Isolated left ventricular noncompaction in adults: Clinical manifestations and diagnosis

INTRODUCTION — Left ventricular noncompaction (LVNC, also known as noncompaction cardiomyopathy [1]) is a complex myocardial disorder with a distinct phenotype characterized by prominent LV trabeculae and deep intertrabecular recesses [2,3]. LVNC was previously also called spongy myocardium or hypertrabeculation syndrome but these terms should not be used interchangeably with LVNC [4].

This review will focus on clinical manifestations and diagnosis of LVNC as an isolated disorder distinct from other clinical settings in which non-compacted myocardium may be seen in association with other cardiac and noncardiac abnormalities. Management and prognosis of isolated LVNC is discussed separately. (See "Isolated left ventricular noncompaction in adults: Management and prognosis".)

DEFINITIONS — LVNC is a phenotype resulting from a genetic trait associated with various cardiomyopathies, congenital heart disease, and/or environmental effects [5]. LVNC has been categorized as an "unclassified" cardiomyopathy (table 1A-B) [3], but mounting evidence now points to reclassification of LVNC as a distinct but not always pathological phenotype. The presence of noncompacted myocardium by itself does not seem to cause disease. By definition, isolated LVNC occurs in the absence of other cardiac or noncardiac congenital abnormalities. (See "Definition and classification of the cardiomyopathies" and 'Differential diagnosis' below.)

LVNC is characterized by the following features:

●An altered myocardial wall with prominent trabeculae and deep intertrabecular recesses, resulting in thickened myocardium with two layers consisting of noncompacted myocardium and a thin compacted layer of myocardium (picture 1) [6-8].

●Continuity between the LV cavity and the deep intertrabecular recesses, which are filled with blood from the ventricular cavity without evidence of communication to the epicardial coronary artery system.

As discussed below, criteria for the extent of noncompaction have been developed to help distinguish the trabeculation seen in LVNC from that seen in other forms of heart disease and in healthy individuals. However, criteria are evolving and there may be morphologic overlap between LVNC and other types of cardiomyopathy and other pathologic and nonpathologic phenotypes. (See 'Diagnosis' below and 'Differential diagnosis' below.)

PREVALENCE — The prevalence of LVNC in the general population is not known and depends on the imaging modality used for diagnosis. The prevalence among patients undergoing echocardiography is estimated at 0.014 to 1.3 percent [9-12]. An earlier review from Switzerland identified 34 cases within 15 years, which represented 0.014 percent of echocardiograms performed [13]. However, this is an underestimate, as improved echocardiographic image quality, increased detection of the entity on nonechocardiographic imaging, and increasing awareness of LVNC lead to enhanced recognition of this phenotype. Among patients with heart failure (HF), the prevalence of LVNC has been reported as 3 to 4 percent [14]. Among patients with HF, criteria for LVNC are more frequently met among Black patients than among White patients [15].

In a systematic review and meta-analysis of 59 studies in patients ≥12 years old, the prevalence estimate of LVNC by echocardiography was 1.28 percent [12]. By cardiovascular magnetic resonance (CMR) imaging, prevalence was 14.79 percent. By both methods, the LVNC criteria were more often fulfilled in athletes (by echocardiography, 3.16 and by CMR, 27.92 percent). These observations demonstrate the difficulty in ascertaining the prevalence of LVNC, as there are a variety of morphologic criteria applied, and diagnostic criteria for LVNC likely have varying specificity in different populations. As examples, most studies have not included wall thickness <8.1 mm as a criterion, and the morphology of papillary muscles has seldom been addressed. Additionally, the ethnicity or gravid state of the patient has to be considered. Diagnosis of noncompaction should be reserved for obvious pathology, especially in the setting of family history of cardiomyopathy, arrhythmias, or symptoms. Studies have shown a high rate of false positives with CMR imaging [16], suggesting that CMR criteria for LVNC require improvement to avoid overestimation of prevalence.

LVNC is rarely reported in children, although the reported incidence may be an underestimate. In children, LVNC occurs mainly in association with congenital heart disease such as ventricular septal defect, atrial septal defect, patent ductus arteriosus, Ebstein anomaly, aortic stenosis, and coarctation of the aorta.

PATHOGENESIS — It has been suggested that LVNC may be due to intrauterine arrest of compaction of the loose interwoven meshwork that makes up the fetal myocardial primordium. However, the term "noncompaction" may be a misnomer: some authors have suggested that noncompaction of the ventricular myocardium results from abnormal persistence of the trabecular layer, rather than from noncompaction of the ventricular wall [17]. Pronounced hypertrabeculation may be the result of altered regulation in cell proliferation, differentiation, and maturation during ventricular wall formation [18]. Trabeculations of the LV may be unique for each individual, like fingerprints [19].

Prominent trabeculations as seen in LVNC may develop during adult life. Remodeling in response to LV loading conditions may explain the phenotypic characteristics of LVNC seen in some athletes and in some individuals who are hypertensive, pregnant, or have HF or hematologic disorders (eg, β-thalassemia) [8,20]. Additionally, LVNC can occur as a transient phenomenon in patients with other disorders, such as myocarditis. (See 'Differential diagnosis' below.)

GENETICS — LVNC can be either sporadic or familial. In various reports, 12 to 50 percent of those with LVNC had a family history of LVNC [7,13]. Other affected individuals can be detected by screening asymptomatic relatives of affected patients [21]. Autosomal dominant inheritance is more common than X-linked inheritance or autosomal recessive inheritance [22]. Differentiation of genotypes is not possible on the basis of current phenotypic data. The yield of genetic testing in patients with LVNC is around 30 to 50 percent [23,24]. Genetic testing is recommended, especially in the presence of additional myocardial abnormalities, syndromic features, or a family history of cardiomyopathy [24].

There is increasing recognition of considerable overlap in the genetic loci implicated in the major cardiomyopathies. Shared molecular etiology has been found for different cardiomyopathic phenotypes, including overlapping phenotypes between LVNC and hypertrophic cardiomyopathy (HCM) [25] and between LVNC and apical HCM [26]. Despite the genetic overlap between LVNC and HCMs, LVNC co-occurs more commonly than HCM in patients with congenital heart disease or Wolff-Parkinson-White syndrome.

Identified genes and their clinical significance — In patients with LVNC, a wide variety of gene mutations have been reported, primarily in genes coding for sarcomeric, cytoskeletal, Z-line, and mitochondrial proteins. The most common mutations involve sarcomeric proteins (82 percent) [27]. In a systematic review including 561 patients from 17 studies, variants in 66 genes in patients with LVNC were described [28], including genes encoding beta-myosin heavy chain (MYH7), titin (TTN), hyperpolarization activated cyclic nucleotide gated potassium channel 4 (HCN4), LIM domain binding protein 3 (LDB3), α-dystrobrevin (DTNA), tafazzin (TAZ), lamin A/C (LMNA), alpha-cardiac actin (ACTC), cardiac troponin T (TNNT2), troponin I (TNN13), cardiac myosin binding protein C (MYBPC3), SCN5A, SNTA1, PRDM16, and tropomyosin 1 (TPM1) [29-31]. Most genes associated with LVNC are associated with additional phenotypes (mainly HCM without noncompaction or dilated cardiomyopathy) [32]. Fibrillin-1 gene mutations were identified in 10 percent of patients with LVNC and reduced LV function and/or LV dilation [33]. A study of 327 unrelated adults and children with LVNC found a pathologic mutation in 32 percent [27]. The following are some key mutations associated with LVNC:

●Sarcomeric protein genes – A number of sarcomeric protein gene mutations have been identified in patients with LVNC, with MYH7 and TTN mutations among the most common [27,28,31]. The E101K mutation in the alpha-cardiac actin gene (ACTC) has been identified in families with LVNC, septal defects, and apical HCM [34]. In a study with 63 unrelated subjects with LVNC, 18 mutations in several sarcomeric protein genes were found (cardiac beta-myosin heavy chain, alpha-cardiac actin, cardiac myosin-binding protein C [MYBPC3], alpha-tropomyosin [TMP1], and troponin T2) [35,36]. A description of cardiac beta-myosin heavy chain defect in two families with LVNC links noncompaction to hypertrophic, restrictive, and dilated cardiomyopathies [37]. Twenty-nine percent of the 63 patients had a sarcomere gene mutation, which did not predict the clinical phenotype [36]. LVNC has also been linked to mutations in tropomyosin 1 [38] and desmin [39]. Titin-truncating variants may be associated with increased risk of HF among patients with LVNC [40].

●Tafazzin – Mutations in the Tafazzin gene (aka G4.5 or TAZ) that result in truncation of tafazzin proteins lead to severe cardiolipin deficiency in the mitochondrial membrane and are responsible for Barth syndrome [9,30,41,42]. Barth syndrome is an X-linked recessive disorder with associated cardiomyopathy, neutropenia, and skeletal myopathy. In a study, 90 percent of patients had a cardiomyopathy, and 53 percent increased LV trabeculations or true LVNC [43]. (See "Inherited syndromes associated with cardiac disease", section on 'Barth syndrome'.)

●Alpha-dystrobrevin (DTNA) – A mutation (P121L) in the gene coding for alpha-dystrobrevin, a cytoskeleton protein, has been identified as a rare cause of LVNC, occasionally in conjunction with congenital heart disease [30,42].

●Additional loci – While most LVNC associated mutations are in sarcomeric, cytoskeletal, Z-line, and mitochondrial proteins, exceptions include a mutation in the NOTCH pathway regulator mindbomb homolog 1 (MIB1) gene (which encodes an E3 ubiquitin ligase) which segregated with autosomal dominant LVNC in two families [44]. Case reports have linked LVNC to additional loci, including lamin A/C [45], Lim Domain Binding 3 (aka Cypher/ZASP) [42,46], and Chromosome 11p15 [47].

A mutation (exon 3 deletion) in the ryanodine receptor gene (RYR2) has been described in patients with LVNC [31], including some who also had a catecholaminergic polymorphic ventricular tachycardia [48].

Genetic evaluation and family screening — The role of genetic evaluation and family screening is discussed separately (See "Isolated left ventricular noncompaction in adults: Management and prognosis", section on 'Genetic testing and family screening'.)

CLINICAL MANIFESTATIONS — Clinical manifestations of LVNC are variable and may include dyspnea, chest pain, palpitations, syncope, or an abnormal electrocardiogram (ECG) or echocardiogram [9,13,49]. Cardiac symptoms and signs may not be present. The major complications of LVNC are HF, atrial and ventricular arrhythmias, sudden cardiac arrest, and thromboembolic events, including stroke [6,13,21,50].

Symptoms and signs — The frequency of these manifestations at presentation is dependent on the population studied.

The following report is illustrative. In a systematic review including five studies with a total of 241 adult patients, 56 percent of patients were referred for HF, 27 percent were referred for suspected LVNC based on prior clinical evaluation, and 11 percent were identified by screening [51]. Baseline characteristics included the following:

●Dyspnea – 60 percent

●New York Heart Association (NYHA) functional class III or IV HF – 31 percent

●Palpitations − 18 percent

●Chest pain − 15 percent

●Syncope or presyncope − 9 percent

●Prior stroke – 3 percent

An increasing number of patients with isolated LVNC are initially diagnosed during childhood, however, criteria for diagnosis in children have not been established in large studies [52]. Initial diagnosis by prenatal ultrasound has been reported [53]. Similar presenting symptoms and signs have been reported in children [49].

Complications — Complications of LVNC include HF, thromboembolism, and arrhythmias.

Heart failure — As noted above, among patients with LVNC, symptoms and signs of HF are common at presentation, and hospitalization for HF is common [51]. Patients with LVNC can present as HF with reduced ejection fraction (HFrEF; LV ejection fraction [LVEF] ≤40 percent), or less commonly, HF with preserved ejection fraction (HFpEF: LVEF ≥50 percent) or HF with mid-range ejection fraction (HFmrEF; LVEF 41 to 49 percent). (See 'Symptoms and signs' above.)

Thromboembolism — The risk of thromboembolism in patients with LVNC has not been established. Given the available data, it is not clear whether the thromboembolic rate in patients with LVNC differs from the rate generally observed in patients with HF. (See "Antithrombotic therapy in patients with heart failure".)

Case series of patients with LVNC have reported varying rates of thromboembolism. A systematic review of five observational studies with a total of 241 patients (with most patients not anticoagulated) found a mean thromboembolic event (largely cardioembolic stroke but included transient ischemic attack) rate of 8 percent during mean 39-month follow-up, with individual series rates varying from 0 to 24 percent [51]. The highest thromboembolic rate of 24 percent during mean 44-month follow-up was reported in the earliest of the five studies in which anticoagulation use was not specified [13].

Given the limited number of reported cases, risk factors for thromboembolism in patients with LVNC are uncertain. As an example, one retrospective case series found that 26 of 169 patients with LVNC had a stroke or embolic event during a period of follow-up ranging from less than one to 16 years [54]. Eighteen of the events were felt to be cardioembolic, five atherosclerotic, and three of undetermined cause. Patients with stroke or embolism had higher rates of hypertension and higher CHADS₂ and CHA₂DS_2-VASc scores than patients without stroke or embolism. LV fractional shortening was similar in patients with and without a stroke or embolism event. Atrial fibrillation was nominally more frequent in patients with stroke or embolic event but there was no significant difference compared to patients without an event.

Arrhythmias — Ventricular and atrial arrhythmias occur commonly in patients with LVNC. In a systematic review, 33 percent of patients had nonsustained ventricular tachycardia and 5 percent had sustained ventricular tachycardia [51]. Atrial fibrillation was documented in 10 percent of patients. There are no data on the sudden cardiac death (SCD) risk of athletes with LVNC. LVNC has not been described in autopsy studies of athletes with SCD; however, LVNC could have been missed at autopsy or described as HCM.

Initial testing — An ECG is commonly obtained in patients with suspected LVNC. The ECG is usually abnormal (32 of 34 patients in the above report), but findings are nonspecific [13]. The abnormalities that may be seen include left or right bundle branch block, fascicular block, atrial fibrillation, and ventricular tachycardia. Sinus bradycardia or Wolff-Parkinson-White syndrome has been described in up to 18 percent of pediatric patients with LVNC [9,55,56].

The role of echocardiography and other cardiac imaging in the diagnosis of LVNC is described below. (See 'Diagnosis' below.)

DIAGNOSIS

When to suspect LVNC — Since the clinical presentation of LVNC is nonspecific, a diagnosis of LVNC should be considered in patients with or without cardiac symptoms with prominent trabeculations on cardiac imaging.

Approach to diagnosis — LVNC is diagnosed using morphologic criteria which should be applied with caution, particularly in individuals who lack other clinical manifestations of LVNC. Clinical findings are not specific and are thus not diagnostic. The range of LVNC includes severe disease (which dominated early case series) and mild phenotypes that may be difficult to distinguish from normal variants. Preventing mislabeling of healthy individuals and overdiagnosis should be a priority [57].

We suggest the following approach for diagnosis of LVNC:

●The diagnosis of LVNC is usually established by identifying morphologic diagnostic criteria on transthoracic echocardiography. We use the Jenni criteria for echocardiographic diagnosis of LVNC (see 'Echocardiography' below and 'Limitations' below).

The Rotterdam criteria of LVNC have been subsequently proposed, which also require absence of septal hypertrophy and presence of cardiac symptoms, family history of HF, sudden cardiac death, abnormal ECG, and/or neuromuscular diseases [1].

●If echocardiography is indeterminate or technically suboptimal, cardiovascular magnetic resonance (CMR) imaging is suggested. Since CMR provides structural details, including evidence of fibrosis and scars, that differ from that provided by echocardiography and may have prognostic value, we perform CMR studies (in addition to echocardiography) in most patients with suspected LVNC.

●If echocardiography is nondiagnostic and CMR is nondiagnostic or unavailable or not feasible due to presence of a contraindication, we suggest cardiac computed tomography (CT).

Since multiple imaging modalities may be required to diagnose LVNC, the diagnosis is often delayed. In an early case series from Switzerland describing 16 patients, the mean time from the onset of symptoms to the correct diagnosis was 3.5 years [6].

●Other causes of noncompacted myocardium should be excluded. The differential diagnosis of LVNC includes other cardiomyopathies, altered phenotype associated with by physiologic or pathologic changes in loading conditions, and as a transient phenotype associated with other pathologic disorders.

Given the association between noncompacted myocardium and neuromuscular disorders, we screen patients with criteria for LVNC for neuromuscular disorder by physical examination, family history (focusing particularly on neurologic disease), and serum creatine kinase level. If this evaluation raises concern about a possible neuromuscular disorder, the patient is referred to a neurologist. (See 'Differential diagnosis' below.)

Echocardiography

Echocardiography criteria — Echocardiography is the test most commonly used both to establish the diagnosis of LVNC and as an aid during follow-up (image 1A-C) [13,58]. For diagnosis of LVNC using echocardiography, we use the Jenni criteria, which are the most widely accepted validated criteria. Alternatively, some clinicians use the Chin or Stöllberger criteria, which have also been validated.

●The Jenni criteria were developed based upon echocardiographic appearance with pathologic confirmation in seven patients with LVNC; the criteria were validated in a second population [58-60]. The criteria are assessed in the parasternal short-axis view at base, mid, and apical levels.

The presence of all four of the following echocardiographic criteria are required for diagnosis:

•A thickened LV wall consisting of two layers: a thin compacted epicardial layer and a markedly thickened endocardial layer with numerous prominent trabeculations and deep recesses with a maximum ratio of noncompacted to compacted myocardium >2:1 at end-systole in the parasternal short-axis view (image 2).

•Color Doppler evidence of flow within the deep intertrabecular recesses.

•Prominent trabecular meshwork in the LV apex or midventricular segments of the inferior and lateral wall and also affecting the right ventricle.

•Compacted wall thickness ≤8.1 mm. The criterion of maximal systolic compacta thickness of ≤8.1 mm was found to be very specific for myocardial thickening in LVNC compared to normal controls or patients with aortic stenosis [60].

In addition, hypokinesis of noncompacted segments and possibly other adjoining segments may be present.

●The Chin criterion is based upon observations from eight patients [61]:

•The presence of X/Y ≤0.5, where X is the distance from the epicardial surface to the trough of the trabecular recess and Y is the distance from the epicardial surface to peak of trabeculation. This criterion is applied to trabeculae at the LV apex on subxiphoid or apical four-chamber views at end-diastole.

●Stöllberger criteria emphasize hypertrabeculation [62]:

•More than three trabeculations protruding from the LV wall, apically to the papillary muscles, visible in a single image plane.

•Intertrabecular spaces perfused from the ventricular cavity, visualized on color Doppler imaging.

The role for contrast echocardiography has been incompletely evaluated in LVNC; in our practice, we routinely use contrast echocardiography for diagnosis of LVNC in patients with suboptimal image quality to help differentiate LVNC from apical HCM, eosinophilic endomyocardial disease, and from apical thrombi [63].

A role for three-dimensional echocardiography in LVNC has not been established. A three-dimensional echocardiographic study found significantly higher trabeculated LV volume and trabeculated LV volume normalized by LV end-diastolic volume in patients with LVNC compared to healthy controls and athletes [64].

Other echocardiographic findings — Nonspecific findings that may be seen on echocardiography include reduced global LV systolic function, diastolic dysfunction, LV thrombi, and abnormal papillary muscle structure [13]. Absence of well-defined papillary muscles is a very typical finding of LVNC [64].

Tissue Doppler imaging has been used to assess patients with LVNC. The diagnostic benefit of strain and strain rate imaging and speckle tracking in LVNC has yet to be determined.

As noted above, the echocardiographic appearance of isolated LVNC is heterogenous, including dilated forms, hypertrophic variant, and restrictive types [65].

Cardiovascular magnetic resonance imaging — CMR is generally used to aid in the diagnosis of LVNC when echocardiographic findings are inconclusive. In addition, since CMR provides morphologic information (including identification of fibrosis by late gadolinium enhancement (LGE) which may have prognostic implications) that differs from that provided by echocardiography, we perform it once in most patients to confirm the diagnosis of LVNC and repeat it as indicated during follow-up as a component of the evaluation for evolving clinical symptoms and complications. (See "Isolated left ventricular noncompaction in adults: Management and prognosis", section on 'Prognosis'.)

CMR criteria — Studies suggest that optimum criteria for diagnosis of LVNC by CMR differ slightly from the above-described echocardiographic criteria [66-68]. In our practice we use these CMR criteria with caution, as these criteria may overestimate the presence of LVNC. As there is no real gold-standard, sensitivity and specificity of CMR is difficult to assess.

LVNC is characterized by a noncompacted myocardial layer in the LV, a finding that can be readily identified by CMR (image 1C-E). Trabeculations and recesses appear differently on CMR compared to echocardiography and CT. CMR offers good spatial resolution of all LV segments, including the apex and lateral wall. Quantitative criteria are helpful since regions of apparent noncompaction (two-layered appearance of trabeculated and compacted myocardium) are common in both LVNC and in other groups with and without cardiovascular disease [66].

CMR criteria for LVNC are evolving and data are needed to identify which diagnostic criteria perform best in various populations and best predict adverse outcomes [69]. The following end-diastolic and end-systolic CMR criteria have been proposed:

●A maximum end-diastolic noncompacted to compacted myocardial thickness ratio of >2.3 was the best criterion for LVNC in a study of seven patients with LVNC and 170 healthy volunteers, athletes, and patients with dilated or HCM, hypertensive heart disease, or aortic stenosis (image 1D) [66]. This ratio was assessed in three long-axis views and yielded a sensitivity of 86 percent and specificity of 99 percent for LVNC.

●A trabeculated LV mass >20 percent of global LV mass was identified as a criterion for LVNC in a study of 16 patients with LVNC, 16 patients with HCM, and 16 control subjects [70]. This metric yielded a sensitivity of 94 percent and a specificity of 94 percent.

●Fractal dimension as a quantitative measure of trabeculation is high in LVNC and may be very accurate and reproducible [71]. However, the fractal dimension in the apical third of the LV is higher in healthy Black patients than in White patients.

A retrospective study found that an end-systolic noncompacted to compacted (thickness) ratio ≥2.0 was more strongly associated with HF and with adverse events (HF, death, HF readmission, embolic events, and ventricular arrhythmias) than other criteria for LVNC (end-diastolic noncompacted to compacted ratio ≥2.3 or trabeculated to global LV mass ratio >40 percent) [72]. In this study, a 40 percent (rather than 20 percent) cutoff was used for trabeculated to global LV mass because papillary muscle was included in the trabeculated mass.

Various CMR criteria have differing sensitivity and specificity for LVNC. In a study comparing four different CMR criteria for LVNC, 3 to 39 percent of patients referred for CMR fulfilled LVNC criteria [73]. The Stöllberger echocardiographic criteria for LVNC (see 'Echocardiography' above) may be insensitive when applied to CMR [68]. In a series of 19 LVNC patients diagnosed by echocardiography using the Stöllberger criteria, only nine met these criteria on CMR (obtained in short- and long-axis views). However, the overall CMR morphologic appearance in all cases confirmed the diagnosis of LVNC.

CMR may be superior to standard echocardiography in assessing the extent of noncompaction as suggested by a small study comparing CMR with echocardiography in 16 patients with LVNC [74]. All 17 left ventricular segments could be analyzed by CMR whereas 88 percent of segments could be analyzed by echocardiography at end-diastole and 87 percent of segments could be analyzed by echocardiography at end-systole. A two-layer structure was identified in more segments by CMR than by the echocardiographic methods. There was no significant difference between the maximum ratio of noncompacted/compacted layers by CMR and echocardiography at end-diastole. Echocardiography at end systole underestimated the ratio of noncompacted/compacted layers compared to CMR.

Late gadolinium enhancement — Myocardial fibrosis or scar detected by late gadolinium enhancement (LGE, also known as delayed hyperenhancement) of trabeculae has been observed in some patients with LVNC and may have prognostic value [75]. LGE distribution in patients fulfilling LVNC criteria can be very heterogeneous, which suggests that there are several distinct cardiomyopathic processes responsible for LVNC [76]. A study in patients with LVNC found that diffuse fibrosis reflected by T1 mapping on CMR was associated with ventricular arrhythmias and myocardial dysfunction [77]. Another study involving 98 patients with LVNC showed that noncompacted mass did not predict adverse events, but, in patients with impaired LV function and/or LV LGE, the risk of MACE was high [78].

The potential prognostic value of LGE is discussed separately. (See "Isolated left ventricular noncompaction in adults: Management and prognosis", section on 'Prognosis'.)

General use and risks of gadolinium contrast for CMR are discussed separately. (See "Clinical utility of cardiovascular magnetic resonance imaging" and "Patient evaluation before gadolinium contrast administration for magnetic resonance imaging".)

RV involvement — The presence of noncompaction of the right ventricular (RV) myocardium is often difficult to confirm by imaging. A CMR study found that LVNC is associated with increased trabeculations of the RV apex and that RV dysfunction in an LVNC population is associated with adverse clinical events [79]. The same impact on prognosis of LVNC in patients with RV involvement was shown by echocardiography [79].

Other cardiac tests — In patients with nondiagnostic echocardiography and nondiagnostic or unavailable CMR results, we suggest cardiac CT.

In patients with LVNC who are candidates for cardiac transplantation, the diagnosis is generally made prior to transplantation. Characteristic cardiac abnormalities have been described in explanted hearts. (See 'Findings at cardiac explant or autopsy' below.)

Computed tomography — CT is a potential alternative method of diagnosing LVNC if the echocardiogram is nondiagnostic and CMR is nondiagnostic or unavailable. A preliminary multidetector CT study of eight patients with LVNC (established by echocardiography or CMR), 51 patients with cardiovascular disease, and 20 controls without cardiovascular disease found that an end-diastolic noncompacted to compacted ratio of >2.3 on CT long-axis views best identified LVNC [80].

Findings at cardiac explant or autopsy — Upon examination at autopsy or cardiac explant at cardiac transplantation, a variety of gross patterns of noncompaction have been noted, including anastomosing broad trabeculae, coarse trabeculae resembling multiple papillary muscles, and sponge-like, interlacing, smaller muscle bundles. Perhaps the absence of well-formed papillary muscles is the best clue to the diagnosis (picture 1) [81]. Since data are limited, the prevalence of these findings is not known. Histologic findings are nonspecific, and interstitial fibrosis can be found adjacent to normal myocytes [58].

Limitations — Since there is no gold standard for diagnosis of LVNC, the sensitivity and specificity of morphologic criteria are uncertain. As discussed below, morphologic criteria for LVNC may be nonspecific, particularly in athletes and Black individuals [15]. Diagnostic criteria for LVNC are evolving and require further standardization in relation to clinical end points that are relevant to management and prognosis. There is limited concordance among the various echocardiographic and other imaging modality criteria for LVNC [15,21]. (See 'Echocardiography' above.)

While LVNC is an "unclassified" cardiomyopathy (table 1A and table 1B) [3], most patients with LVNC also have features of other morphologic categories of cardiomyopathy, particularly dilated cardiomyopathy, occasionally HCM (especially the apical variant), or rarely restrictive cardiomyopathy [30,34,82,83]. Within the same family, the phenotypic expression can vary considerably [84].

As an example, lack of specificity of most of the above echocardiographic LVNC criteria [58,61,62] was noted in a retrospective study of 199 patients with systolic dysfunction referred to an HF clinic and 60 normal controls [15]. In this study, 24 percent of patients with systolic dysfunction and five (including four Black patients) of the 60 normal controls fulfilled one or more of the three sets of echocardiographic criteria for LVNC. Despite considerable agreement, there remains substantial interobserver disagreement on the diagnosis of LVNC by echocardiography in up to 35 percent of cases [85].

In a study with 1146 athletes, 8.1 percent of athletes fulfilled LVNC criteria with no adverse events during a mean four-year follow-up [86]. Therefore, in athletes, the diagnosis of LVNC should be made with caution.

The prevalence of individuals with LVNC was examined among 2742 participants (more than 50 percent with hypertension) in the MESA (Multi-Ethnic Study of Atherosclerosis) study [87]. By CMR, 25.7 percent fulfilled LVNC criteria. The maximal NC/C ratio and changes in end-systolic volume index were examined. Greater extent of or excessive LV trabeculation at end-diastole was common and appeared to be benign and was not associated with deterioration in LV volumes or function during 9.5 years follow-up.

Given this finding, it has been proposed that definitive diagnosis of LVNC should include short-axis echocardiographic (Jenni [58]) or CMR (Jacquier [70]) criterion plus one of the following features: LVNC diagnosed in another family member; regional wall motion abnormalities; LVNC-related complications (arrhythmia, HF, or thromboembolism); and being a carrier of a pathogenic mutation in a gene previously associated with LVNC in various families [88].

DIFFERENTIAL DIAGNOSIS — LVNC is diagnosed using criteria that are evolving and have limited specificity, so care must be taken to distinguish LVNC from other conditions with similar morphology. The differential diagnosis of LVNC includes other cardiomyopathies, altered phenotype associated with physiologic or pathologic changes in loading conditions, and as a transient phenotype associated with other pathologic disorders.

The differential diagnosis of LVNC includes other cardiomyopathies (table 1A-B) such as dilated cardiomyopathy, HCM (particularly the apical form), arrhythmogenic RV cardiomyopathy [89], and restrictive cardiomyopathy (including Fabry disease); endomyocardial fibrosis; and aberrant chordae tendineae [15,90,91]. Since there is no gold standard for diagnosis of LVNC, LVNC is distinguished from other cardiomyopathies based upon morphologic criteria for noncompaction or hypertrabeculation. LVNC is diagnosed when the morphologic criteria for LVNC are met, though morphologic criteria for another type of cardiomyopathy may also be present [92]. Genetic studies suggest overlap between LVNC and other types of cardiomyopathy. In patients with features of both LVNC and another type of cardiomyopathy (eg, unexplained LV hypertrophy with echocardiographic or other clinical features suggestive of cardiac Fabry disease), both diagnoses should be considered [90]. (See 'Limitations' above and "Definition and classification of the cardiomyopathies" and 'Genetics' above.)

The morphologic appearance of LVNC can also occasionally be seen with altered loading conditions, with hypertensive heart disease, in healthy individuals, particularly athletes, pregnant women, and Black individuals [15,32,86], as well as in individuals with various hematologic disorders [93]. A reversible increase in LV trabeculations that fulfill criteria for LVNC can occur in up to 8 percent of pregnant women; most of the changes resolve within two years [32].

Additionally, LVNC can occur as a transient phenomenon in patients with other disorders such as myocarditis [94], amyloidosis [92], or systemic lupus erythematosus [95].This transient phenotype should be distinguished from isolated LVNC.

Isolated LVNC is defined as occurring in the absence of other cardiac or noncardiac congenital abnormalities. Thus, the diagnosis is made after exclusion of disorders with similar myocardial abnormalities associated with other clinical features. Noncompacted myocardium is seen in the following clinical settings:

●Noncompacted myocardium with intramyocardial sinusoids and coronary artery fistulae is observed in some patients with congenital RV or LV outflow tract abnormalities, such as pulmonary atresia with intact ventricular septum, tetralogy of Fallot, or aortic coarctation [96-98]. Coronary artery abnormalities are common in patients with RV or LV outflow tract abnormalities. In contrast, patients with LVNC usually have normal coronary artery circulation, although coronary fistulae have been rarely reported [99].

●Noncompacted myocardium is occasionally seen accompanying other congenital cardiac disorders, such as Ebstein anomaly, bicuspid aortic valve, atrial and ventricular septal defects, patent ductus arteriosus, coarctation, aorta-to-LV tunnel, congenitally corrected transposition, hypoplastic left heart syndrome, and isomerism of the atrial appendages [98,100-104].

●Noncompacted myocardium has also been identified in patients with neuromuscular disorders, including Barth syndrome, muscular dystrophies (including Becker muscular dystrophy, Duchenne muscular dystrophy, dystrobrevinopathy, Emery–Dreifuss muscular dystrophy, myotonic dystrophy types 1 and 2, and zaspopathy) and neuropathies (including Charcot-Marie-Tooth disease type 1A), metabolic myopathies (including mitochondrial disorder), and other genetic syndromes, including Melnick-Fraser syndrome, and nail-patella syndrome [105,106].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cardiomyopathy".)

SUMMARY AND RECOMMENDATIONS

●Although left ventricular noncompaction (LVNC) has been categorized as an "unclassified" cardiomyopathy, mounting evidence points to reclassification of LVNC as a distinct but not always pathological phenotype. By definition, isolated LVNC occurs in the absence of other cardiac or noncardiac congenital abnormalities. (See 'Definitions' above and 'Differential diagnosis' above.)

●LVNC is characterized by the following features (see 'Definitions' above):

•A myocardial wall with prominent trabeculae with two layers consisting of noncompacted myocardium and a thin compacted layer of myocardium (picture 1).

•Continuity between the LV cavity and the deep intertrabecular recesses.

●The clinical manifestations of LVNC are variable and cardiac symptoms and signs may not be present. Clinical features may include dyspnea, chest pain, palpitations, syncope, or an abnormal electrocardiogram or echocardiogram. Complications include heart failure, thromboembolism, and arrhythmias. (See 'Clinical manifestations' above.)

●LVNC is diagnosed using morphologic criteria which should be applied with caution, particularly in individuals who lack other clinical manifestations of LVNC. The range of LVNC includes severe disease and mild phenotypes that may be difficult to distinguish from normal variants. Preventing overdiagnosis should be a priority. (See 'Approach to diagnosis' above.)

●The diagnosis of LVNC is usually established by identifying morphologic diagnostic criteria on transthoracic echocardiography. We use the Jenni criteria for echocardiographic diagnosis of LVNC, which are the most commonly used criteria, although all criteria are subject to limitations. (See 'Echocardiography' above and 'Limitations' above.)

●Cardiovascular magnetic resonance (CMR) imaging is suggested in most patients with known or suspected LVNC. CMR provides structural information (eg identification of fibrosis by late gadolinium enhancement) that differs from that provided by echocardiography and may have prognostic value. (See 'Cardiovascular magnetic resonance imaging' above and "Isolated left ventricular noncompaction in adults: Management and prognosis", section on 'Prognosis'.)

●Since LVNC is diagnosed using criteria that are evolving and have limited specificity, care must be taken to distinguish LVNC from other conditions with similar morphology. The differential diagnosis of LVNC includes other cardiomyopathies, altered phenotype associated with by physiologic or pathologic changes in loading conditions, and as a transient phenotype associated with other pathologic disorders. (See 'Differential diagnosis' above.)