Coronary Angiography in Patients With Left Ventricular Hypertrabeculation/Noncompaction.

BACKGROUND: Left ventricular hypertrabeculation/noncompaction (LVHT) is a cardiac abnormality of unknown pathogenesis, frequently associated with neuromuscular disorders. The relevance of coronary artery disease (CAD) in LVHT is largely unknown. This study aimed to assess the role of CAD as a prognostic marker in LVHT. METHODS: Data from patients with LVHT were collected from an echocardiographic laboratory. The hospital information system was retrospectively screened for coronary angiography. The association of CAD with clinical, echocardiographic, and neurologic baseline parameters was assessed. End points were all-cause death and heart transplantation. RESULTS: A total of 154 patients (mean [SD] age, 57 [13.7] years; 31% female) who had undergone coronary angiography between 1995 and 2020 were included in the study. Coronary angiography disclosed CAD in 53 of 154 patients. Patients with CAD were older (mean [SD] age of, 64.2 [12.9] years vs 52.7 [12.4] years; P < .001); more frequently had angina pectoris (P = .05), diabetes (P = .002), and hypertension (P = .03); and more frequently had 3 or more electrocardiographic abnormalities (P = .04) than patients without CAD. During a median (IQR) follow-up period of 6.48 (2.44-11.20) years, 39% of patients reached an end point (death, n = 56; heart transplantation, n = 4). Mortality was 4.5% per year, and the rate of death or heart transplantation did not differ between patients with and without CAD (P = .26). Patients with 3-vessel disease had a worse prognosis than patients with 1- or 2-vessel disease (P = .046). CONCLUSION: In patients with LVHT, CAD does not appear to be associated with an increased rate of death or heart transplantation.

Advances and challenges in the diagnosis and management of left ventricular noncompaction in adults: A literature review.

In the realm of cardiovascular health, isolated left ventricular noncompaction (LVNC) stands out for its distinct morphological features and the clinical challenges it presents, particularly in adults. This literature review explores the intricacies of LVNC, aiming to unravel its epidemiological spread, diagnostic hurdles, and therapeutic strategies. Despite technological advancements in cardiac imaging that have improved the recognition of LVNC, a significant gap persists alongside a fragmented understanding of its pathogenesis. The studies scrutinized reveal a broad spectrum of prevalence rates influenced by diverse diagnostic tools and demographic variables. This variation underscores the complexity of accurately identifying LVNC and the resultant implications for clinical management. The review succinctly addresses the need for precise guidelines to navigate the diagnosis of LVNC and outlines the imperative for tailored clinical management approaches that cater to the wide array of patient presentations, from asymptomatic cases to those with severe cardiac dysfunction. By highlighting the critical gaps in current literature-namely the absence of standardized diagnostic criteria and a comprehensive pathogenic model-the review sets the stage for future research directions. These endeavors are essential for enhancing diagnostic accuracy, refining management protocols, and ultimately improving patient outcomes in this complex subset of cardiomyopathy, thus contributing significantly to the advancement of cardiovascular medicine.

A review regarding the article 'Advances and Challenges in the Diagnosis and Management of Left Ventricular Noncompaction in Adults.'

Left ventricular noncompaction (LVNC) is a rare genetic and congenital disorder characterized by the excessive formation of blood-filled trabeculae and intertrabecular recesses in the uncompressed inner endocardial wall associated with a thin, compact wall, the mesocardium. Although LVNC was described for the first time as long ago as 1984, our understanding of the disease with regard to its genetic pattern, diagnosis, clinical presentation, and treatment is still scanty. LVNC can be present as an isolated condition or associated with congenital heart disease, genetic syndromes, or neuromuscular disease. This suggests that LVNC is not a distinct form of cardiomyopathy, but rather a morphological expression of different diseases. Recognition of the disease is of fundamental importance because its clinical manifestations are variable, ranging from the absence of any symptom to congestive heart failure, lethal arrhythmias, and thromboembolic events. The main cardiac symptoms associated with LVNC are related to HF, occurring in up to half of the patients. Atrial fibrillation can affect 25 % of adult patients and ventricular tachyarrhythmias up to around 50 %. There is a possible association between bradycardia and Wolff-Parkinson-White syndrome in pediatric patients with LVNC. Other frequent manifestations are related to thromboembolic events, such as stroke, pulmonary embolism, and mesenteric ischemia. In asymptomatic patients, LVNC is identified by echocardiography or when the patient is subjected to family screening. However, when the disease is identified during the fetal period, the presence of systemic diseases, such as mitochondrial alterations and metabolic disorders, is frequently reported.

Electrophysiological phenotyping of left ventricular noncompaction cardiomyopathy in pediatric populations: A systematic review.

Left ventricular noncompaction cardiomyopathy (LVNC) is a structural heart defect that has been associated with generation of arrhythmias in the population and is a cause of sudden cardiac death with severe systolic dysfunction and fatal arrhythmias. LVNC has gained increasing acknowledgment with increased prevalence. We conducted a systematic review of reported electrocardiogram (ECG) results for pediatric LVNC patients. EMBASE database query was performed, yielding 4531 articles related to LVNC between 1990 and December 2023. Patient age ranged from prenatal to 18 years of age. Qualitative analyses were performed to characterize individual arrhythmias, and summative interpretation of ECG evaluations was gathered for the entire cohort. Systematic review of 57 LVNC cases and ECG presentation revealed many waveform consistencies, including abnormal left ventricular, atrioventricular node, and interventricular septal patterns, and specifically a high incidence of Mobitz type II and Wolff-Parkinson-White waveforms. This review of ECG analysis reinforces the clinical and etiologic significance of pediatric LVNC. While LVNC in pediatric populations may not always present as acute clinical cases, further investigation into the electrophysiology of the disease supports the need for further evaluation and risk stratification for patients with suspected LVNC and/or ventricular arrhythmia.

Sudden unexpected intrapartum death and left ventricular noncompaction involving the right ventricle.

Left ventricular noncompaction (LVNC), involving mainly the right ventricle, is a rare form of congenital heart disorder characterized by a developmental arrest in myocardial compaction, resulting in a spongy appearance of the myocardium, mainly of the right ventricle, rarely detected in fetuses. We report the case of a female fetus with a gestational age of 41+4 weeks who came to our attention for intrapartum sudden unexpected death, resulting in stillbirth. The ventricular walls, particularly the right ventricular wall, appeared thick, hypertrabeculated and spongy, leading to the diagnosis of LVNC involving mainly the right ventricle. The atrioventricular node and His bundle presented areas of fetal dispersion and resorptive degeneration; islands of conduction tissue were detected in the central fibrous body. Arcuate nucleus of the brainstem showed bilateral severe hypoplasia. The right bundle branch was hypoplastic. The final cause of death was an electrical conduction disfunction in an LVNC involving mainly the right ventricle. To the best of our knowledge, the herein described case is the first reported observation of sudden intrapartum death from LVNC involving mainly the right ventricle well documented post-mortem with cardiac conduction and brainstem studies. Our findings confirm the need of an accurate post-mortem examination including the study of the cardiac conduction system on serial section in every case of sudden unexpected fetal death, although there are no universally recognized guidelines.

RCAN family member 3 deficiency contributes to noncompaction of the ventricular myocardium.

Noncompaction of the ventricular myocardium (NVM), the third most diagnosed cardiomyopathy, is characterized by prominent trabeculae and intratrabecular recesses. However, the genetic etiology of 40%-60% of NVM cases remains unknown. Here, we identify two infants with NVM, in a nonconsanguineous family, with a typical clinical presentation of persistent bradycardia since the prenatal period. A homozygous missense variant (R223L) of RCAN family member 3 (RCAN3) is detected in both infants using whole-exome sequencing. In the zebrafish model, marked cardiac dysfunction is detected in rcan3 deficiency (MO-rcan3ATG-injected) and rcan-/- embryos. Developmental dysplasia of both endocardial and myocardial layers is also detected in rcan3-deficient embryos. RCAN3 R223L variant mRNAs can not rescue heart defects caused by rcan3 knockdown or knockout; however, hRCAN3 mRNAs rescue these phenotypes. RNA-seq experiments show that several genes involved in cardiomyopathies are significantly regulated through multiple signaling pathways in the rcan3-knockdown zebrafish model. In human cardiomyocytes, RCAN3 deficiency results in reduced proliferation and increased apoptosis, together with an abnormal mitochondrial ultrastructure. Thus, we suggest that RCAN3 is a susceptibility gene for cardiomyopathies, especially NVM and that the R223L mutation is a potential loss-of-function variant.

Novel compound heterozygous variants in EMC1: Overlapping phenotypes of left ventricular noncompaction and long QT syndrome warranting in-depth exploration.

A couple was referred for prenatal counseling at the gestational age of 35 weeks of a male fetus (II-2) with sinus bradycardia and suspected first degree atrioventricular block with left ventricular noncompaction (LVNC). A previous pregnancy for the couple of a female fetus (II-1) was diagnosed prenatally as sinus bradycardia at the gestational age of 30 weeks. Both fetuses were confirmed to have long QT syndrome (LQTS) with LVNC after birth, and died of heart failure during infancy. The genetic cause of the combined cardiovascular disorders was investigated by trio whole-exome sequencing and Sanger sequencing on DNA extracted from parental blood samples and umbilical cord serum of the proband. Compound heterozygous variants were identified in the endoplasmic reticulum membrane protein complex subunit 1 gene (EMC1, NM_015047.3), including paternally inherited c.245C>T (p. Thr82Met) and maternally inherited c.1459delC (p. Arg487Alafs*49). Pathogenic variants in EMC1 have been associated with a recessive neurodevelopmental disorder, whereas Emc10 knockout mice exhibit cardiovascular issues. The present study shows that EMC1 variation potentially causes the overlapping phenotypes of LVNC and LQTS and may expand the spectrum of diseases caused by EMC1 variation.

Thinning of compact layer and systolic dysfunction in isolated left ventricular non-compaction: A cardiac magnetic resonance study.

BACKGROUND: The Petersen' index reflects an excess of myocardial trabeculation which is not a specific morpho-functional feature of left ventricular non-compaction (LVNC) cardiomyopathy, but a "phenotypic trait" even observed in association with other myocardial diseases and over-loading conditions. The present study was designed to evaluate the relation between a critical thinning of compact layer and the development of systolic dysfunction and LVNC cardiomyopathy. METHODS: We compared CMR morpho-functional features and measurements of LV wall thickness using a 17 segment model of a cohort of patients fulfilling the Petersen criterion for LVNC with LV systolic dysfunction versus those of a cohort of age- and sex-matched controls with LVNC and preserved LV systolic function. All the study patients had an "isolated" LVNC defined as positive Petersen criterion in the absence of other diseases such as hypertrophic and dilated cardiomyopathy, valvular heart disease, or congenital heart disease and over-loading conditions. RESULTS: he study population included 33 patients with "isolated" LVNC: 11 consecutive index patients with a reduced LV ejection fraction (LVNCrEF) and 22 controls with a preserved LVEF (LVNCpEF). The compact myocardial layer was thinner in patients with LVNCrEF than in those with LVNCpEF patients, both in mid-ventricular and apical LV segments. On linear regression analysis, there was a linear correlation between median thickness of mid-ventricular free wall segments and left ventricular ejection fraction (r = 0.51, p = 0.005). On the ROC curves analysis, ≥2 segments with a compact myocardial layer <5 mm in the free wall mid-ventricular segments showed the best accuracy for reduced LVEF (100% sensitivity and 60% specificity; AUC 0.81, p < 0.01). The negative predictive value for LV systolic dysfunction of <2 free wall mid ventricular segments <5 mm was 100%. On quantitative analysis, the mass of papillary muscles was lower in patients with LVNCrEF [1.2 (0.8-1.4) versus 1.6 (1.1-1.8) g/mq; p = 0.08]. CONCLUSIONS: A thinned compact layer of mid-ventricular segments of the LV free wall was associated with a reduced systolic function and "isolated" LVNC cardiomyopathy.

The Trouble with Trabeculation: How Genetics Can Help to Unravel a Complex and Controversial Phenotype.

Excessive trabeculation of the cardiac left ventricular wall is a complex phenotypic substrate associated with various physiological and pathological processes. There has been considerable conjecture as to whether hypertrabeculation contributes to disease and whether left ventricular non-compaction (LVNC) cardiomyopathy is a distinct pathology. Building on recent insights into the genetic basis of LVNC cardiomyopathy, in particular three meta-analysis studies exploring genotype-phenotype associations using different methodologies, this review examines how genetic research can advance our understanding of trabeculation. Three groups of genes implicated in LVNC are described-those associated with other cardiomyopathies, other cardiac/syndromic conditions and putatively with isolated LVNC cardiomyopathy-demonstrating how these findings can inform the underlying pathologies in LVNC patients and aid differential diagnosis and management in clinical practice despite the limited utility suggested for LVNC genetic testing in recent guidelines. The outstanding questions and future research priorities for exploring the genetics of hypertrabeculation are discussed.

A novel mutation in the TTN gene resulted in left ventricular noncompaction: a case report and literature review.

BACKGROUND: Left ventricular noncompaction (LVNC) is a specific type of cardiomyopathy characterized by coarse trabeculae and interspersed trabecular crypts within the ventricles. Clinical presentation varies widely and may be nonsignificant or may present with progressive heart failure, malignant arrhythmias, and multiorgan embolism. The mode of inheritance is highly heterogeneous but is most commonly autosomal dominant. The TTN gene encodes titin, which is not only an elastic component of muscle contraction but also mediates multiple signalling pathways in striated muscle cells. In recent years, mutations in the TTN gene have been found to be associated with LVNC, but the exact pathogenesis is still not fully clarified. CASE PRESENTATION: In this article, we report a case of an adult LVNC patient with a TTN gene variant, c.87857G > A (p. Trp29286*), that has not been reported previously. This 43-year-old adult male was hospitalized repeatedly for heart failure. Echocardiography showed reduced myocardial contractility, dilated left ventricle with many prominent trabeculae, and a loose texture of the left ventricular layer of myocardium with crypt-like changes. During the out-of-hospital follow-up, the patient had no significant signs or symptoms of discomfort. CONCLUSION: This case report enriches the mutational spectrum of the TTN gene in LVNC and provides a basis for genetic counselling and treatment of this patient. Clinicians should improve their understanding of LVNC, focusing on exploring its pathogenesis and genetic characteristics to provide new directions for future diagnosis and treatment.

Missense Mutation in Human CHD4 Causes Ventricular Noncompaction by Repressing ADAMTS1.

BACKGROUND: Left ventricular noncompaction (LVNC) is a prevalent cardiomyopathy associated with excessive trabeculation and thin compact myocardium. Patients with LVNC are vulnerable to cardiac dysfunction and at high risk of sudden death. Although sporadic and inherited mutations in cardiac genes are implicated in LVNC, understanding of the mechanisms responsible for human LVNC is limited. METHODS: We screened the complete exome sequence database of the Pediatrics Cardiac Genomics Consortium and identified a cohort with a de novo CHD4 (chromodomain helicase DNA-binding protein 4) proband, CHD4M202I, with congenital heart defects. We engineered a humanized mouse model of CHD4M202I (mouse CHD4M195I). Histological analysis, immunohistochemistry, flow cytometry, transmission electron microscopy, and echocardiography were used to analyze cardiac anatomy and function. Ex vivo culture, immunopurification coupled with mass spectrometry, transcriptional profiling, and chromatin immunoprecipitation were performed to deduce the mechanism of CHD4M195I-mediated ventricular wall defects. RESULTS: CHD4M195I/M195I mice developed biventricular hypertrabeculation and noncompaction and died at birth. Proliferation of cardiomyocytes was significantly increased in CHD4M195I hearts, and the excessive trabeculation was associated with accumulation of ECM (extracellular matrix) proteins and a reduction of ADAMTS1 (ADAM metallopeptidase with thrombospondin type 1 motif 1), an ECM protease. We rescued the hyperproliferation and hypertrabeculation defects in CHD4M195I hearts by administration of ADAMTS1. Mechanistically, the CHD4M195I protein showed augmented affinity to endocardial BRG1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4). This enhanced affinity resulted in the failure of derepression of Adamts1 transcription such that ADAMTS1-mediated trabeculation termination was impaired. CONCLUSIONS: Our study reveals how a single mutation in the chromatin remodeler CHD4, in mice or humans, modulates ventricular chamber maturation and that cardiac defects associated with the missense mutation CHD4M195I can be attenuated by the administration of ADAMTS1.

Noncompaction Cardiomyopathy: Issues, Contradictions, and Search for Effective Diagnostic Criteria. Literature Review. Part 1.

Active research of noncompaction cardiomyopathy (NCM) has been going on for more than 30 years. A significant amount of information has been accumulated that is familiar to a much larger number of specialists than in the most recent past. Despite this, numerous issues remain unresolved, ranging from classification (congenital or acquired, nosology or morphological phenotype) to the ongoing search for clear diagnostic criteria that separate NCM from physiological hypertrabecularity and secondary noncompaction myocardium with the background of existing chronic processes. Meanwhile, a high risk of adverse cardiovascular events in a certain group of people with NCM is quite high. These patients need timely and often quite aggressive therapy. This review of sources of scientific and practical information is devoted to the current aspects of the classification, extremely diverse clinical picture, extremely complex genetic and instrumental diagnosis of NCM, and the possibilities of its treatment. The purpose of this review is to analyze current ideas about the controversial problems of noncompaction cardiomyopathy. The material for its preparation is the numerous sources of databases Web Science, PubMed, Google Scholar, eLIBRARY. As a result of their analysis, the authors tried to identify and summarize the main problems of the NCM and identify the ways to resolve them.

Noncompaction Cardiomyopathy: Issues, Contradictions and Search for Effective Diagnostic Criteria. Literature Review. Part 2.

Active research of noncompaction cardiomyopathy (NCM) has been going on for more than 30 years. A significant amount of information has been accumulated that is familiar to a much larger number of specialists than in the most recent past. Despite this, numerous issues remain unresolved, ranging from classification (congenital or acquired, nosology, or morphological phenotype) to the ongoing search for clear diagnostic criteria that separate NCM from physiological hypertrabecularity and secondary noncompaction myocardium with the background of existing chronic processes. Meanwhile, a high risk of adverse cardiovascular events in a certain group of people with NCM is quite high. These patients need timely and often quite aggressive therapy. This review of sources of scientific and practical information is devoted to the current aspects of the classification, extremely diverse clinical picture, extremely complex genetic, and instrumental diagnosis of NCM, and the possibilities of its treatment. The purpose of this review is to analyze current ideas about the controversial problems of noncompaction cardiomyopathy. The material for its preparation is the numerous sources of databases Web Science, PubMed, Google Scholar, eLIBRARY. As a result of their analysis, the authors tried to identify and summarize the main problems of the NCM and identify the ways to resolve them.

Excessive Trabeculation of the Left Ventricle: JACC: Cardiovascular Imaging Expert Panel Paper.

Excessive trabeculation, often referred to as "noncompacted" myocardium, has been described at all ages, from the fetus to the adult. Current evidence for myocardial development, however, does not support the formation of compact myocardium from noncompacted myocardium, nor the arrest of this process to result in so-called noncompaction. Excessive trabeculation is frequently observed by imaging studies in healthy individuals, as well as in association with pregnancy, athletic activity, and with cardiac diseases of inherited, acquired, developmental, or congenital origins. Adults with incidentally noted excessive trabeculation frequently require no further follow-up based on trabecular pattern alone. Patients with cardiomyopathy and excessive trabeculation are managed by cardiovascular symptoms rather than the trabecular pattern. To date, the prognostic role of excessive trabeculation in adults has not been shown to be independent of other myocardial disease. In neonates and children with excessive trabeculation and normal or abnormal function, clinical caution seems warranted because of the reported association with genetic and neuromuscular disorders. This report summarizes the evidence concerning the etiology, pathophysiology, and clinical relevance of excessive trabeculation. Gaps in current knowledge of the clinical relevance of excessive trabeculation are indicated, with priorities suggested for future research and improved diagnosis in adults and children.

Prognosis and subtype analysis of left ventricular noncompaction in adults: A retrospective multicenter study.

BACKGROUND: Left ventricular noncompaction (LVNC) is a heterogeneous myocardial disorder with an uncertain prognosis. There was a lack of studies on LVNC subtypes at present. This study sought to identify the prognosis of the overall population of LVNC and to describe the distribution of different subtypes and compare their prognosis. HYPOTHESIS: Patients with different subtypes of LVNC may have different prognoses. METHODS: Patients who fulfilled the Jenni criteria and/or Petersen criteria were included. Major adverse cardiovascular events (MACE) were defined as a combination of heart failure (HF) hospitalization and all-cause mortality. RESULTS: A total of 200 patients from four hospitals were included. The mean age at diagnosis was 48.2 years, and 61.5% of the patients were male. Left ventricular ejection fraction (LVEF) < 50% was present in 54% of the patients. Over a mean retrospective time period of 22.2 months, 47 (23.5%) patients experienced MACE. Age (hazard ratio [HR] 1.03; 95% confidence interval [CI] 1.01-1.06; p = .004), LVEF < 50% (HR 2.32; 95% CI 1.09-4.91; p = .028) and ventricular tachycardia/ventricular fibrillation (HR 2.17; 95% CI 1.08-4.37; p = .03) were significantly associated with the risk of MACE. The most common subtype was dilated LVNC (51.3%), followed by benign LVNC (21.3%) and LVNC with arrhythmias (10.5%). Patients with dilated LVNC had significantly increased cumulative incidence of MACE, HF hospitalization, and all-cause mortality (p < .05). CONCLUSIONS: Age, LVEF < 50%, and ventricular tachycardia/ventricular fibrillation were independent risk factors for prognosis of LVNC. The most common subtype was dilated LVNC, which had a worse prognosis.