Left ventricular noncompaction cardiomyopathy: cardiac, neuromuscular, and genetic factors.

REVIEWS Left ventricular noncompaction cardiomyopathy: cardiac, neuromuscular, and genetic factors Josef Finsterer1, Claudia Stöllberger2 and Jeffrey A. Towbin3

Abstract | Left ventricular hypertrabeculation (LVHT) or noncompaction is a myocardial abnormality of unknown aetiology, frequently associated with monogenic disorders, particularly neuromuscular disorders, or with chromosomal defects. LVHT is diagnosed usually by echocardiography by the presence of a bilayered myocardium consisting of a thick, spongy, noncompacted endocardial layer and a thin, compacted, epicardial layer. The pathogenesis of LVHT is unsolved, and the diagnostic criteria, prognosis, and optimal treatment of patients with LVHT are under debate. LVHT is categorized as distinct primary genetic cardiomyopathy by the AHA and as unclassified cardiomyopathy by the ESC. LVHT is usually asymptomatic, but can be complicated by heart failure, thromboembolism, or ventricular arrhythmias, including sudden cardiac death. Mortality of patients with LVHT ranges from 5% to 47%. Anticoagulation is indicated if atrial fibrillation, severe heart failure, previous embolism, or intracardiac thrombus formation are present. In patients with LVHT with late gadolinium enhancement, an implantable cardioverter–defibrillator might be considered if systolic dysfunction, a family history of sudden cardiac death, nonsustained ventricular tachycardia, or previous syncope is additionally present. In this Review, we discuss the current findings on the aetiology and pathophysiology of LVHT, and provide an overview of the diagnosis, available treatment, and prognosis of this cardiomyopathy.

Krankenanstalt Rudolfstiftung, Postfach 20, 1180 Vienna, Austria. 2 Second Medical Department with Cardiology and Intensive Care Medicine, Krankenanstalt Rudolfstiftung, Juchgasse 25, 1030 Vienna, Austria. 3 The Heart Institute, Le Bonheur Children’s Hospital, University of Tennessee Health Science Center, and St. Jude Children’s Research Hospital, 51 N Dunlap Street #100, Memphis, Tennessee 38105, USA. 1

Correspondence to J.F. [email protected] doi:10.1038/nrcardio.2016.207 Published online 12 Jan 2017

Left ventricular noncompaction — also known as noncompaction cardiomyopathy or left ventricular hypertrabeculation (LVHT), spongy myocardium, fetal myocardium, honeycomb myocardium, or hyper trabeculation syndrome — is a structural abnormality of the left ventricular myocardium of unknown cause1,2. In the majority of patients, LVHT is associated with genetic disease, particularly neuromuscular disorders (NMDs) and chromosomal defects1,2. We prefer to use the term LVHT because this term is descriptive of the condition, and because the noncompaction hypothesis is unproven. LVHT is characterized by a two-layered structure usually of the apical and lateral left ven tricular myocardium, distal to the papillary muscles. The two-layered structure consists of a spongy endo cardial layer and a compacted epicardial layer, which is usually thinner than the endocardial layer. Contrary to persisting sinusoids, which are perfused from coro nary arteries, intertrabecular spaces in LVHT are per fused entirely from the ventricular side. LVHT is usually asymptomatic, but can be complicated by heart failure,

thromboembolism, or ventricular arrhythmias, includ ing sudden c ardiac death (SCD)1,2. LVHT is diagnosed primarily by echocardiography, and is frequently associ ated with myocardial fibrosis, as shown by the presence of late gadolinium enhancement (LGE) on cardiac MRI3. LVHT is categorized as distinct primary genetic cardiomyopathy by the AHA4 and as unclassified cardio myopathy by the ESC5. Patients with LVHT should be screened for NMDs and chromosomal defects, and patients with NMDs and chromosomal defects should be investigated for LVHT. This Review provides an update on findings concerning the aetiology, pathophysiology, diagnosis, treatment, and prognosis of LVHT.

History LVHT was first described on autopsy in 1969 by Feldt et al., who reported a biventricular, bizarre, spongy myo cardium in a white female patient aged 3 months, with complete situs inversus6. Further history of LVHT7–14 is depicted in FIG. 1 . Of note, the frequently cited paper by Grant et al., published in 1926, is not the first

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REVIEWS Key points • Patients with left ventricular hypertrabeculation (LVHT) should undergo evaluation for neuromuscular disorders, and patients with neuromuscular disorders should be screened for cardiac involvement • The minimal set of neurological investigations includes a thorough collection of individual and family history, a clinical exam, determination of creatine-kinase activity, and an electromyograph • Relatives of patients with LVHT should be screened for LVHT, with the same diagnostic work‑up as for index patients with LVHT • Partially in accordance with guidelines for oral anticoagulation in patients with LVHT, we recommend oral anticoagulation if a patient has atrial fibrillation, severe heart failure, previous embolism, or intracardiac thrombus formation • Patients with LVHT require an implantable cardioverter–defibrillator if ventricular arrhythmias are recorded; if the family history is positive for sudden cardiac death, arrhythmias, or LVHT; or if late gadolinium enhancement is associated with systolic dysfunction

description of LVHT, because this article definitively is a description of persisting sinusoids15. Arguments against LVHT being the condition in the patient reported by Grant et al. are that the current diagnostic criteria are not met, hypertrabeculation was predomin antly seen in the right portion of the single ventricle, predominantly the basal segments were affected, and intertrabecular spaces communicated with myocardial and epicardial vessels 15. In addition, the report in 1932 by Bellet and Gouley on a new-born infant with aortic atresia and coronary–ventricular fistula does not describe noncompaction, but persisting sinusoids16.

Classification LVHT can be categorized according to various criteria. According to the onset, LVHT can be classified as con genital or acquired, or as paediatric or adult. Congenital LVHT is assumed to be the result of a disturbed com paction process during early cardiac development. Congenital LVHT can be diagnosed in utero. Acquired LVHT is not present in utero or at birth, but devel ops at any stage of life after birth13. According to the presence or absence of additional structural cardiac abnormalities, LVHT is classified as isolated or non isolated. Nonisolated LVHT is associated with struc tural cardiac abnormalities other than LVHT (TABLE 1). In addition, LVHT can be classified as symptomatic or asymptomatic. LVHT can become symptomatic if the condition is associated with heart failure, arrhythmias, conduction defects, or embolism2. LVHT can be associ ated with a point mutation, deletion or duplication, or a chromosomal defect 17. LVHT can be present or absent in other family members of an index patient18. Lastly, LVHT can be present with or without a NMD, or with or without another cardiomyopathy 17. In addi tion, LVHT was proposed to be divided in subtypes that include hypertrabeculation of the left ventricle with normal left ventricular size, thickness, and func tion (also called the ‘benign form’, which is the subtype present in approximately 30% of paediatric patients with LVHT); biventricular noncompaction; arrhythmo genic noncompaction; dilated form of noncompaction; hypertrophic form of noncompaction; hypertrophic

and dilated form of noncompaction; restrictive form of noncompaction; hypertrophic and restrictive form of noncompaction; and congenital heart disease non compaction2,19. The reason for this different classifi cation is the uncertainty about the aetiology of LVHT. For clinicians, differentiating between asymptomatic and symptomatic LVHT is important.

Aetiology and pathophysiology The aetiology of LVHT is unknown, but one hypoth esis is that LVHT results from a disturbed compaction process during early development of the left ventricular myocardium20. Noncompaction hypothesis. According to the non compaction hypothesis, LVHT results from a failure of the final phase of cardiac development, the myo cardial compaction process 1. Cardiomyocyte pre cursors originating from the mesodermal layer form a median tube in the embryo, which differentiates to myocardium under the influence of various genetic or humoral regulators21. In gestational week 12, pro trusions from the endocardial layer develop into myo cardial trabeculations. These trabeculations enable an increased surface-to-volume ratio and an increased myocardial mass before coronary arteries are formed20. In the next step, these trabeculations undergo a com paction process, which is largely accomplished by the end of gestational week 16 (REFS 21,22). During the com paction process, the myocardium gradually compacts inwards from the epicardium and from the base to the apex, and the intertrabecular recesses are compressed to capillaries8,23. Accumulating evidence shows that the epicardium and epicardial-derived cells have a crucial role not only in the development of the compacted layer, but also of the noncompacted layer 21. The compaction process continues with myocardial growth and increas ing intracardial pressure20. Some data indicate that the compaction process is triggered by vascular endothelial growth factor A or by angiopoietin 1 (REF. 24). Failure of the compaction process results in deep intertrabecular spaces, which are hypothesized to communicate with the left ventricle in isolated LVHT and with the coronary arteries in nonisolated LVHT25–27. However, communi cation of the intertrabecular spaces with the coronary arteries means persisting sinusoids, and contradicts the definition of LVHT. Concomitantly, the spiral pattern of cardiomyocytes develops, which is the prerequisite for the twisting contraction pattern of the left ventricu lar myocardium20. If the compaction process remains incomplete, myocardial dysfunction ensues owing to impaired rotational contractile performance20. Studies published in the past 15 years have shown that mutations in Bmp10 (REF. 28), Casz1 (REF. 29), Daam1 (REF. 30), Jarid2 (REF. 31), Fkbp1a32, and Mest 33, which are involved in car diac morphogenesis, are implicated in the development of LVHT during embryogenesis. Left ventricular hypertrabeculation and neuromuscular disorders. When patients with LVHT are systematically referred to a myologist, a NMD might be found in up

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REVIEWS First description of LVHT by Feldt et al., as biventricular, spongy myocardium in a white female aged 3 months with complete situs inversus6

1969

1975

LVHT first described on echocardiography by Engberding et al.9

1984

Westwood et al. report the first description of endocardial fibroelastosis in LVHT7

1990

LVHT is visualized by cardiac MRI for the first time by Hany et al.11

1997

The term noncompaction is introduced by Chin et al.10

2003

Acquired LVHT first described in a patient with a mitochondrial disorder by Finsterer et al.13

2004

Finsterer et al. report the first description of a patient with LVHT and a neuromuscular disorder12

2007

Menon et al. document LVHT for the first time in a fetus14

First report of postnatal persistence of a spongy myocardium by Dusek et al.8

Figure 1 | Timeline of history of left ventricular hypertrabeculation (LVHT).

to 80% of the patients34–36. However, some studies have not found NMDs as a comorbidity in patients with LVHT 37. The NMDs most frequently associated with LVHT include mitochondrial disorders, Barth syndrome, zaspopathy, myotonic dystrophy type 1, dystrobrevinopathy, and Emery–Dreifuss muscular dys trophy owing to LMNA mutations17 (TABLE 2). Arguments against a causal relationship between NMDs and LVHT include the observation that LVHT can be found in only a small number of patients with a particular NMD, even if patients with NMD are systematically screened for LVHT, and that the variety of different NMDs associ ated with LVHT is large, suggesting that LVHT results from a compensatory rather than a genetic mechanism. Acquired left ventricular hypertrabeculation. Since the first description of acquired LVHT in 2004 (REF. 13), this condition has been reported in other patients with NMDs38, in top athletes performing professional, vigor ous training 39, and in pregnant women40. In a study in primigravida pregnant women, 7% of the women devel oped noncompaction during pregnancy and 25% developed hypertrabeculation40; however, the delineation between noncompaction and hypertrabeculation in this study was not comprehensive. Another study reported a single patient in whom LVHT developed 2 weeks postpartum41. The development of LVHT during preg nancy has been attributed to increased preload condi tions40. Whether hormonal imbalance contributes to the development of LVHT in pregnant women is unknown. Several other hypotheses have been proposed to explain the pathophysiological mechanism of acquired LVHT. These hypotheses attribute the development of acquired LVHT to adaptation of the left ventricular myocardium to systolic dysfunction or volume overload38, a reduced adhesion of cardiomyocytes, an ineffective attempt to overcome a metabolic defect, a ‘weak’ myocardium, microinfarctions, or the need to enlarge the endocardial surface to increase stroke volume or improve oxygen ation38. In some patients, LVHT has been reported to disappear over time42,43. Disappearance might be the result of thickening of the compacted layer and ‘swallow ing’ of the noncompacted layer, or owing to dilatation of the left ventricle resulting in stretching, flattening, and ‘disappearance’ of LVHT.

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Concomitant congenital defects. Nonisolated LVHT, also called the congenital heart disease form of noncompac tion, is characterized by the presence of congenital cardiac defects other than LVHT, in particular obstruction of the left ventricular outflow tract and anomalies of coronary arteries2,19,44,45. In a study including 202 patients with LVHT, 12% of the patients had nonisolated LVHT44. The most frequent congenital defects in this cohort were left ventricular outflow tract abnormalities (46%), Ebstein anomaly (25%), tetralogy of Fallot (8%), and double outlet right ventricle44 (TABLE 1). Other congenital cardiac abnor malities occurring more rarely in association with LVHT are listed in TABLE 1. We do not believe that LVHT is an intrinsic part of a given congenital heart defect, because only a few patients with such congenital defects also have LVHT. In congenital heart defects, LVHT instead might result from activation of a developmental pattern to compensate for impaired left ventricular performance. Genetics of left ventricular hypertrabeculation. Although LVHT has been reported in association with mutations in >40 genes (TABLE 2) and even more chromo somal defects17,46 (TABLE 3), a causal relationship between any of these mutations and LVHT remains to be estab lished17,44,47. One argument against a causal relationship between LVHT and any of these genetic defects is that the same genetic defect is hardly ever associated with the same phenotype in different individuals. A strong genotype–phenotype correlation has been reported only for HCN4 mutations and LVHT being associated with sinus arrhythmia48, and for LMNA mutations and LVHT being associated with atrioventricular blocking and ventricular arrhythmias49. Other arguments against a causal relationship are that LVHT often does not segre gate with a particular mutation within a family; that in families carrying such mutations, cardiac manifestations are highly variable; that LVHT can be acquired; and that in families with a dominantly transmitted disease, LVHT might not occur in each generation47. Conversely, argu ments in favour of a causal relationship between LVHT and any of these genetic defects are that LVHT is more frequent in patients carrying a particular genetic defect (for example, mutations in TAZ, Barth syndrome)47 com pared with mutations in other genes (such as DMPK), and that LVHT has familial occurrence.



REVIEWS Table 1 | Congenital cardiac abnormalities in patients with nonisolated LVHT Congenital cardiac anomaly in LVHT

Mutated gene

Refs

Absence of pericardium

Unknown

Aortic coarctation

MATR3, TBL1Y, WDPCP

Aortic hypoplasia

Unknown

44

Aortic interruption

Unknown

132

Aortic valve dysplasia

SEMA3C

133

Atrial septal defect

ACTC1, NKX2‑5, TBX20

133

Congenital aortic stenosis

Unknown

134

Congenital atresia of coronary arteries

Unknown

135

Congenital transposition of great arteries

ISL1

136

Coronary aneurysms

Unknown

137

Coronary artery to right ventricle fistulae

Unknown

138

Double chamber left ventricle

Unknown

139

Double orifice mitral valve

Unknown

140

Double outlet right ventricle

GATA5, TBX20, ZIC3

Ebstein anomaly

MYH7, SLC19A2, TPM1

141

Giant aneurysm of right coronary artery

Unknown

137

Hypoplastic right ventricle

Unknown

142

Ill-defined papillary muscles

Unknown

143

Left atrial isomerism

Unknown

133

Mitral regurgitation

MPLKIP

144

Mitral valve prolapse

DCHS1, LTBP3

145

Myocardial bridges

Unknown

146

Patent ductus arteriosus

MATR3, TFAP2B

Persistent left superior vena cava

Unknown

147

Pulmonary atresia, stenosis

Unknown

142

Pulmonary valve dysplasia

Unknown

133

Right ventricular coronary sinusoids

Unknown

148

131 44

44

74

(athletes, pregnant women), LVHT in cardiomyopathy, LVHT in patients with congenital heart disease, LVHT in patients with renal or haematological disease, LVHT in patients with a chromosomal defect, and LVHT in which the right ventricle is also affected46. LVHT has not been associated with mutations in FKBP12, FXN (Friedreich ataxia), GAA (Pompe disease), or COL7A1 (epidermiolysis bullosa).

Epidemiology Frequency. Only a small number of studies have cal culations on the prevalence or incidence of LVHT. The prevalence of LVHT reported in a study including 104 paediatric patients with primary cardiomyopathy was 9%52. In adult individuals referred for echocardiography, the prevalence of LVHT was 0.01–0.30%53,54. Patients with heart failure have a higher prevalence of LVHT, up to 3–4%55,56. In adults, the incidence of LVHT is reported as 0.05%57. In infants, the incidence is calculated as 0.80 per 100,000 individuals per year and in children as 0.12 per 100,000 individuals per year 25,58. The low reported prevalence and incidence of LVHT might be because LVHT is frequently missed on transthoracic echocardiography (TTE), and can be missed even on ventriculography and cardiac MRI, and because LVHT can remain a symptomatic over a long period of time. Sex ratio, ethnicity, and age. Men are more frequently affected by LVHT than women, with men accounting for 56–82% of the cases of LVHT10,23,25,34,57. LVHT is more prevalent in black than in white populations59,60. Age at which LVHT is detected is highly variable, ranging from early infancy to late adulthood27. Median age at diagnosis is 40–50 years in adults25,34,57, and 5–7 years in paediatric patients10,23,61.

Clinical presentation LVHT is usually diagnosed when the condition becomes symptomatic or when complications occur. These compli Tricuspid atresia MT‑ND1, NFATC1 142 cations include the classic triad of heart failure, arrhyth Unicuspid or bicuspid aortic valves MATR3, NKX2‑5, NOTCH1 44 mias, conduction disturbances, or thromboembolism. Interestingly, noncompaction in children can have an Ventricular septal defects HAND2, MYH7, NKX2‑6 142,150,151 ‘undulating phenotype’, in which the associated cardio LVHT, left ventricular hypertrabeculation. myopathic features change, for instance, from a dilated and hypertrophic presentation with poor cardiac function, Familial occurrence of LVHT, particularly in first- to a hypertrophic and hypercontractile form of noncom degree relatives of affected patients, has been reported paction, and then to the final ‘destination’, a dilated and in 13–50% of patients with LVHT10,25,50,51. These find dysfunctional form of noncompaction with heart failure, ings support the recommendation to investigate usually taking place over several months62. Only sparse LVHT at least in first-degree relatives of these patients. data exist on the frequency of complications. Some stud In patients with familial LVHT, transmission of the ies have shown a low complication rate26, whereas other abnormality can follow an autosomal dominant trait studies found higher complication rates63. Complication (for example, MYH7 mutations in distal myopathy), rates seem to be different between adults and children23,64. an autosomal recessive trait (for example, GBE1 muta Additionally, complication rates might increase with age23. tions), an X‑linked trait (for example, Barth syndrome), Complications of LVHT manifest clinically as chest or a maternal trait (mitochondrial disorders owing to pain, dyspnoea, palpitations, syncope, falls, leg oedema, mutations in m itochondrial DNA). exercise intolerance, embolic ischaemic stroke, myocardial Different categories of LVHT have been defined, infarction, peripheral embolism, or SCD65. If LVHT is which can be associated with mutations in distinct genes46. associated with a NMD, the affected patients can have These categories include LVHT in healthy individuals easy fatigability, exercise intolerance, myalgias, muscle Subaortic stenosis

Unknown

Tetralogy of Fallot

HAND2, PITX2, TBX5

44

149



REVIEWS Table 2 | Mutated genes associated with LVHT Disease

Mutated gene

Refs

Muscular dystrophies Becker muscular dystrophy

DMD

152

Duchenne carrier

DMD

153

Duchenne muscular dystrophy

DMD

154

Dystrobrevinopathy

DTNA

35

Emery–Dreifuss muscular dystrophy, laminopathy LMNA

155

Myotonic dystrophy 1

DMPK

156

Myotonic dystrophy 2

CNBP

157

Oculopharyngodistal muscular dystrophy

Unknown

158

Zaspopathy

LDB3

159

Congenital fibre type disproportion

MYH7B

160

Integrin myopathy

ITGA7

160

Multi-minicore disease

RYR1

161

MYH7 myopathy

MYH7

162

Nemaline myopathy

TPM1

163

Danon disease (glycogenosis IIb)

LAMP2

164

Glycogen storage disease type IV

GBE1

165

Glycogenosis Ib

Not provided

166

Malonyl-CoA decarboxylase deficiency

MLYCD

167

Mitochondrial disorder

HADHB

168

Mitochondrial myopathies

mtDNA genes, nDNA genes

168

Myoadenylate-deaminase deficiency

AMPD1

169

Succinate dehydrogenase deficiency

SDHD

170

Barth carrier

TAZ

171

Barth syndrome

TAZ

172

Cobalamin-C deficiency, methylmalonic aciduria

MMACHC

173

Epidermiolysis bullosa simplex

PLEC

174

Hereditary inclusion body myositis

Not provided

175

Muscular dystrophy

Not provided

176

Myopathy with spherocytosis

Not provided

177

β-Thalassaemia

HBB

178

Charcot–Marie–Tooth neuropathy type 1A

PMP22

179

Fabry disease

GLA

180

Congenital myopathies

Metabolic myopathies

Other hereditary myopathies

Neuronopathies / neuropathies

Other cardiac diseases Cardiomyopathy

ACTC1, ACTN2, DNAJC19, MT‑ND1 (mtDNA), PRDM16, TNNT2

109, 181– 186

Carvajal syndrome

DSP

187

Dilated cardiomyopathy

PLEKHM2

188

Leopard syndrome, pulmonary stenosis

PTPN11

189

MIDAS/MLS syndrome

HCCS

190

Noonan syndrome

Not provided

191

cramps, muscle stiffness, myotonia, or muscle weakness66. The history of patients with LVHT and an NMD can be positive for episodes of malignant hyperthermia during general anaesthesia, blood tests can show elevated levels of muscle enzymes, and needle electromyography can show a myogenic or neurogenic pattern. Systolic dysfunction and heart failure. About two-thirds of the patients with LVHT develop heart failure owing to ventricular dysfunction during the disease course10,25. Ventricular dysfunction can be systolic or diastolic. The cause of systolic dysfunction in LVHT is unclear, but evidence indicates that systolic dysfunction could be a result of subendocardial hypoperfusion despite normal coronary arteries10,26. Another possible cause of systolic dysfunction in LVHT is that the subendocardial layer of the myocardium accounts for two-thirds of the left- ventricular contractility. Diastolic dysfunction is attrib uted to abnormal relaxation or a restrictive filling pattern owing to hypertrabeculation67. Data indicate that perfu sion of the noncompacted layer is worse than perfusion of the compacted layer 68. Subendocardial perfusion defects in LVHT have been demonstrated on cardiac MRI69, PET70, thallium scintigraphy 23, and histological investi gations at autopsy 26. PET studies have shown a reduced coronary flow reserve in compacted and noncompacted segments71. Reduced coronary flow reserve has been explained by failure of the microcirculation to grow ade quately with the ventricular mass or by compression of the intramural coronary bed by the thickened myocardium26. In adult patients with LVHT, the rate of systolic dysfunction is 58–76% and the rate of heart failure is 53–73%25,34,57. In paediatric patients, systolic dysfunction occurs in 60–63% and heart failure in 30–63% of the patients10,23. Diastolic dysfunction was found in half of 34 adult patients with LVHT, of whom 36% had a restric tive filling pattern25. Children with LVHT also can present with a restrictive filling pattern23,72. In some patients with LVHT, hypokinesia of the noncompacted or the nor mally compacted segments has been reported, and has been attributed also to microcirculatory dysfunction25. Whether patients with LVHT are prone to experience myocarditis is unknown, but myocarditis has been repeat edly reported in patients with LVHT, and a study pub lished in 2015 suggests that myocarditis in patients with LVHT can easily progress to dilated cardiomyopathy 73. Conduction defects, arrhythmias, and sudden cardiac death. In adult 25,34,57 and paediatric10,23 patients with LVHT, the frequency of electrocardiogram (ECG) abnormalities is high: 88–94% in adult patients and 88% in paediatric patients26. Supraventricular arrhythmias or conduction defects occur in about 25% of patients with LVHT, including atrial fibrillation, atrial flutter, paroxysmal supraventricular tachycardia, or complete atrioventricular block10,23,57. Wolff–Parkinson–White syndrome was found in 0–3% of adult patients with LVHT, but in 13–15% of paediatric patients with LVHT26. Atrial fibrillation occurs in 5–29% of adult patients with LVHT, but has not been described in paediatric patients with LVHT26. Sinus node dysfunction can be the initial



REVIEWS Table 2 (cont.) | Mutated genes associated with LVHT Disease

Mutated gene

Refs

Other cardiac diseases (cont.) Restrictive cardiomyopathy

MYBPC3

192

Sotos syndrome

NKX2‑5

193

Nonmyopathic, noncardiac, genetic disorders Adrenal congenital hypoplasia

Not provided

Beals–Hecht syndrome

FBN2

194

62

Central nervous system disease

ARFGEF2

195

Melnick Fraser syndrome

EYA1, SIX1, SIX5, TFAP2A

196

Seizure, acidosis

HMGCL

197

Isolated LVHT Isolated LVHT

CASQ2, HCN4, KCNQ1, MIB1, NKX2‑5, NNT, PKP2, RYR2, SCN5A, TNNI3, TTN, YWHAE

198– 209

LVHT, left ventricular hypertrabeculation; mtDNA, mitochondrial DNA; nDNA, nuclear DNA.

clinical manifestation of LVHT74. Bundle branch block was reported in 26–56% of adult patients with LVHT and in 15–25% of paediatric patients with LVHT26. Ventricular arrhythmias are even more prevalent in patients with LVHT, with a frequency of 18–47% in adults75 and 0–38% in paediatric patients23,26. SCD occurs in 18% of adult patients with LVHT and in 0–13% of paediatric patients with LVHT26. Rhythm-related SCDs are a pre dominant feature in children with LVHT and with heart failure or arrhythmias64. Additionally, PQ‑prolongation, QT‑prolongation, ST‑segment depression, ST‑segment elevation, T‑wave inversion, fragmented QRS complex, low voltage, and early repolarization have been reported in patients with LVHT76. Cardioembolism. Cardioembolism can manifest as stroke, transient ischaemic attack, mesenteric infarction, myocardial infarction, renal infarction, or peripheral embolism26. Thrombi can originate from the ventricular cavity in instances of severe systolic dysfunction, from the intertrabecular spaces, from the atrium in patients with atrial fibrillation, or from the right ventricle or right atrium through a ventricular septal defect or an atrial septal defect, respectively 77. The risk of thrombus formation might be further increased in patients with an NMD and reduced mobility 78. The frequency of thromboembolism is variable: 13–24% in adults25,77 and 0–38% in paediatric patients26. Dysmorphism. Facial dysmorphism has been described in a number of patients with LVHT, and occurs in approximately one-third of the paediatric LVHT population, but more rarely in adults with LVHT26. Dysmorphism might be attributed to the frequent association of LVHT with genetic or chromosomal defects. Facial dysmorphisms described in the literature include prominent forehead, epicanthic folds, broad eyebrows, broad nasal tip, hypertelorism, low-set ears, strabismus, high-arched palate, or micrognathia10,79.

Diagnosis LVHT is diagnosed when the diagnostic criteria are satisfied and when valve obstruction, coronary heart disease, and all differential possibilities have been excluded26. LVHT is usually diagnosed using TTE, and more rarely by transoesophageal echocardiography (TEE), ventriculography, cardiac CT, or cardiac MRI. However, at present, no consensus has been reached concerning the diagnostic criteria for LVHT and the best diagnostic methods. Pathoanatomical findings currently seem to be the gold standard for diagnosing LVHT80. At autopsy, LVHT is diagnosed if three or more trabeculations are present, disregarding the presence or absence of other cardiac abnormalities and the thickness of the noncompacted layer 80. The diagnosis might be missed in 89% of paediatric patients23, but these f igures are improving with increasing awareness of LVHT57. Overall, the diagnostic criteria that are based predomin antly on the ratio of noncompacted layer to compacted layer have flaws related to measurements, physiological sense, and, potentially, the use of left ventricular seg ments for the assessment of the ratio. Therefore, better criteria for diagnosing LVHT are needed. In the past 3 years, fractal analysis of LVHT has shown increased fractal dimension in LVHT compared with healthy con trols, but to what degree this parameter is dependent on systolic function, heart rate, or the MRI resolution remains unclear 81. Diagnosis of LVHT might be further supported by the use of the twist and untwist parameters (indices of clockwise and anticlockwise left ventricular rotation during systole and diastole). In patients with LVHT, longitudinal, circumferential, and radial myo cardial deformation are impaired82. Accordingly, the twist rate is low and the onset of untwist is delayed82. Echocardiography. Three different proposals for a diag nostic algorithm with echocardiographic criteria have been introduced10,34,71 (TABLE 4). According to the criteria outlined by Chin et al., LVHT is diagnosed if prominent trabeculations with deep recesses are present and if the ratio of the distance between epicardium to trough of trabeculations (X) and the distance between epicardium to peak of trabeculations (Y) is decreasing from the papil lary muscles to the apex (starting with a value of 2 at end-systole, absence of other congenital cardiac abnormalities (TABLE 1), and intertrabecular recesses perfused from the ventricu lar side71 (TABLE 4). A disadvantage of the Swiss criteria is that they rely on images in the parasternal short-axis view and, therefore, tend to overdiagnose LVHT because delineation between trabeculations, papillary muscles, and aberrant bands can be challenging in this plane. According to the criteria described by Stöllberger et al. (the Vienna criteria), LVHT is diagnosed on echocardio graphy if three or more trabeculations are present, if the left ventricular myocardium has a bilayered structure



REVIEWS Table 3 | Chromosomal defects associated with LVHT Clinical manifestation

Chromosomal defect

Refs

1p36 deletion syndrome (also known as monosomy 1p36)

Deletion of 1p36

210

1q43 deletion syndrome

Deletion (1) (q43q43)

211

5q– syndrome

Deletion (5) (q35.1q35.3)

212

Coffin–Lowry syndrome

Mutations in RPS6KA3, which maps to Xp22.2

213

Cornelia De Lange syndrome

Interstitial deletion of 8p23.1

214

DiGeorge syndrome

Deletion of 22q11.2

215

Distal 4q trisomy/distal 1q monosomy

Derivative chromosome (4) translocation (1;4) (q42.1;q35.1)

216

Hunter McAlpine syndrome

Tetrasomy 5q35.2–5q35.3

217

Mosaic trisomy 22

Trisomy of chromosome 22 in some cells

218

Ohtahara syndrome

Microdeletion (9) (q33.3q34.11)

219

Pierre Robin sequence

Not provided

220

Translocation (10;11)

Unbalanced translocation (10;11)

221

Trisomy 13

Trisomy 13

222

Turner syndrome

Mos45,X(28)/46,X,+mar(21)/47,X,+2mar(1)

223

LVHT, left ventricular hypertrabeculation.

(irrespective of the ratio of noncompacted to compacted layer), and if the intertrabecular recesses are perfused from the ventricular side83 (FIG. 2; TABLE 4). Quantifying the ratio of noncompacted to compacted layer is not necessary with the Vienna criteria, because any ratio is compatible with LVHT. Additionally, the ratio of non compacted to compacted layer is highly dependent on the echocardiographic view and location of the measurement. Although the American Society of Echocardiography Guidelines for Chamber Quantification recommend measuring wall thickness in end-diastole84, the question of whether LVHT should be diagnosed at end-diastole or end-systole is not resolved. In the past 2 years, data indicate that application of both modalities can increase their sensitivity and decrease the interobserver variabil ity 85. In a retrospective study of 100 cine loops acquired by three, experienced, independent echocardiographers, Stöllberger et al. found that the interobserver variability is lowest if four diagnostic criteria are satisfied: more than three prominent trabeculations distal to the papillary muscles at end-diastole, which are distinct from aberrant bands or false tendons; trabeculations that move syn chronously with the compacted myocardium; bilayered structure of the left ventricular myocardium, best visible at end-systole; and intertrabecular recesses, which are perfused from the ventricular side, as shown by colour- Doppler imaging at end-diastole85. Agreement between the echocardiographic diagnostic criteria described by Chin et al., Jenni et al., and Stöllberger et al., however, is poor 59. When applying all three echocardiographic criteria to a group of 199 patients with LVHT, only 30% of the included patients met all three definitions59. In a retrospective, case–control study of 104 echocardio graphic investigations of patients with LVHT, performed by two echocardiographers blinded to the diagnosis, the interobserver agreement was only 67%86.

Application of speckle tracking echocardiography e nables identification of the abnormal rotational contrac tion dynamics of the left ventricle in LVHT — a rotation of the basal and apical segments in the same direction and, therefore, absence of the physiological left ventricu lar twist (clockwise on the base and anticlockwise on the apex)87. Real-time 3D echocardiography is another newly introduced method, which allows a more accur ate quantification of the number of trabeculations and left ventricular mass88. Contrast echocardiography can increase the sensitivity of echocardiography for diag nosing LVHT89, as can ‘colourizing’ the myocardium (tissue Doppler). Disadvantages of TTE for diagnosing LVHT, however, include the inaccuracy of off-axis or oblique image planes and the challenges of evaluating the apex 20. Having the apical four-chamber view projected as upside down or right-side up can help to visualize the apex. These disadvantages can be partially over come by the use of TEE, which in some cases can allow the diagnosis of LVHT that has been missed on TTE90. Hypertrabeculation or noncompaction of the right ven tricle should not be diagnosed, because reference limits for this condition are unavailable, but identifying qualita tively coarse trabeculations in the right ventricular apex should be stated26. Cardiac MRI. Advantages of cardiac MRI compared with echocardiography for diagnosing LVHT include the high spatial resolution; better delineation between the noncompacted and compacted layer; the ability to visualize the apex, false tendons, prominent papil lary muscles, and aberrant bands; and the use of con trast medium to assess LGE (a hyperintensity signal in the myocardium 7–15 min after injection of contrast medium that occurs in 80% of patients with LVHT91) for the evaluation of fibrosis, oedema, or myocarditis20. Cardiac MRI studies have shown that the compacted layer increases and the noncompacted layer decreases after age 40 years92. Criteria for diagnosing LVHT on cardiac MRI were proposed by Petersen et al. in 2005 (REF. 93). According to these criteria, LVHT is diagnosed on cardiac MRI if a bilayered myocardium is present and if the ratio of noncompacted to compacted myocardium is >2.3 at end-diastole93 (FIG. 3). A study published in 2012, how ever, showed that 43% of patients without cardiac disease or hypertension have at least one out of eight myocardial segments with a ratio >2.3 (REF. 94). The mass of trabecu lations was proposed by Jacquier et al. as a further diag nostic criterion for delineating normal from abnormal trabeculations95. According to this criterion, LVHT is diagnosed if the trabecular mass exceeds 20% of the left ventricular global mass95. The usefulness of determining LVHT mass by cardiac MRI, however, is questionable, because this parameter does not differentiate between mass of intertrabecular tissue (black blood) and mass of trabeculations (myocardium)1. Accordingly, LVHT mass varies considerably between patients with LVHT, making the trabecular mass an unreliable diagnostic, cardiac MRI marker 1. Possibly, T2‑black-blood, fast spin echo images can be helpful in this respect 96.



REVIEWS Table 4 | Criteria for diagnosing LVHT on transthoracic echocardiography Criteria

Chin’s criteria Swiss criteria

Vienna criteria

Number of trabeculations

NR

NR

>3.0

X/Y ratio

2.0

NR

Two-layered myocardium

Yes

Yes

Yes

ITRPFV

NR

Yes

Yes

No other cardiac abnormality

NR

Yes

NR

ITRPFV, intertrabecular perfusion from the ventricular side; LVHT, left ventricular hypertrabeculation; NC/C ratio, ratio of noncompacted layer thickness and compacted layer thickness; NR, not relevant; X/Y ratio, ratio of the distance between epicardial surface and trough of the intertrabecular recesses (X) and the distance between epicardial surface and peak of the trabeculations (Y).

LVHT is frequently associated with s ubendocardial or myocardial fibrosis, as demonstrated by the pres ence of LGE97. LGE can be classified as ischaemic or nonischaemic98. The distribution of LGE can be sub endocardial, midmyocardial, subepicardial, or trans myocardial3. Ischaemic LGE always follows a vascular subendocardial distribution progressing to the subepi cardial regions98. Nonischaemic LGE can be linear or patchy, and a result of fibrosis, oedema, or myocarditis (in midmyocardial or subepicardial LGE)98. The most frequent distribution of LGE in LVHT is midmyocardial (68% of patients with LVHT and LGE)3. Myocardial fibro sis can cause wall motion abnormalities, cardiac conduc tion defects, or arrhythmias99. In one study, the degree of LGE correlated with the ejection fraction and the severity of LVHT100, but in another study, LGE characteristics were nonspecific and heterogeneous3. Despite good spatial res olution for diagnosing LVHT and the capacity to assess coronary heart disease, cardiac CT is not established for standard use in the evaluation of LVHT, because this tech nique is associated with a high radiation exposure and with the risk of renal failure owing to the contrast dye20. Ventriculography. Ventriculography is carried out as part of cardiac catheterization and provides a 2D projection of the ventricle, but each image alone will not include all ventricular segments. The most commonly used standard views for ventriculography are RAO 30°, which demonstrates the anterior, apical, and inferior ventricular walls, and the LAO 60°20° cranial view, which allows for better imaging of the lateral and septal ventricular walls. As LVHT is frequently located in the apical and lateral walls, both views would be necessary to diagnose LVHT; however, both are not always available. If only a single RAO projection is applied, LVHT can be missed by ventriculography. Unfortunately, no criteria for diagnosing LVHT on ventriculography have been established101. Disadvantages of the method are the use of contrast medium and that image planes are frequently not compatible with those of echocardiography or cardiac MRI. Nonetheless, invasive cardiologists should be encouraged to per form ventriculography when carrying out coronary angiography or congenital heart disease evaluation in

a standardized way to learn more about the utility of the method for diagnosing LVHT. Electrocardiography. To detect silent arrhythmias or arrhythmias that occur only during sleep, and to avoid SCD, long-term ECG recordings might be necessary, either by repeated Holter monitoring or by implantation of a loop-recorder. Electrophysiological studies can help to unmask severe ventricular arrhythmias27. Holter ECG should be carried out annually in all patients with LVHT without an implantable cardioverter–defibrillator (ICD)26. In a study of five paediatric patients with LVHT, signal-averaged ECG showed late potentials in three patients and prolonged QT‑dispersion in one of the patients70. In a study of two adult patients with LVHT, Holter ECG showed multiple premature ectopic beats and nonsustained ventricular tachycardia102. Longterm ECG recording by a loop recorder detected aborted SCD owing to polymorphic ventricular tachycardia with asystole, and an ICD was implanted102. Spectral analysis of the Holter signal revealed that heart-rate variability is reduced in patients with LVHT and a history of heart fail ure103. In a study of 238 patients with LVHT of whom four had palpitations and four a history of syncope, Holter monitoring every 6 months over a period of 4 years revealed atrial fibrillation in nine patients104. Endomyocardial biopsy. In a study of five patients with LVHT undergoing right ventricular endomyocardial biopsy, interstitial fibrosis and endocardial fibroelastosis were found in three patients105. Unfortunately, the researchers did not correlate the histological findings with LGE. In some cases endomyocardial biopsy had histo logical features of histiocytoid cardiomyopathy 106. In a study of two patients with LVHT, endomyocardial biopsy of the right ventricle showed thickened endocardium, interstitial fibrosis, myocardial damage, and lymphocyte infiltration107. Generally, LVHT has no indication for endomyocardial biopsy. Endomyocardial biopsy should be considered only if myocarditis is suspected. Genetic testing, familial studies. Contrary to other clin icians108,109, we do not recommend screening patients with LVHT for any of the mutations so far reported in associ ation with LVHT (TABLE 2), because the genetic testing has neither therapeutic nor pathogenetic implications and because a causal relationship has never been proven. In patients in whom the underlying genetic disorder is clinically evident on the basis of the phenotype or the fam ily history, confirmation of the suspected diagnosis with a genetic test is considered justified. In the USA, genetic testing of children with LVHT is considered, but pursued more when other family members have noncompaction or other cardiomyopathy. Genetic testing is reportedly diagnostic in 20–40% of patients. Because of the familial occurrence of LVHT, TTE of first-degree relatives of an index patient is strongly recommended. As LVHT can be associated with NMDs and because LVHT in NMDs has prognostic implications, patients with LVHT should be referred to a neurologist, and all patients with NMD should be screened for LVHT using noninvasive imaging.



REVIEWS a

b

Figure 2 | Left ventricular hypertrabeculation on transthoracic Natureechocardiography Reviews | Cardiology and autopsy. a | Echocardiographic apical four-chamber view showing a dilated left ventricle with six ventricular trabeculations within the apical and lateral region. The trabeculations are located apically to the papillary muscles. b | Postmortem specimen 8 days after echocardiography showing the hypertrabeculated apex. During life, the patient had received an implantable cardioverter–defibrillator.

Differential diagnoses. Differential diagnoses that must be excluded before diagnosing LVHT include dilated cardiomyopathy, hypertrophic cardiomyopathy, api cal type of hypertrophic cardiomyopathy, hypertensive heart disease, eosinophilic endomyocardial disease, aber rant bands or false tendons, focal type of hypertrophic cardiomyopathy, arrhythmogenic right ventricular dys plasia, left ventricular thrombi, cardiac metastases, and endocardial fibroelastosis27. A bilayered myocardium can also be seen in healthy volunteers, athletes, pregnant women, and patients with hypertrophic cardiomyopathy, hypertensive heart disease, or aortic stenosis1,2. However, if coarse trabeculations exist, the overlapping syndrome of noncompaction with another c ardiomyopathy or congenital heart defect should be defined.

Treatment Available data about treatment options for LVHT are limited. The crucial points of treatment are heart failure therapy (including heart transplantation), antiarrhyth mic therapy (including ablation and implantation of an ICD), and oral anticoagulation. Noninvasive approaches. Generally, patients with LVHT associated with arrhythmias, congenital heart disease, or other cardiomyopathies should avoid heavy physical exercise and strenuous activities, particularly burst activities. Patients with LVHT with systolic dys function or increased diastolic dimension should not engage in professional sport activities. Patients with asymptomatic LVHT, however, should not be detained from carrying out competitive sport. Pregnancy is not a contraindication in female patients with LVHT27. LVHT diagnosed in a fetus is no indication for terminating pregnancy, as has been proposed in a study published in 2015 (REF. 110). Heart failure in LVHT should be treated in the same way as heart failure owing to other causes27. β‑Blockers, angiotensin-converting-enzyme inhibitors, angiotensin II‑receptor blockers, mineralocorticoid- receptor antagonists, and/or diuretics can be used to manage systolic or diastolic dysfunction26,27. β‑Blockers

can additionally reduce left ventricular mass111,112. Oral anticoagulation is recommended in patients with atrial fibrillation, after a cardioembolic event, in those with severe systolic dysfunction, or if an atrial or a ventricu lar clot has been identified. No studies are available on the preference for vitamin K antagonists or new oral anticoagulants in patients with LVHT; we recommend the use of vitamin K antagonists because of their practi cability concerning monitoring and antagonization, and the approval of these anticoagulants for patients aged >75 years113. In babies and children with LVHT, the use of daily baby aspirin (81 mg) in all patients is becoming standard. The decision for or against anticoagulation can be supported by the use of the CHADS2 and CHA2DS2VASc scores114, because patients with heart failure and atrial fibrillation develop cardioembolic events more fre quently than those without77. In patients with severe heart failure, positive inotropic agents might be necessary 115. Invasive approaches. Patients with LVHT require implantation of an ICD if ventricular tachycardias are recorded. The decision for or against implantation of an ICD in patients with LVHT should follow the g eneral guidelines for primary or secondary prevention116. In a study of 44 patients with LVHT, implantation of an ICD was indicated for primary prevention according to these guidelines in 75% of the patients116. In patients with n ormal systolic function but with LGE, an ICD is recommended if an additional risk factor is present, such as reduced systolic function, a family history of SCD, nonsustained ventricular tachycardia on 24 h‑ECG, or previous syncope20. The strongest indication for an ICD is nonsustained ventricular tachycardia, because 7% of patients receiving the ICD for primary prevention and 8% of patients who received the ICD for secondary prevention had ventricular tachycardia on 24 h‑ECG116.

Figure 3 | Left ventricular hypertrabeculation on Nature Reviews | Cardiology cardiac MRI. Cardiac magnetic resonance (1.5 Tesla, cine TRUE FISP) long-axis two-chamber view showing left ventricular hypertrabeculation affecting the left ventricular apex and the apical posterior wall (arrows).



REVIEWS Whether patients with LVHT should undergo electro physiological studies before ICD implantation is under debate, but some clinicians advocate such an approach117. Left ventricular ablation of intertrabecular substrates and right ventricular catheter ablation have been repeatedly performed with success for treating ventricular arrhythmias118. In patients with heart failure, reduced systolic function, and prolonged intraventricular conduction, a cardiac resynchronization therapy system might be beneficial26. In heart failure owing to LVHT that is refrac tory to humoral therapy, heart transplantation should be considered. However, when considering heart trans plantation for treating intractable heart failure owing to LVHT, it should be kept in mind that LVHT is frequently associated with NMDs and that necessary immuno suppression might be myotoxic and might worsen a Table 5 | Predictors of mortality in left ventricular hypertrabeculation (LVHT) Predictor of mortality

Patients (n)

Frequency (%)

Advanced age

220

Not reported

Refs 78

140

Not reported

66

Arterial hypotension

106

Not reported

129

Atrial fibrillation

220

16

78

162

17

224

141

17

225

140

16

66

105

16

226

Cardiovascular complications

115

39

126

Diabetes mellitus

141

19

225

Heart failure

220

68

78

162

35

224

140

63

66

115

65

126

50

56

227

Increased left atrial diameter

106

Not reported

129

Increased left ventricular end-diastolic diameter

106

67

129

50

46

227

Increased QRS width

105

19

226

Low-voltage electrocardiogram

140

5

66 226

105

4

LVHT extension

140

Not reported

LVHT of lateral wall

140

46

66

Male sex

105

66

226

Presence of a neuromuscular disorder

220

61

78

162

65

224

66

140

61

66

Pulmonary hypertension

106

27

129

Right bundle branch block

106

5

129

Sinustachycardia

220

8

78

Tall QRS

105

33

226

clinically manifest or subclinical NMD. Previous investi gations on mortality after heart transplantation found higher mortality 25 than that found in studies published in the past 2 years (REFS 2,119). In a study of 78 patients with LVHT undergoing orthotopic heart transplan tation, the overall outcome was similar to that of patients with dilated cardiomyopathy 119. Of note, whether LVHT develops in an implanted heart in a patient with LVHT in the explanted heart is unknown. If heart failure becomes intractable with conven tional measures, and if heart transplantation is not feasible immediately or because of contraindications, implantation of a ventricular assist device should be considered120. Surgical reconstruction of left ventricular diastolic function has been performed once121, but the overall benefit of this intervention has not been appropri ately assessed. Patients with LVHT with additional con genital cardiac defects might require surgery for cardiac congenital abnormalities (TABLE 1) in addition to LVHT122. Surgery in these patients can have a beneficial effect by relieving heart failure, improving cardiac function, and decreasing heart size122,123. Therapy for children with LVHT might differ from these approaches.

Outcome and prognosis The outcome of patients with LVHT is determined by the complications that occur and by their magnitude. Complications that strongly determine the outcome of patients with LVHT include ventricular arrhythmias, heart failure, and cardioembolism124. Few studies have been carried out on the long-term outcome of patients with LVHT. The outcomes and phenotypes seem to differ between children and adults61. Paediatric patients. Depending on the duration of the follow‑up, the reported mortality in paediatric LVHT ranges from 13% to 23%. In a study of eight paediatric patients with LVHT, mortality was 12.8%10. In this study, the highest risk of death was associated with ventricular arrhythmias and heart failure10. In a study of 27 paedi atric patients with LVHT, the outcome of these patients was better 23 than in a previous study of eight paediatric patients10, although 90% of the patients had developed systolic dysfunction during a follow‑up of 10 years23. In the National Australian Childhood Cardiomyopathy study 125, children with LVHT had a 23% incidence of SCD over a median follow‑up of 11.9 years. Adult patients. In a study of 17 patients with LVHT, 47% of the patients died and 12% had undergone heart trans plantation within 6 years after diagnosis57. In another study including 34 patients with LVHT, 35% of the patients died and 12% had undergone heart transplantation during a mean follow‑up of 3.6 years25. A study of 115 patients with LVHT aged >14 years showed that 31% of those with symptomatic LVHT died or underwent heart transplan tation during a mean follow‑up of 2.7 years126. In a study that included 172 patients with LVHT (of whom 72% had a NMD), mortality was 4.8% per year over a mean follow‑up period of 5.3 years127. Similarly, mortality was 5.7% per year during a mean follow‑up of 4.5 years in a



REVIEWS study of 140 patients with LVHT, but only 11 patients died from heart failure and only three from SCD63. In a study including 55 patients with LVHT and systolic dysfunc tion, 12.7% of the patients died during a mean follow‑up of 17 months128. In a study of 106 patients with LVHT, the annual incidence of death or heart transplantation was 9.1%129. Altogether, mortality in adult patients with LVHT is 5–12% per year, and can be higher or lower than mortality in paediatric patients with LVHT depending on the clinical severity of the cardiac and extracardiac conditions. Predictors of mortality in LVHT are listed in TABLE 5. Few data are available about the rate of thrombo embolism in LVHT. In a study in patients with LVHT and heart failure, a thromboembolic event occurred in only one of the 39 patients who did not receive vitamin K antagonists128. In single patients with LVHT, thrombosis of the entire left ventricle leading to embolic myocardial infarction has been reported130.

Conclusions LVHT is a myocardial abnormality of uncertain aetio logy, but frequently associated with monogenic dis orders, particularly NMDs, or with chromosomal defects. LVHT is commonly associated with overlapping cardiac abnormalities, including all other cardiomyo pathy forms and congenital heart disease. LVHT can have familial occurrence. LVHT is usually diagnosed by echocardiography upon the presence of a bilayered myo cardium consisting of a thick, spongy, noncompacted endocardial layer and a thin, compacted, epicardial layer. Contrary to persisting sinusoids, which are per fused from coronary arteries, intertrabecular spaces in LVHT are entirely perfused from the ventricular side.

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LVHT is occasionally associated with myocardial fibro sis, as shown by the presence of LGE on cardiac MRI. LVHT is usually asymptomatic, but can be complicated by heart failure, thromboembolism, or ventricular arrhythmias, including SCD. Anticoagulation is indi cated in adults if complications such as atrial fibrillation, severe heart failure, previous embolism, or intracardiac thrombus formation are present. In children with LVHT, baby aspirin is routinely used. Implantation of an ICD follows the general guidelines for ICD implantation in cardiomyopathies. In adult patients with LVHT and LGE, an ICD is indicated if the patients have additional systolic dysfunction, a family history of SCD, non sustained ventricular tachycardia, or previous syncope. In children with LVHT, primary prevention with ICD implantation is uncommon, and is typically provided after syncope or in children with malignant arrhyth mias and/or a family history of malignant arrhythmias. Mortality in patients with LVHT is 5–47%. Patients with LVHT should be screened for NMDs, and patients with NMD should be investigated for LVHT. Unresolved areas in LVHT concern the lack of uni formly accepted diagnostic criteria, the unclear aetio logy and pathogenesis of LVHT, the relevance of clinical parameters as prognostic factors, the unclear association between LVHT and NMDs, and the question of which therapy patients with LVHT should receive and at what time point the therapy should be initiated. How fre quently patients with LVHT should be followed up and whether all relatives of index cases should be screened for LVHT is also unclear. Future research should be particularly directed towards these unresolved questions to improve the management and outcome of patients with LVHT.

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Author contributions

J.F. wrote the manuscript. J.F., C.S., and J.A.T. researched data for the article, provided substantial contribution to the discussion of content, and reviewed and edited the manuscript before submission.

Competing interests statement

The authors declare no competing interests.

Review criteria

Data for this Review were identified by searches in MEDLINE, Current Contents, EMBASE, Web of Science, Web of Knowledge, LILACS, SCOPUS, and Google Scholar by using the search terms “noncompaction”, “non-compaction”, “hypertrabeculation”, “spongy myocardium”, “two-layered myocardium”, “honeycomb structure”, in combination with “pathophysiology”, “treatment”, “therapy”, “drugs”, and “medication”. Randomized (blinded or open-label) clinical trials, longitudinal studies, case series, and case reports were considered. Abstracts and reports from meetings were not included. Only articles published in English, French, Spanish, or German in 1966–2016 were considered. Appropriate papers were studied and discussed for their suitability to be incorporated in this Review.



Left ventricular noncompaction cardiomyopathy.

noncompaction in vacuolar non-neuromuscular cardiomyopathy.

Left ventricular noncompaction cardiomyopathy: a case report and literature review.

noncompaction.

Left ventricular noncompaction cardiomyopathy: adult association with 1p36 deletion syndrome.

Left ventricular noncompaction cardiomyopathy: three decades of progress.

Adherence to thresholds: overdiagnosis of left ventricular noncompaction cardiomyopathy.

Left ventricular noncompaction: a distinct cardiomyopathy or a trait shared by different cardiac diseases?

Ebstein's Anomaly, Left Ventricular Noncompaction, and Sudden Cardiac Death.

noncompaction remains vague.

Right ventricular morphology and systolic function in left ventricular noncompaction cardiomyopathy.

Left ventricular noncompaction associated with hypertrophic cardiomyopathy: echocardiographic diagnosis and genetic analysis of a new pedigree in China.

Left ventricular noncompaction and athletes-reply.

noncompaction.

Echocardiographic characteristics of isolated left ventricular noncompaction.

Fetal left ventricular noncompaction cardiomyopathy and fatal outcome due to complete deficiency of mitochondrial trifunctional protein.

The Current Approach to Diagnosis and Management of Left Ventricular Noncompaction Cardiomyopathy: Review of the Literature.

Juvenile neuronal ceroid-lipofuscinosis with hypertrophic cardiomyopathy and left ventricular noncompaction: a case report.

Successful palliation of a child with left ventricular noncompaction cardiomyopathy and tricuspid atresia to Fontan procedure.

Left ventricular noncompaction cardiomyopathy: an under-recognized disease diagnosed by echocardiography and computed tomography.

noncompaction in an Eritrean war invalid with neuromuscular disease.

Left ventricular noncompaction presenting like a double-chambered left ventricle.

Left Ventricular Noncompaction Cardiomyopathy Presenting with Heart Failure in a 35-Year-Old Man.

Cardiomyopathy Phenotypes and Outcomes for Children With Left Ventricular Myocardial Noncompaction: Results From the Pediatric Cardiomyopathy Registry.