Left ventricular noncompaction (LVNC) is a rare cardiomyopathy. Prevalence is less than 0.02% [1] and is male predominant [1]. It can occur in isolation or association with other pathologies of the heart, with or without associated gene mutations [1, 2]. LVNC may be familial with an autosomal dominant mode of inheritance or sporadic [1, 2]. The sporadic occurrence was found in up to 60–70% of the cases [1]. Prominent trabeculations on the endocardial surface with deep recesses extending into the left ventricle (LV) wall characterize the disease [1].
Genetic studies showed that mutations were significantly more frequent in sarcomere genes (82%) [2]. Non-sarcomere gene mutations might be identified in a minority of genetic cases and rare cases presenting with complex genotypes [2]. Some genes involved in LVNC are also involved in hypertrophic cardiomyopathy and dilated cardiomyopathy (genes that encode sarcomere proteins) [2]. LV systolic dysfunction seems to be more frequent in genetic than in sporadic cases. In a patient with a myocardial phenotype of LVNC, the association between a genetic mutation and LV dysfunction as a risk factor of the worse outcome supports the hypothesis that LVNC is a genetically determined cardiomyopathy [2].
In 2006, The American Heart Association (AHA)-led working groups and councils classified LVNC as congenital genetic cardiomyopathy [4]. In 2008, the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases considered it an unclassified familial cardiomyopathy [5].
In embryogenesis, before the development of coronary arteries, the myocardium has a trabeculated aspect. The process of trabecular compaction in the human heart starts at the base of the LV and progresses toward the apex [6]. LVNC is considered to be the consequence of early cessation of compaction during embryogenesis. This anomaly may be why ventricular noncompaction usually involves the apical regions [6]. The result is an epicardial layer that is compacted and an endocardial layer with prominent trabeculae and deep intertrabecular recesses that communicate with the left ventricle cavity [6]. Segments involved in more than 80% of patients are apical and mid-ventricular inferior wall segments and the mid-ventricular lateral wall [6].
In LVNC, there is a mismatch between the myocardial mass and the number of capillaries, leading to hypoperfusion of the endocardial myocardium despite normal epicardial coronary arteries [6]. The disease is usually associated with reduced ejection fraction and systolic dysfunction, attributed to hypoperfusion and to asynchronism of contraction between the compacted and noncompacted myocardial layers. Hypokinesia was observed both in compacted and in noncompacted segments [6]. Papillary muscles are not well developed. The right ventricular apex may be involved as well [6]. Trabeculations diminish ventricular compliance, leading to diastolic dysfunction, that is, an abnormal relaxation or a restrictive filling pattern [6]. Ischemia is responsible for the progressive fibrosis, which also contributes to the decrease of LVEF and predisposes to ventricular arrhythmias [6].
Patients with LVNC can be asymptomatic or may present symptoms of heart failure (HF), supraventricular and ventricular arrhythmias, thromboembolic events, and sudden cardiac death. Symptoms of HF occur in more than half of the patients with LVNC, LV dysfunction being reported in up to 84% of them. In total, 36% of study patients had heart failure of function class III and class IV [6]. Systemic embolic events are frequent in patients with LVNC. The incidence of thromboembolic complications ranges from 5% to 38% [6]. Cardioembolic events are secondary to mural thrombi formed in the recesses between trabeculations in the noncompacted myocardium, but also to the depressed LVEF or the development of atrial fibrillation [6]. Systemic embolic complications secondary to LVNC are cerebral, myocardial, renal, and mesenteric [6].
ECG can be normal in 13% of cases [6]. Early repolarization abnormalities were found in 40% of patients with LVNC, and QTc prolongation in over 50% of patients [6]. Repolarization disturbances predispose patients to malignant ventricular tachyarrhythmias and sudden cardiac death [6]. Atrial fibrillation has been reported in over 25% of cases, and ventricular tachyarrhythmias in 47% [6]. Paroxysmal supraventricular tachycardia and complete heart block have also been reported [6].
According to the 2006 AHA scientific statement, the LVNC cardiomyopathy diagnosis is obtained by using imaging techniques, that is, TTE, CMR imaging, or LV angiography with ventriculography, but no specific guidelines or imaging criteria recommendations are formally provided [4].
The most used method of diagnosis is echocardiography [7]. There are two sets of echocardiographic criteria: the Jenni criteria focused on the presence of a two-layered structure [8], and the Chin criteria focused on the depth of the recess compared with the height of the trabeculations [9]. Jenni criteria [8] are the most accepted validated echo criteria and consist of evidence of a two-layer structure: a compacted thin epicardial layer and a thicker noncompacted endocardial layer with prominent trabeculation and deep intertrabecular recesses. In the short-axis view, the end-systolic ratio of noncompacted to compacted layers > 2.0 is diagnostic [8]. Additional criteria that must be met include the absence of any coexisting cardiac abnormalities and color Doppler evidence of deep perfused intertrabecular recesses [8]. Chin criteria [9] considered for diagnosis are the presence of numerous, excessively prominent trabeculations and deep intertrabecular recesses with the ratio of the distance from the epicardial surface to the trough of the trabecular recesses and distance from the epicardial surface to the peak of trabeculation ≤ 0.5, assessed at end-diastole on short-axis parasternal views and/or apical views. It is also important that no other cardiac structural abnormalities be present [9]. Stollberger et al. defined LVNC as trabeculations >/ 3, prominent formations along the left ventricular endocardial border, located apically to the papillary muscles, visible in end-diastole, in one imaging plane, moving synchronously with the compacted myocardium, distinct from the papillary muscles, false tendons, or aberrant bands [10]. Ghebhard et al. considered compacted myocardium systolic thickness < 8 mm for diagnosis of LVNC [11].
In difficult cases, other echocardiographic techniques can be used for diagnosis: contrast enhancement, three-dimensional echocardiography, speckle tracking, and tissue Doppler imaging. Speckle-tracking echocardiography (STE) was used in borderline cases because LVNC affects the left ventricle twist [12]. In a normal heart, left ventricular twisting motion is caused by rotation in a clockwise direction (as seen from the apex) at the level of the mitral valve (basal level) and counterclockwise rotation of the apex (apical level). This movement contributes 60% to ejection fraction and 15% to fiber shortening. Left ventricular untwisting is involved in active diastolic filling [12]. In patients with LVNC, an abnormal rotation pattern was described, that is, with basal and apical rotation in the same direction, resulting in almost total absence of left ventricular twist. This rotation pattern was described by Dalen et al. in 2008 as left ventricular solid body rotation, and it was proposed as a sensitive and specific marker for LVNC diagnosis that could differentiate it from DCM [13]. It has also demonstrated its importance in prognosis: patients with rigid body rotation and noncompaction cardiomyopathy had a lower NYHA functional status as compared with patients without rigid body rotation [13]. Peters et al. found rigid body rotation in 53% of patients with LVNC, and they highlighted the importance of left ventricular twist evaluation in cardiomyopathies [14].
Echocardiography is the current gold standard for the diagnosis of this entity [14]. There are frequent doubtful cases that need multimodal confirmation (echocardiography and magnetic resonance imaging) [15].
CMR imaging is superior to echocardiography for the identification of noncompacted myocardium, with better image quality and increased sensitivity for identifying trabeculations, particularly at end-diastole [15]. Petersen et al. criteria elaborated in 2005 are accepted cardiac MRI diagnostic parameters for the evaluation of LVNC, that is, the presence of two distinct myocardial layers and marked trabeculations with deep intertrabecular recesses within the inner noncompacted layer; a noncompacted/compacted myocardium ratio > 2.3 at end-diastole was considered suggestive [15]. Additional parameters have been introduced for the assessment of LVNC. Jacquier et al. considered a trabeculated left ventricular mass > 20% of the global left ventricular mass measured at end-diastole as a sensitive and specific finding for the diagnosis of LVNC [16]. Grothoff et al. introduced a quantitative measurement for LVNC diagnosis: trabeculated mass should represent > 25% of the LV global mass and > 15 g/m2 [17]. It was suggested that CMR should play a significant role in the evaluation when the diagnosis by the echocardiogram is not confirmed, a good-quality echocardiogram cannot be obtained, and/or the degree of fibrosis may help in delineating the severity of the disease [17].
Genes coding for sarcomere proteins, ion channels, and cellular signaling pathways implicated in other cardiomyopathies have been associated with LVNC [18]. LVNC may appear in isolation or can be associated with other cardiomyopathies, including DCM, hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, or congenital heart disease, such as Ebstein anomaly [18]. It might also be associated with Barth syndrome, mitochondrial disorders, and myotonic dystrophy [18]. Mutations in genes MYH7, MYBPC3, and TTN are the most common in patients with LVNC [18].
The 2011 HRS/EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies states that, owing to the low rate of a positive genetic test in index cases, the utility of genetic testing for the definitive diagnosis and care of the index case is of limited use [19].
Family screening in patients diagnosed with LVNC can help determine if a cardiac abnormality is sporadic or familial. Relatives may present with isolated LVNC and with other forms of congenital heart disease or cardiomyopathy with or without LVNC [19]. For family members in whom trabeculations or LVNC are identified, close clinical surveillance should be recommended [19].
There is no therapy specific for patients with LVNC [20]. Data from randomized controlled trials to guide the management of LVNC cardiomyopathy are limited, and interventions are focused on complications, that is, heart failure, systemic embolism, and sudden cardiac death [20]. The same treatment is recommended to patients with DCM and reduced ejection fraction [20]. Prevention of systemic embolism is an important management goal in these patients [20]. Whether anticoagulants should be administered to every LVNC patient is, however, still debated [20]. Anticoagulation therapy must be targeted to the individual patient after careful assessment of the benefit and risks. Oral anticoagulation therapy (target INR 2.0–3.0) was recommended in patients with impaired systolic function (LV ejection fraction ≤ 40%), previous history of embolism, transient ischemic attack, atrial fibrillation, and intracardiac thrombi identified on echocardiogram or another cardiac imaging modality [20]. Otherwise, risk assessment based on CHADS2/CHADS2-Vasc scores as guidance and preference of the patient is recommended [20].
Patients with LVNC and sustained ventricular tachycardia or ventricular fibrillation require cardioverter-defibrillator (ICD) implantation. These patients are at higher risk for SCD, even with normal EF [21]. This should be based on current ICD primary and secondary prevention guidelines [21]. ICD for primary prevention of sudden cardiac death is indicated for patients with LVNC who present with cardiomyopathy and ejection fraction ≤ 35% [21]. Patients with malignant ventricular tachyarrhythmia should undergo ICD implantation for secondary prevention [21].
Prognosis is proportional to the severity of systolic dysfunction of the left ventricle [22]. In 2012, Greutmann et al. found that NYHA class of heart failure >/ 3 and cardiovascular complications at presentation were strong predictors for adverse outcomes [22]. In 2020, a systematic review and meta-analysis of observational studies of Aung N. et al. found that, compared with DCM, patients with LVNC have similar risks of cardiovascular mortality, all-cause mortality, thromboembolic complications, and ventricular arrhythmia. The most important predictor of worse outcomes in patients with LVNC was low LVEF [23].
