New concept of left ventrichlar non-compaction cardiomyopathy The AHA in 2006 classified left ventrichlar non-compaction cardiomyopathy (LVNC) as a primary genetic cardiomyopathy. LVNC is classified as a primary hereditary cardiomyopathy. The pathology is characterized by an abnormal increase in ventricular myocardial trabeculae and deep trabecular fossa, mostly involving the apical part of the left ventricle, but also involving both ventricles or the right ventricle. The pathogenesis of LVNC has been a hot topic of research in recent years, and although many murine models have been studied, they remain unclear. The most common conclusion to date is that the large number of myocardial trabeculae is caused by abnormal regulation of cell proliferation, differentiation, and maturation during ventricular wall formation, particularly the influence of the NOTCH signaling pathway, but other hypotheses also exist. The epidemiology of LVNC lacks definitive data so far, therefore LVNC is still considered a rare abnormality and its actual prevalence is not clear. LVNC has been reported in the literature to account for the top three cardiomyopathies. The increased incidence reported in recent years is closely related to the increased clinical awareness and the improved resolution of ultrasound images. Recognition of high familial aggregation and emphasis on ultrasound screening of first-degree relatives has also been a factor. The Department of Pediatric Cardiology at Beijing Anzhen Hospital has enhanced the screening of first-degree relatives for LVNC since 2012. Of the 120 children with LVNC with prior evidence, all 240 of their parents completed echocardiography and 21 cases of LVNC (21/240, 8.8%), including 6 cases with significantly decreased left ventricular systolic function in UCG (EF< 55%), accounting for 28.6% of the 21 parents, and EF< 50% in 4 cases, which is an alarming number. Moreover, most of these screened parents had no obvious clinical symptoms. Although, we lack epidemiological data on LVNC in China, the attention and detailed measurement of myocardial trabeculae by cardiac sonographers will certainly promote more clinical awareness of LVNC, and ultrasound screening of LVNC prevalent first-degree relatives will in turn detect patients with potentially serious heart disease and give early intervention to improve prognosis. III The clinical presentation of LVNC varies in severity, with age of onset ranging from fetal-elderly, asymptomatic or end-stage heart failure, or fatal arrhythmias, sudden death, or thromboembolism, or a coexistence of various clinical manifestations. Many asymptomatic patients are diagnosed by a heart murmur, or by a diagnosis in a family screening for LVNC, or by arrhythmia or conduction block. Ichida reported almost asymptomatic and good survival in children, with few deaths or heart transplants, whereas chin reported 3 out of 7 deaths. towbin JA reported that although neonates and small infants are often clinically critical and have high mortality due to concomitant systemic diseases such as mitochondrial disease or genetic metabolic disorders, LVNC in children 18 months to 3 years of age has been associated with a high mortality rate. The prognosis for LVNC in children 18 months to 3 years of age is good, with a 5-year non-cardiac transplant survival rate of 75%. There are several reports of a high risk of ventricular tachycardia and sudden cardiac death in adults with LVNC. In adult patients, mortality was 47% within 6 years from diagnosis and 75% within 6 years in symptomatic patients.Bhatia et al. reviewed 241 cases of ultrasound-diagnosed isolated LVNC with 39 months of follow-up, with 4% cardiac death per year, 6.2% cardiac death, heart transplantation and ICD implantation combined, and 8.6% cardiac events per year overall (death, stroke, ICD, shock, heart transplantation ). First-degree relative ultrasound screening for LVNC accounts for 30%. The rate of malignant ventricular arrhythmias in LVNC is uncertain, but reports of benign process LVNC and lower ventricular arrhythmia rates have increased significantly in recent years. The morphology and increase in ventricular myocardium is the key to diagnosis, and there are two clinical diagnoses of isolated LVNC and combined preexisting LVNC. the clinical manifestations of LVNC are diverse and vary greatly in severity, and it is the fact that not many people have ventricular myocardium that meets the diagnostic criteria for LVNC but has no clinical symptoms throughout their lives that reduces the importance clinicians attach to increased myocardial myocardium, which in turn affects poor prognosis Early diagnosis and intervention in patients with LVNC seriously affects the prognosis. the diagnostic ideas of 8 LVNC subtypes proposed by Towbin JA deserve our consideration. Giving reasonable follow-up to patients who meet the diagnostic criteria of LVNC by ultrasound, set large data in order to address the current situation of overdiagnosis or underdiagnosis of LVNC and avoid malignant prognosis in high-risk LVNC patients. In our work there is the same knowledge that not only the following 8 types of staging exist, but also mixed types or called unknown classification. (1) Benign LVNC: The absence of enlargement of the left ventricle, no wall thickening, and normal ventricular systolic-diastolic function is called benign LVNC, accounting for about 35%. The prognosis is good if no arrhythmia is present. For this type, some adult cardiologists consider that it cannot be classified as heart disease and is a normal variant. In other words, most of the severe clinical manifestations of LVNC occur in children who are either successfully cured, have a heart transplant or die, mostly without visiting an adult cardiologist. Benign LVNC can be classified as normal, but should be given standardized follow-up. (2) Arrhythmogenic LVNC: LVNC with arrhythmia has normal left ventricular size, systolic function, and ventricular wall thickness. However, the arrhythmia is insidious, and the diagnosis is given only when the arrhythmia is mostly present. Ventricular arrhythmias are an independent risk factor for death. The prognosis of LVNC with arrhythmias is worse than that of ventricular arrhythmias without LVNC. Emphasis on ultrasound screening of LVNC is easier to diagnose. (3) Dilated LVNC: The dilated subtype of LVNC is an enlarged ventricle with poor left ventricular systolic function. The clinical course can present with ventricular wall thickening and normal cardiac function, which later progresses to ventricular enlargement and decreased cardiac function. The prognosis of dilated LVNC in adults is similar to that of dilated cardiomyopathy of unknown origin. However, the prognosis of dilated LVNC in neonates and infants is worse than that of other dilated cardiomyopathies, which may be related to the coexistence of genetic metabolic diseases and hereditary arrhythmias. (4) Hypertrophic LVNC: Hypertrophic LVNC is characterized by thickened left ventricular wall, asymmetric septal hypertrophy, diastolic restriction, and excessive systolic enhancement. In some cases with LV dilatation, systolic insufficiency can occur in late stages. The prognosis is similar to that of hypertrophic cardiomyopathy. (5) Hypertrophic dilated LVNC: The clinical manifestations are varied, showing thickening of the left ventricular wall, ventricular enlargement, and systolic insufficiency. This type has a high mortality rate, and pediatric patients are often combined with genetic metabolic disease or with mitochondrial disease. Hypertrophic dilated LVNC is the most common type of LVNC with variable symptoms and results in enlarged left heart, cardiac insufficiency, and heart failure. This type has the worst prognosis compared to other mixed LVNC types. (6) Restrictive LVNC: It is rare and presents with left atrial or biventricular enlargement and diastolic insufficiency. The clinical symptoms and prognosis are very similar to those of restrictive cardiomyopathy, and the prognosis is poor. Typical cases are at high risk of sudden arrhythmic death and less frequently death from heart failure. (7) Right ventricular or biventricular LVNC: As the name implies, right ventricular LNVC or biventricular LVNC, but there is no clear diagnostic criteria for right ventricular LVNC, and some literature reports the application of diagnostic criteria for left ventricular LVNC.JA Towbin et al. diagnosed with a marked increase in myocardial trabeculae in the right ventricle, similar to sponge-like. In most of these cases, the myocardial trabeculae involved the right ventricular lateral wall and even extended to the level of the tricuspid valve. Biventricular LVNC is rare and clinically unclear. (8) LVNC with congenital heart disease: Almost all kinds of congenital heart disease have been reported with LVNC, which can lead to cardiac insufficiency and arrhythmias, or both. Congenital right heart structural abnormalities are more common, especially Ebstein's malformation, pulmonary stenosis, pulmonary atresia, tricuspid atresia, and double outlet of the right ventricle. Septal defects or left heart dysplasia are also common. Prognosis is dependent on cardiovascular anomalies. However LVNC increases the postoperative risk with the presence of preoperative heart failure and a poor prognosis. [5] Having a diagnosis of benign LVNC facilitates interpretation to patients with asymptomatic LVNC and gives a more reasonable clinical diagnostic pathway and follow-up plan. IV The main clinical diagnostic tests for LVNC are noninvasive: transthoracic UCG and MRI. but the diagnostic criteria for these two methods are still highly controversial. Transthoracic echocardiography, due to easy identification, wide application and low cost, is the most commonly used diagnostic method. Ultrasound diagnostic methods currently mainly use the four diagnostic criteria proposed by Jenni et al [8] 2001, with the ratio of end-systolic non-compaction ( non-compaction , NC) to dense myocardial layer ( compaction, C) greater than 2 as the main diagnosis. However, the diagnostic criteria for NC/C vary between 2:1 and 3:1 and have not been uniformly reported because of the different judgments and opinions between ultrasonographers regarding the normal variant and LVNC. The difficulty in making a definitive diagnosis using NC/C or myocardial trabecular thickness imaging is mainly due to the variation in location, density, and morphology of myocardial trabeculae.Punn and Silverman et al. retrospectively analyzed patients with LVNC using the 16-segment method of the American AHA and American Society of Ultrasonography and found that LVEF values were inversely related to the number of segments involved in non-dense myocardium. That is, the greater the extent of involvement, the worse the cardiac function. The prognosis (death and heart transplantation) was more pronounced in younger age groups, especially between 0 and 3 years of age, the more extensive the involvement. With the development of ultrasound techniques such as strain, strain rate and speckle tracking have been used to study LVNC, and although some investigators have done statistical analysis using NC/C, there is still a lack of a gold standard, and it is because of the lack of agreement in diagnosis that LVNC has been overdiagnosed or underdiagnosed. The use of cardiac MRI for the diagnosis of LVNC in both children and adults is increasing. The diagnostic criteria for LVNC on cardiac MRI are end-diastolic NC/C > 2.3, but the same controversy exists as for LVNC on echocardiography, and Jacquier et al. have suggested that a myocardial trabecular mass of 20% or more of the total LV myocardial mass is the diagnostic criterion for LVN C. Radiologists believe that the use of MRI myocardial 17 anatomical segment analysis provides a clearer identification of the myocardial trabecular layer and that MRI provides more information on myocardial fibrosis and delayed gadolinium visualization. It is important to note that thinning of the dense myocardial layer in the apical region of LVNC on cardiac MRI should be differentiated from apical ventricular wall tumors. The diagnostic study of LVNC by cardiac CT was started in 2001 and was considered to clearly demonstrate the structure of the non-dense myocardial layer of the left ventricle. since 2007 there has been an increasing trend, but CT diagnosis is not yet advocated because of the risk of tumors due to radiation exposure, especially in children and in patients with long term follow-up. The imaging diagnosis of LVNC at Cincinnati Children’s Medical Center in the United States uses several methods of data analysis. First, NC/C was measured by transthoracic echocardiography, and the traffic between the LV blood flow and the trabecular space was observed by color Doppler. The extent of non-dense myocardial layer involvement and the thickness of the dense myocardial layer were measured in detail and compared with normal values. Transthoracic short-axis views were used to find possible non-dense myocardium with stepwise rotational views. In addition, CMRI was used to assist in the diagnosis of LVNC, and gadolinium imaging was used to observe myocardial scarring, along with LV size, ventricular wall thickness, and ventricular systolic and diastolic function, while paying attention to the exclusion of congenital heart disease. Finally, the ventricle and myocardial trabeculae were carefully observed under cardiac dynamics. V. Clinical genetics has developed considerably in recent years, and it is clear that most patients with LVNC are inherited in an X-linked recessive or autosomal dominant manner. X-linked LVNC is often associated with multisystem abnormalities, such as Barth syndrome (TAZ gene mutation), and has been reported in males, with some cases in females with cardiomyopathy. LVNC with congenital cardiovascular anomalies have a genetic predisposition, consistent with autosomal dominant inheritance. These families do not suffer from the same cardiovascular malformations; some members may have only minor malformations, such as small VSD, ASD, PDA, or even have closed spontaneously without being diagnosed, while others have severe precocious heart, such as hypoplastic left heart syndrome and Ebstein’s malformation. Ichida et al. reported that 44% of LVNC is hereditary, of which 70% is autosomal dominant and 30% is X-linked recessive. In addition to genetic mutations, multiple chromosomal abnormalities resulting in LVNC should also be of clinical concern. mutations include 1p36 deletion, 7p14q3p14q1 deletion, 18p subtelomeric trend, 22q11q2 deletion, 22q11q2 distal segment deletion, trisomy 18 and trisomy 13, 8p23q1 deletion, 5q35q2-5q35 tetrasomy,. genetics of LVNC diagnostic route, it may be more reasonable to rule out chromosomal abnormalities first and then do genetic testing. With the leap forward in molecular genetics, there are a large number of reports of gene mutation studies in LVNC. Several genetic variants cause autosomal dominant LVNC, including mutations causing congenital heart disease combined with LVNC. Pathogenic mutations in DTNA have been identified in patients with LVNC combined with left heart dysplasia. Mutations in NKX2-5 were identified in children with LVNC combined with atrial septal defect, whereas mutations in MYH7 were found in patients with LVNC combined with Ebstein malformation. Mutations in LDB3, encoding the Z-lineage protein, were identified in LVNC without combined congenital heart disease, whereas mutations in MYH7, ACTC1, TNNT2, MYBPC3, TPM1, and TNNI3, encoding myosin, accounted for more than 20% of LVNC alone.Hoedemaekers et al. showed that LVNC was associated with mutations in two calcium-handling genes, TAZ and LMNA A further study by Probst et al. showed the importance of myosin genetic mutations, accounting for approximately 29% of the mutations, with MYH7 and MYBPC3 being the most frequently mutated (13% and 8%, respectively). In addition to mutations in myosin-encoding genes and cytoskeleton-encoding genes, mutations in the sodium channel gene SCN5A are associated with LVNC and arrhythmias. Another cytoskeletal protein associated with LVNC is myotonic dystrophy protein, and mutations in the gene encoding this protein cause Duchenne and Becker myotonic dystrophy in boys. In addition, mutations in DSP, a gene encoding a hemibranchial protein, can cause arrhythmogenic cardiomyopathy and dilated cardiomyopathy, and a pure-sibling mutation with a 2 bp deletion in the DSP splice region was found in LVNC. Mutations in the mitochondrial genome have also been associated with LVNC. We screened 53 children with LVNC for known mutations associated with hereditary cardiomyopathy, with a detection rate of 41.5% (22/53) and 10 known mutated genes with 29 mutation sites listed by frequency: MYH7, MYBPC3, SCN5A, TNNT2, ACTC1, TPM1, PRDM16, LDB3,TAZ, CASQ2. In conclusion, LVNC has attracted worldwide attention in recent years and has gradually become a hot spot for clinical and basic research. We believe that LVNV may be a syndrome with the same myocardial structural abnormalities but different clinical manifestations and different etiologies. It is necessary and feasible to establish a reasonable clinical diagnostic pathway by combining imaging diagnosis and clinical manifestations, supplemented by the concept of precision medicine.