Left Ventricular Noncompaction: A New Form of Heart Failure
Section snippets
LVNC: overview
This disorder has been considered to be a rare disease and has been identified by a variety of names including spongy myocardium, fetal myocardium, noncompaction of the left ventricular myocardium, hypertrabeculation syndrome, and LVNC.2, 4, 5, 6, 7 As noted earlier, the abnormality is believed to represent an arrest in the normal process of myocardial compaction, the final stage of myocardial morphogenesis, resulting in persistence of multiple prominent ventricular trabeculations and deep
Historical delineation of LVNC
LVNC was first described by Grant11 in 1926 and, in the past 75 years, has been identified in association with a variety of congenital heart malformations affecting the coronary arteries, left and right ventricular outflow tracts, and interventricular and interatrial septa.11, 12, 13, 14, 15, 16 In the past 20 years, isolated LVNC (ie, not associated with CHD) has also been described, albeit more rarely.17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29
Normal cardiac structure
Cardiac muscle fibers comprise separate cellular units (myocytes) connected in series.30 In contrast to skeletal muscle fibers, cardiac fibers do not assemble in parallel arrays but bifurcate and recombine to form a complex three-dimensional network. Cardiac myocytes are joined at each end to adjacent myocytes at the intercalated disc, the specialized area of interdigitating cell membrane (Fig. 1). The intercalated disc contains gap junctions (containing connexins), mechanical junctions,
Pathology of LVNC
In the early embryo, the heart is a loose interwoven mesh of muscle fibers.16 The developing myocardium gradually condenses, and the large spaces within the trabecular meshwork disappear, condensing and compacting the ventricular myocardium and solidifying the endocardial surfaces. Trabecular compaction is normally more complete in the LV than in the myocardium of the right ventricle (RV). The situations in which this compacting pathway fails are believed to be caused by an arrest in
Incidence of LVNC
The incidence and prevalence of LVNC is unknown but the disease is considered to be rare. Ritter and colleagues17 reported the prevalence of isolated LVNC to be 0.05% of all adult echocardiographic examinations in a large institution. No other reliable data have been reported to date.
Clinical features and diagnosis of LVNC
LVNC commonly presents in infancy with signs and symptoms of congestive heart failure (CHF).4, 7 Echocardiographically, this disorder is characterized by systolic dysfunction associated with a dilated, hypertrophic LV. The characteristic deep trabeculations are typically noted in the LV apex and lateral wall; regional wall motion abnormalities are common. Multiple forms of LVNC are reported. One group of cases of LVNC occurs in the absence of other structural heart disease and is believed to be
Subtypes of LVNC
Although an increasing number of clinicians are beginning to recognize the clinical features of LVNC, several key points have failed to be described. One of the important issues in the diagnosis and outcomes of these patients, particularly in childhood, is the specific LVNC phenotype that exists in any 1 patient. There are at least 7 different phenotypes of LVNC and these different phenotypes have different outcomes (Fig. 2). The subtypes include the following:
Imaging of LVNC
Echocardiography has been used to diagnose and describe LVNC. Recently, Punn and Silverman45 investigated LVNC using the 16-segment model described by the American Heart Association and the American Society of Echocardiography in 44 children with LVNC. Using the ratio of noncompaction to compaction, the investigators analyzed the 16 segments and determined whether severity was correlated with poor outcomes in these affected children. The 16-segment noncompaction/compaction ratio, shortening
Electrocardiography in LVNC
The ECG in patients with LVNC is typically abnormal and commonly has giant voltages (Fig. 3).2, 7 These patients, particularly the childhood forms of LVNC, may be associated with pre-excitation. In approximately 30% of patients with LVNC, particularly children, there is extreme midprecordial voltages that mimic the ECG seen in Pompe disease. Arrhythmias, including supraventricular tachycardia and ventricular tachycardia, are common and dangerous accompaniments to all subtypes of LVNC.
Clinical genetics of LVNC
LVNC most commonly has X-linked recessive or autosomal dominant inheritance.7, 8 In X-linked LVNC, female carriers have not been found to develop frank clinical disease, and are echocardiographically normal. Consistent with X-linked inheritance, no male-to-male transmission of the disease occurs.19 In some cases of LVNC without CHD, and most, if not all, cases of the form associated with CHD, autosomal dominant inheritance is seen in familial cases.7, 8 When LVNC is associated with CHD, the
Molecular genetics of LVNC
A genetic cause of isolated LVNC was initially described by Bleyl and colleagues19 when they identified mutations in the gene G4.5/TAZ in patients and carrier women. This gene, known as G4.5 or tafazzin (TAZ), encodes a novel protein family (tafazzins) with unclear function, and is also responsible for Barth syndrome (BTS)47 and other forms of infantile cardiomyopathies.48, 49 BTS is a clinical association of myocardial dysfunction, neutropenia, skeletal myopathy, abnormal mitochondria, organic
Final Common Pathway Hypothesis
To put the mechanisms responsible for cardiovascular disorders into perspective, a unifying hypothesis has been developed that helps to predict the central targets and interacting, modifying cascades that, when disordered, result in a specific phenotype. For instance, familial hypertrophic cardiomyopathy (FHC) is a genetically heterogeneous disease in which 17 genes have been identified to cause this phenotype when mutated.61 As previously noted, the mutated gene most commonly encodes a
Animal models of LVNC
A significant number of mouse models with cardiomyopathy have been described in the past several years. However, few have a clear phenotype similar to LVNC, although several have had a hypertrophic, dilated heart with systolic dysfunction. One of the best models of LVNC to date is the FKBP12-deficient mouse, but others exist.73, 74 Models deficient in the sarcoglycan complex and its associated proteins (ie, sarcospan, syntrophin) have commonly been shown to develop a hypertrophic, dilated heart.
Therapy and outcome
The specific therapy depends on the clinical and echocardiographic findings. In patients with systolic dysfunction and heart failure, anticongestive therapy identical to those used in patients with DCM is appropriate. In particular, ACE inhibitors such as captopril and enalapril are useful, as well as β-adrenergic blocking agents such as metoprolol or carvedilol. Diuretics may also be needed. However, in those patients exhibiting findings more consistent with an HCM or diastolic dysfunction
BTS
Initially described as X-linked cardioskeletal myopathy with abnormal mitochondria and neutropenia by Neustein and colleagues51 and Barth and colleagues,50 this disorder typically presents in male infants as CHF associated with neutropenia (cyclic) and 3-methylglutaconic aciduria.52 Mitochondrial dysfunction is noted on electron microscopy and electron transport chain biochemical analysis. In addition, abnormalities in cardiolipin have been noted.103 Echocardiographically these infants
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Funding Support: Dr Towbin is funded, in part, by the National Institutes of Health, National Heart, Lung and Blood Institute (R01 HL53392, and R01 HL087000, the Pediatric Cardiomyopathy Registry and Pediatric Cardiomyopathy Specimen Repository, respectively), and the Cincinnati Children's Kindervelt-Samuel Kaplan Chair in Cardiology.