  evaluated a large group of patients presenting with TTC. Several interesting findings were described. Of 136 patients with TTC, 121 had significant stressful events 12 h preceding their TTC. Sixty-four patients had emotional stress and 57 had a physical stress. As with all other studies of TTC, post-menopausal women were more commonly affected, but 10% of patients were pre-menopausal, 10% were male and 10% did not recover LV function immediately .
CMR is an excellent imaging modality for the evaluation of the rare and unclassified cardiomyopathy. It allows the detection, morphology, function and myocardial contrast-enhancement characteristics of these cardiomyopathy to be accurately and reproducibly analysed.