Left Ventricular Noncompaction Cardiomyopathy

Etiology

Historically, it was thought that in the developing myocardium, the mesh of embryonic loose muscle fibers (present until coronary artery development) condensed to form a compact left ventricular myocardium, and an arrest in the embryogenic process caused the trabecular tissue to "non-compact" into the thinner myocardial layer. However, more recent data using pulse labeling and immunohistochemical staining suggest that the trabecular layers and compact layers of the myocardium develop independently of each other. Therefore, the terminology of "noncompaction" may actually be a misnomer, as the trabecular tissue does not normally compact.[3] In addition, more recent studies suggest that the pattern of increased trabeculations causing thickened endocardium may not necessarily be embryologic because this pattern is also found in healthy individuals, athletes, and pregnant adults. The morbidity in patients with increased trabecular tissue may be due to co-occurrence with other recognized myocardial disorders. At this time, it is unclear if this phenotype is related to hemodynamic stress (such as increased preload), a genetic predisposition, or, most likely, a combination of both.[1][3][4]

Some patients have sporadic LVNC with no family history or a proven genetic mutation. About 15% to 20% of cases are thought to be inherited and present earlier than those without a family history.[4] From 17% up to 50% of patients with LVNC have first-degree relatives with another cardiomyopathy, such as hypertrophic cardiomyopathy or dilated cardiomyopathy.[5] Currently, up to 40 different gene loci are associated with trabecular complexity.[3] Most of the known genetic mutations encode proteins linked to functions involving sarcomeres, mitochondria, arrhythmia, and congenital heart disease.[6][7]

The most commonly found mutations are in the β-Myosin heavy chain (MYH7), MYBPC3 (which encodes the cardiac isoform of myosin-binding protein C), and the titin (TTN) gene. The risk of lower systolic function is higher in patients carrying a genetic mutation, with the highest risk in those with TTN and in those who have more than one genetic mutation.[8] Other recognized genes associated with LVNC include cardiac troponin T (TNNT2), α-cardiac actin (ACTC), tafazzin, α-dystrobrevin, lamin A/C, ZASP/LDB3, dystrophin, HCN4, and MYH7. These genes encode the sarcomeric proteins associated with cardiac contractility.[9] 

One associated syndrome is Barth syndrome, attributed to mutations in the tafazzin gene.[10] HCN4 mutations have been identified in patients with LVNC and bradycardia.[11] LVNC is also prevalent in up to 20% of patients with Duchenne muscular dystrophy and Becker muscular dystrophy, where its presence is highly associated with a rapid deterioration in LV function and higher mortality.[12] LVNC is also associated with other neuromuscular disorders, such as myotonic dystrophy and mitochondrial disorders. The causal relationship is yet to be identified but may be related to a fragile cytoskeleton.[3] 

Epidemiology

LVNC can be present in utero, with a reported incidence in infants of 0.8/100,000/year and an incidence of 0.12/100,000/year in children. LVNC physiology can be found in patients of all ages but appears to be more common in children. Many cases are asymptomatic (ie, never diagnosed), but prevalence is thought to be very rare at 0.014% to 0.26%. The prevalence increases significantly in those with a positive family history of cardiomyopathy or in families with known genetic mutations. LVNC is 2 to 3 times more common in men than in women.[6]

Pathophysiology

In general, patients with LVNC are at increased risk of developing atrial and ventricular arrhythmias. Microischemia with wall motion abnormalities can lead to progressive dilatation and failure of the affected myocardium.[10] According to the cardiac morphology and the symptoms at clinical presentation, patients with LVNC can be grouped into the following categories:[6]

• Isolated LVNC will show an increased trabecular layer with normal function and thickness. No genetic component is known, and patients are asymptomatic. This may be discovered incidentally through an imaging study, from a heart murmur, or because of a family history of cardiomyopathy.

• LVNC-associated cardiomyopathy with dilation and dysfunction at infancy can result in early complications and increased morbidity and mortality. An example of this would be Barth syndrome or any of the other 40 known causative genetic mutations.

• LVNC meeting criteria for dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, or arrhythmogenic right ventricular dysplasia will show an associated hemodynamic profile depending on the characteristics of each category.

• LVNC is associated with congenital heart diseases—such as atrial or ventricular septal defects, patent ductus arteriosus, Ebstein anomaly, pulmonary stenosis, tetralogy of Fallot, or hypoplastic left heart syndrome. This category will also show increased morbidity and mortality related to structural heart abnormalities.

• Syndromes associated with LVNC, such as Anderson-Fabry disease or Danon disease. Neuromuscular disorders are pervasive in this category as well.

• Acquired and potentially reversible LVNC associated with physiologic conditions such as athletic activity, pregnancy, sickle cell anemia, myopathies, and chronic renal failure. This is often reversible.

• Right ventricular noncompaction either isolated or in conjunction with LVNC. This requires familiarity with radiologic interpretation, as the right ventricle normally has more trabecular tissue than the left.

Systemic Conditions Associated with LVNC Pathophysiology

Pregnancy: Pregnant women can develop de novo anatomical changes associated with LVNC, which are attributed to increased preload. One longitudinal study followed pregnant women with normal echocardiographs throughout pregnancy. Results showed  that 25% of patients developed increased left ventricular trabeculation, but were asymptomatic and without decreased ejection fraction (EF). The majority (72%) showed regression of the trabeculation within the first 8 months postpartum, and most of the other women showed gradual regression of the myocardial abnormality within 2 years.[13]

Athleticism: Another increased preload-associated condition is found in professional athletes (or those with a similar level of physical activity). One large study of Olympic athletes showed that 1.4% had echocardiography findings consistent with LVNC; but only 0.1% (of the 1.4%) patients had either EF less than 50%, family history or genetic testing suggestive of LVNC.[14] LVNC morphology in athletes is not known to have adverse effects.[15]

Hemoglobinopathies: Sickle cell anemia and other hemoglobinopathies are associated with LVNC thought to be related to increased preload and high cardiac output.[16][17] Other types of anemia and thalassemias are also associated with LVNC morphology. LVNC associated with anemia or hemoglobinopathy does not seem to cause adverse clinical effects.[18][19]

Histopathology

A gross histological specimen will demonstrate deep myocardial trabeculations, which are muscle bundles covered by endocardium, similar to the rest of the left ventricular cavity, and a thinner compact epicardial layer. The trabeculations are most frequently observed near the apex and gradually decrease in depth and number as they reach the papillary muscles.[2] Microscopically, the non-compacted tissue shows cardiomyocyte enlargement, enlarged and irregular nuclei, and sometimes fibrosis. Specimens do not show significant cellular infiltrate.[5]

History and Physical

Patients may present at any age, from infancy to late adulthood. Symptomatic presentation varies, with some patients diagnosed incidentally after an echocardiogram, others presenting with symptoms later during adulthood, and yet others presenting in childhood or even infancy.[2] When symptoms are present, the most frequent clinical manifestation involves heart failure.[10] Other clinical presentations include arrhythmias (especially ventricular), thromboembolic events, and sudden death.[20] An interesting finding from a single-center prospective study was that 61% of patients diagnosed with LVNC also showed neuromuscular disease on detailed neurologic exam.[21]

The deep myocardial trabeculations of LVNC predispose to thrombus formation and embolism. The reported frequency of thromboembolism ranges from 13% to 24% in adults and from 0% to 38% in children. Clinical manifestations include transient ischemic attacks, stroke, mesenteric infarction, myocardial infarction, or peripheral embolism.[22] 

For patients with LVNC who are asymptomatic, have a normal ECG, and have normal left ventricular function at the time of an incidental diagnosis, it is recommended that a family history be obtained to ensure no history of cardiomyopathy or sudden cardiac death.[9] These patients require follow-up, with some experts recommending an echocardiogram every 3 years.[2] 

Evaluation

Imaging Studies

LVNC is primarily diagnosed using non-invasive imaging, namely transthoracic echocardiography and cardiac magnetic resonance (CMR). Computed tomography (CT) and transesophageal echocardiogram have also been used to diagnose LVNC.

Echocardiography is routinely used initially as the non-invasive investigation of choice due to its ease of use. The diagnosis of spongy myocardium is made in the presence of prominent trabeculations with a non-compacted to compacted myocardium ratio >2.0 in end-systole on the short-axis view.[3] Transthoracic echocardiography is also useful for detecting associated lesions such as muscular ventricular septal defects or other congenital heart disease. In those with challenging acoustic windows, such as adult patients with obesity, contrast echocardiography can improve the sensitivity in diagnosing LVNC, as it enhances the contrast between the myocardium and the blood pool.[2]

CMR uses a steady-state free precession sequence to differentiate between the compacted and non-compacted myocardial layers. Because this technique provides a better ratio of noncompacted-to-compacted myocardium, it is used to confirm the diagnosis of LVNC when the echocardiographic images cannot provide a definitive diagnosis. It also gives superior visualization of the presence of ventricular thrombi and shows any myocardial fibrosis, which can predispose to arrhythmia. CMR criteria to diagnose LVNC requires a higher non-compacted to compacted myocardium ratio than echocardiography, a ratio greater than 2.3 at end-diastole.[10] CT can also provide an adequate definition of the increased trabeculations with less time and expense (but also less definition).[23]

ECG Findings

The ECG of patients with LVNC is rarely normal, and the most commonly found abnormalities include increased voltage of the QRS complex, left bundle branch block, and ST/T wave abnormalities. However, no specific EKG finding is diagnostic of LVNC.[24]

Cardiac Monitoring/Arrhythmia Findings

Arrhythmia is a common presentation of LVNC, including atrial fibrillation, bradycardia, other supraventricular arrhythmias, and atrial flutter. Ventricular arrhythmia and fibrillation are more common when EF is less than 35% and are associated with sudden cardiac death. Atrial fibrillation is by far the most common arrhythmia in adults, estimated at 25% to 30% of patients with LVNC.[7] Children often present with Wolf-Parkinson-White syndrome or sinus bradycardia.[6]

Treatment / Management

Treatments for LVNC include treating the associated clinical sequella, including atrial fibrillation, thromboembolism, and arrhythmias. Without additional risk factors of atrial fibrillation, LV thrombus, or decreased EF, it is difficult to assess the embolic risk of LVNC alone. Clinical judgment must take all corresponding factors into account. The CHADS₂/CHA₂DS₂-Vasc scores have been used to stratify at-risk patients.[7] Anticoagulation is recommended over antiplatelet agents, which have not proven to be effective. Direct oral anticoagulants (DOACs) are usually the suggested method of preventative anticoagulation. Vitamin K antagonists are the standard treatment of established thrombus; but growing evidence supports the use of DOAC in the setting of established thrombi as well.[7] The use of DOACs has also not been studied in pediatric patients. 

Anticoagulation Therapy

LVNC with normal ventricular function: Deep recesses cause sluggish blood flow, which induces hypercoagulability with thrombi formation, even with normal ventricular function. Therefore, although no formal recommendation for thromboembolic event prevention exists, experts suggest considering the use of anticoagulant therapy.[7]

LVNC with reduced ventricular function: In those with reduced left ventricular function, the hypertrabeculations predispose to clot formation and cerebrovascular events due to blood stagnation. Most clinicians implement anticoagulation when EF is lower than 40% or with a history of previous thromboembolic events or atrial fibrillation.[25]

LVNC with associated arrhythmias: Atrial fibrillation affects 25% to 30% of patients with LVNC. These patients tend to have worse systolic function and a higher prevalence of atrioventricular valve regurgitation. In these patients, oral anticoagulation is recommended.[7]

Management of congestive heart failure: Additional management of symptomatic patients with dilated LVNC and congestive heart failure may require diuretics, angiotensin-converting enzyme (ACE) inhibitors, or angiotensin receptor blockers (ARB). Patients with hypertrophic cardiomyopathy and LVNC may benefit from beta blockers or calcium channel blockers. Approximately 12% of patients with LVNC develop end-stage congestive heart failure and will require cardiac transplantation.[10]

Arrhythmia management: Cardiac rhythm abnormalities are managed by a standard protocol, and some patients may benefit from an implanted cardiac defibrillator (ICD) for severe ventricular tachyarrhythmias to prevent sudden death.[26] ICDs are recommended in those with EF lower than 35%, in addition to anticoagulation.[10]

Differential Diagnosis

The differential diagnosis of LVNC includes processes that can appear as increased left ventricular wall thickness, such as left ventricular hypertrophy, dilated or hypertrophic cardiomyopathy, LV thrombus, false tendons, cardiac fibromas, endomyocardial fibrosis, and cardiac metastasis.[9] 

Prognosis

The prognosis of patients with LVNC is highly variable, depending on the clinical status of the patient and whether a genetic cause has been determined. Those with ventricular dysfunction, thromboembolic events, and atrial and ventricular arrhythmias have a worse prognosis. If a patient is diagnosed with LVNC with a known mutation, first-degree relatives should also be tested.[4]

In children diagnosed with LVNC, a 10-year follow-up showed that 90% had developed systolic dysfunction. When LVNC was associated with cardiac failure and ventricular arrhythmias it carries a 13% mortality. In adults with LVNC, a 6-year follow-up showed a 50% mortality rate, and 12% undergoing cardiac transplant. Some have reported a high association with neuromuscular disease, which carries a worse prognosis. In general, mortality predictors include decreased EF, atrial fibrillation, ventricular arrhythmias, and thromboembolic events.[22] 

Complications

LVNC can lead to cardiac failure, lethal ventricular arrhythmias, and mural thrombi leading to thromboembolic events. In LVNC which is related to genetic mutations and presents in childhood, morbidity is often related to associated cardiac structural abnormalities or neuromuscular disease. In adults, much of the morbidity is related to decreased ejection fraction which predisposes to arrhymias and thromboembolic events.[22]