Left Ventricular Noncompaction Cardiomyopathy Research Articles

Characterisation of the novel SCN5A-P1891A variant, implicated in left ventricular noncompaction cardiomyopathy in a Finnish family, using human induced pluripotent stem cell-derived cardiomyocytes

Abstract Introduction Left ventricular noncompaction (LVNC) is a heterogenous cardiomyopathy characterised by an extensively trabeculated left ventricle (LV). Several genetic variants that perturb trabeculae compaction, and thus LV maturation, have been reported [1]. However, the precise mechanisms underpinning this have proven contentious with, for example, differentially aberrant cardiomyocyte proliferation implicated in the development of LVNC [2,3]. Purpose In this study, we investigate a novel SCN5A variant, P1891A, which is associated with LVNC in a Finnish family. We ascertain the effects of this variant through the characterisation of variant-carrying human induced pluripotent stem cell-derived cardiomyocytes (P1891A-hiPSC-CMs). Methods We isolated dermal fibroblasts from a symptomatic member of a Finnish family carrying the SCN5A-P1891A variant; derived P1891A-hiPSCs via nucleofection with reprogramming plasmids [4]; and differentiated these into hiPSC-CMs alongside healthy control-hiPSCs. We determined the action potential (AP) and sodium- (INa) and calcium-current (ICa) densities of hiPSC-CMs via patch-clamp. We investigated gene expression in hiPSC-CMs through qPCR and employed Multiple Approaches Combined (MCA) proteomics [5] in SCN5A-transfected HEK293-like cells to elucidate protein-protein interactions (PPI). We subjected hiPSC-CMs to mechanical stretch [6] to examine their stress response and assessed their proliferation capacity via high-content analysis for the percentage of BrdU positive hiPSC-CMs following mitogenic stimulation (5 µM CHIR99021 and 1 µM SB203580). Finally, we ascertained contractile kinetics and apparent contractile force using fibrin hydrogel-based engineered heart tissues (EHTs) [7]. Results The P1891A-hiPSC-CMs demonstrated elevated INa density alongside enhanced arrhythmogenicity relative to healthy control hiPSC-CMs although, AP kinetics and ICa density were unperturbed (Fig. 1). Under baseline conditions, P1891A-hiPSC-CMs exhibited higher SCN5A gene expression and proteomics revealed a reduction in PPI. Baseline proliferation was unchanged; however, aged P1891A-hiPSC-CMs had enhanced proliferative capacity following mitogenic stimulation. Further, the P1891A-hiPSC-CMs displayed impaired tolerance to mechanical stretch as evidenced by upregulated NPPB and ACTA1 expression. In the context of the EHT, P1891A-hiPSC-CMs yielded disparate phenotypes. Whilst a subset compacted fully and yielded weaker contractile parameters relative to healthy control EHTs, the majority of P1891A-hiPSC-CM EHTs failed to fully compact thereby recapitulating the LVNC phenotype (Fig. 2). Conclusions This study presents a unique aetiology of LVNC and links, for the first time, SCN5A mutations with enhanced human cardiomyocyte proliferation. The ability to recapture the noncompaction phenotype in EHTs presents a powerful model for future mechanistic research and drug development.

Cardiac screening with ECG in the young: significance of T wave inversion, T wave depth and T wave/QRS ratio

Abstract Background In young apparently healthy individuals, repolarization changes at the ECG may suggest an underlying cardiomyopathy. Purpose This study aims to investigate the clinical significance of T waves depth and T/QRS ratio in young individuals who underwent cardiac screening and exhibited T wave inversion (TWI) at the ECG. Methods We analysed a database of individuals aged 14 to 35 years who underwent cardiac screening, which included a health questionnaire and 12-lead ECG with a charitable organisation, between 2008 and 2013. All individuals included had recently responded to a follow-up online health questionnaire or had documented outcomes on a national digital database. The amplitudes of QRS (peak to peak) and T waves (mV) were measured in the leads where TWI was present; the average T/QRS ratio and average TWI depth were calculated. Results Our cohort comprised 5360 subjects (mean age of 21 ± 6 years, 61% males). Of the 358 (7%) who were referred for further investigations based on their screening findings, 255 (5%) had an abnormal ECG. TWI was documented in 120 (2%) individuals [anterior TWI in 78, inferior TWI in 16, lateral TWI in 6, and overlaps in 20 cases]. After further investigations, 16/120 (13%) individuals were diagnosed with cardiomyopathy [9 hypertrophic cardiomyopathy (HCM), 5 arrhythmogenic cardiomyopathy (ACM), 1 dilated cardiomyopathy (DCM), and 1 left ventricular non-compaction cardiomyopathy (LVNC)]. Of the remaining 104/120 individuals, 18 were diagnosed with other cardiac conditions and 86 were not found to have a cardiac disease. During a mean follow-up of 8.1 ± 1.2 years, no deaths were documented among the 16 individuals diagnosed with a cardiomyopathy, but 3 of them experienced a sudden cardiac arrest (all of them had ACM). In individuals diagnosed with a cardiomyopathy both average T/QRS ratio and average TWI depth were higher compared to the rest (0.128 vs 0.117; p = 0.54 and 0.281 vs 0.162 mV; p = 0.03, respectively). Average T/QRS ratio and average TWI depth were higher in individuals diagnosed with HCM compared with the ones diagnosed with other cardiomyopathies (0.133 vs 0.115; p = 0.68 and 0.336 vs 0.164 mV; p = 0.05, respectively). Conclusion T wave inversion is a relatively common ECG finding in young apparently healthy individuals and this feature leads to a diagnosis of cardiomyopathy in 13% of cases. Among subjects exhibiting TWI, T/QRS ratio and T wave depth appear higher in the ones who are eventually diagnosed with cardiomyopathies.Figure 1.Flowchart of patient selection

MYH7-related myopathies: clinical, myopathological and genotypic spectrum in a multicentre French cohort

BackgroundMyosin heavy chain 7 (MYH7)-related myopathies (MYH7-RMs) are a group of muscle disorders linked to pathogenic variants in the MYH7 gene, encoding the slow/beta-cardiac myosin heavy chain, which is highly...

Morphological, electrophysiological, and molecular alterations in foetal noncompacted cardiomyopathy induced by disruption of ROCK signalling.

Left ventricular noncompaction cardiomyopathy is associated with heart failure, arrhythmia, and sudden cardiac death. The developmental mechanism underpinning noncompaction in the adult heart is still not fully understood, with lack of trabeculae compaction, hypertrabeculation, and loss of proliferation cited as possible causes. To study this, we utilised a mouse model of aberrant Rho kinase (ROCK) signalling in cardiomyocytes, which led to a noncompaction phenotype during embryogenesis, and monitored how this progressed after birth and into adulthood. The cause of the early noncompaction at E15.5 was attributed to a decrease in proliferation in the developing ventricular wall. By E18.5, the phenotype became patchy, with regions of noncompaction interspersed with thick compacted areas of ventricular wall. To study how this altered myoarchitecture of the heart influenced impulse propagation in the developing and adult heart, we used histology with immunohistochemistry for gap junction protein expression, optical mapping, and electrocardiography. At the prenatal stages, a clear reduction in left ventricular wall thickness, accompanied by abnormal conduction of the ectopically paced beat in that area, was observed in mutant hearts. This correlated with increased expression of connexin-40 and connexin-43 in noncompacted trabeculae. In postnatal stages, left ventricular noncompaction was resolved, but the right ventricular wall remained structurally abnormal through to adulthood with cardiomyocyte hypertrophy and retention of myocardial crypts. Thus, this is a novel model of self-correcting embryonic hypertrabeculation cardiomyopathy, but it highlights that remodelling potential differs between the left and right ventricles. We conclude that disruption of ROCK signalling induces both morphological and electrophysiological changes that evolve over time, highlighting the link between myocyte proliferation and noncompaction phenotypes and electrophysiological differentiation.

Left Ventricular Non-Compaction: Evolving Concepts

Left ventricular non-compaction (LVNC) is a rare heart muscle disease defined by the presence of prominent left ventricular trabeculation, deep intertrabecular recesses, and a thin compact layer. Several hypotheses have been proposed regarding its pathogenesis, with the most recently accepted one being that compact layer and trabeculated layers develop independently according to an “allometric growth”. The current gold-standard diagnostic criteria (in particular, the Petersen index non-compaction/compaction ratio > 2.3) reflect an excess of myocardial trabeculation, which is not a specific morpho-functional feature of LVNC cardiomyopathy but merely a “phenotypic trait”, even described in association with other myocardial disease and over-loading conditions. Accordingly, the European Society of Cardiology (ESC) guidelines have definitively abolished the term ‘LVNC cardiomyopathy’. Recently, evolving perspectives led to the restoration of LVNC cardiomyopathy by distinguishing “hypertrabeculation phenotype” and “non-compaction phenotype”. It has been proposed that the disease-specific pathophysiologic mechanism is a congenitally underdevelopment of the compact layer accounting for an impairment of the left ventricular systolic function. Future prospective research should focus on the clinical and prognostic relevance of compact layer thinning rather than excessive trabeculation, which could significantly influence the management of patients with LVNC. The review aims to update current knowledge on the pathogenesis, genetics, and diagnostic criteria of LVNC, offering modern insights for future perspectives.

Abnormal left atrial strain and left atrial stiffness index are associated with adverse outcomes in children with cardiomyopathies: a pilot study

Conventional diastolic dysfunction parameters seem to be imperfect when applied to the pediatric cardiomyopathy population. The aim of this pilot study was to search for novel echocardiographic parameters associated with adverse outcomes in children with the most common cardiomyopathies. Fifty-six patients with pediatric cardiomyopathies (28 with dilated, 21 with hypertrophic, 7 with left ventricular non-compaction cardiomyopathy) and 28 healthy subjects were included in the study. Left atrial reservoir (LASr), conduit (LAScd) and contraction (LASct) strain, left atrial stiffness index (LASI), as well as conventional diastolic dysfunction parameters were measured using echocardiography. Adverse outcomes were defined as heart failure (including heart transplant) and arrhythmic endpoints. Patients with adverse outcomes presented with significantly lower LASr (16.68% ± 8.64% vs. 33.97% ± 9.99%, p-value < 0.001), lower LAScd (− 10.37% ± 5.83% vs. − 25.50% ± 9.24%, p-value < 0.001) and higher values of LASI (0.69 [IQR 0.34; 1.11] vs. 0.21 [IQR 0.16; 0.31], p-value < 0.001). LASr < 20%, LAScd ≥ − 12%, and LASI ≥ 0.26 were all associated with reduced survival. LASr, LAScd and LASI seem to be promising parameters in predicting adverse outcomes in the most common pediatric cardiomyopathies. Left atrial strain parameters and LASI are helpful in differentiating healthy control subjects from children with hypertrophic and dilated cardiomyopathies.

Abstract We090: Antagonistic and Cooperative Dynamics of Irx3 and Irx4 in Ventricular Compaction

Left ventricular non-compaction cardiomyopathy (LVNC) is a rare heart condition characterized by excessive trabeculae and intertrabecular recesses in the left ventricle of the heart. It is believed to be caused by abnormal trabecular compaction process, which involves trabecular remodelling to form a thick myocardial wall. Embryonic trabeculae consist of bipotent progenitors that differentiate into the ventricular conduction system (VCS) and contractile cardiomyocytes, yet it remains to be further understood how the pathways involved in trabecular cell specifications play a role in the compaction process. Here we present two transcription factors, Iroquois homeobox 3 ( Irx3 ) and Irx4 , playing antagonistic and cooperative roles during trabecular specification and maturation, thereby facilitating proper ventricular compaction. Our single-cell RNA sequencing analysis revealed that the differentiation of trabecular cells into VCS cells was accompanied by increased Irx3 but decreased Irx4 expression. In addition, we found that the loss of Irx4 led to both an increased expression level of Irx3 and an expansion in the number of Irx3 -expressing cells. Conversely, the loss of Irx3 resulted in an upregulation of Irx4 expression within VCS cells. Next, to investigate the functional importance of the antagonistic relationship between Irx3 and Irx4 in trabecular differentiation, we generated Irx3 and Irx4 compound knockout (KO) mice and examined the structure and function of their hearts. Notably, unlike Irx3 KO hearts showing normal ventricular myocardium, Irx4 KO hearts exhibited mild LVNC, and Irx3 and Irx4 double knockouts ( Irx3 /4dKO) hearts displayed severe LVNC. Multiome sequencing of E14.5 ventricles revealed that Irx3 /4dKO ventricles contained an increased number of trabecular cells, expressing higher levels of cell proliferation markers and altered trabecular identity genes, compared to littermate controls. Collectively, our results demonstrate that balanced antagonism between Irx3 and Irx4 is crucial for establishing trabecular identity. This highlights the importance of proper differentiation of trabeculae into the VCS and non-VCS contractile cells during ventricular compaction, thereby preventing noncompaction cardiomyopathy.

COQ7 defect causes prenatal onset of mitochondrial CoQ10 deficiency with cardiomyopathy and gastrointestinal obstruction

COQ7 pathogenetic variants cause primary CoQ10 deficiency and a clinical phenotype of encephalopathy, peripheral neuropathy, or multisystemic disorder. Early diagnosis is essential for promptly starting CoQ10 supplementation. Here, we report novel compound heterozygous variants in the COQ7 gene responsible for a prenatal onset (20 weeks of gestation) of hypertrophic cardiomyopathy and intestinal dysmotility in a Bangladesh consanguineous family with two affected siblings. The main clinical findings were dysmorphisms, recurrent intestinal occlusions that required ileostomy, left ventricular non-compaction cardiomyopathy, ascending aorta dilation, arterial hypertension, renal dysfunction, diffuse skin desquamation, axial hypotonia, neurodevelopmental delay, and growth retardation. Exome sequencing revealed compound heterozygous rare variants in the COQ7 gene, c.613_617delGCCGGinsCAT (p.Ala205HisfsTer48) and c.403A>G (p.Met135Val). In silico analysis and functional in vitro studies confirmed the pathogenicity of the variants responsible for abolished activities of complexes I + III and II + III in muscle homogenate, severe decrease of CoQ10 levels, and reduced basal and maximal respiration in patients’ fibroblasts. The first proband deceased at 14 months of age, whereas supplementation with a high dose of CoQ10 (30 mg/kg/day) since the first days of life modified the clinical course in the second child, showing a recovery of milestones acquirement at the last follow-up (18 months of age). Our study expands the clinical spectrum of primary CoQ10 deficiency due to COQ7 gene defects and highlights the essential role of multidisciplinary and combined approaches for a timely diagnosis.

Analysis of long-term prognosis and risk factors in patients with dilated cardiomyopathy

Objective: To investigate the risk factors and long-term prognosis of major adverse cardiovascular events(MACEs) in patients with dilated cardiomyopathy (DCM). Methods: This study was a single-center retrospective cohort study. Clinical information from 300 patients with DCM hospitalized in Peking Union Medical College Hospital from April 2013 to April 2023 was collected. Based on echocardiography results, the patients were divided into two groups: isolated DCM and DCM with left ventricular non-compaction cardiomyopathy (LVNC). The MACEs, including major heart failure events, severe ventricular arrhythmias, and cardiovascular death, were recorded by outpatient or telephone follow-up. Univariate and multivariate Cox proportional hazard regression models were used to analyze the risk factors affecting the prognosis of patients with DCM. Kaplan-Meier curve and log-rank were used for survival analysis to compare the difference in the incidence of cardiovascular events between the two groups. Results: The included 300 DCM patients were (47.8±16.8) years old, with 197 males (65.7%), of which 237 (79.0%) were isolated DCM and 63 (21.0%) were DCM with LVNC. The follow-up time was 4.0 (1.9, 6.2) years. A total of 142 (47.3%) MACEs occurred, including 117 (39.0%) major heart failure events, 20 (6.7%) severe ventricular arrhythmia events, and 53 (17.7%) cardiovascular death events. Multivariate Cox proportional hazard regression analysis showed that increased left ventricular end-diastolic diameter (HR=1.21, 95%CI: 1.01-1.44, P=0.042), moderate or severe mitral regurgitation (HR=1.71, 95%CI: 1.19-2.47, P=0.004), increased ln (N-terminal pro-B-type natriuretic peptide) (HR=1.30, 95%CI: 1.10-1.54, P=0.002) were independent risk factors for dverse cardiovascular events in DCM patients, and angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB)/angiotensin receptor neprilysin inhibitor (ARNI) treatment (HR=0.45, 95%CI: 0.26-0.78, P=0.004) was independent protective factor. Kaplan-Meier survival analysis found no significant difference in the risk of MACEs between isolated DCM and DCM with LVNC (P=0.22). Similarly, there were no significant differences in the incidence of major heart failure, severe ventricular arrhythmia, and cardiovascular death between the two groups (all P>0.05). Conclusion: An increase in left ventricular end-diastolic diameter, moderate or severe mitral regurgitation, elevated N-terminal pro-B-type natriuretic peptide, and non use of ACEI/ARB/ARNI are independent predictors of cardiovascular events in DCM patients. There was no significant risk of MACEs in patients with isolated DCM and DCM with LVNC, and suggested that LVNC may be a unique phenotype and should be accurately managed in combination with genetic background.

Isolated left ventricular non-compaction cardiomyopathy: case report and brief review on diagnostic imaging methods

Left ventricular non-compaction cardiomyopathy (LVNC) is a rare congenital heart disease with an estimated incidence of 0.014-0.045% in a general population. It occurs due to a morphogenetic abnormality during embryogenesis that inhibits myocardial compaction and determines prominent trabeculae with deep intertrabecular spaces and thickening of the adjacent myocardium in two distinct layers. Diagnosis is generally established via transthoracic echocardiogram (TTE) with further confirmation with cardiac magnetic resonance (CMR). A 57-year-old male patient previously diagnosed with systemic arterial hypertension and chronic obstructive pulmonary disease reported chest pain and dyspnea upon exertion, headache, and dizziness. During outpatient investigation, the patient was submitted to a stress electrocardiogram that was positive for ischemia and led to a cineangiocoronariography with no signs of coronary artery obstruction. At the echocardiography lab, several trabeculations were detected in the apical region of the left ventricle. A diagnosis of LVNC was established and the results were confirmed via CMR. Management was initiated with the goal of symptom relief. LVNC is a relatively unknown pathology that is frequently underdiagnosed at earlier stages. As presented, we highlight the importance of multimodality imaging, especially TTE and CMR, in the diagnosis of this congenital heart condition.

Rare case of super-response to Cardiac Resynchronization Therapy in Macedonian patient with Dilated Left Ventricular Non-Compaction Cardiomyopathy

Background: Left ventricular non-compaction (LVNC) is rare cardiomyopathy with increased and prominent endomyocardial trabeculations also known as spongy myocardium. It is often found in association with a dilated cardiomyopathy (DCM) and has high incidence of Heart failure (HF). Cardiac resynchronization therapy (CRT) is currently recommended by the available guidelines for selected patients with Heart failure with reduced ejection fraction (HFrEF). Aim: Our case report aims to highlight the therapeutic benefits and superresponse to CRT in a patient with Left ventricular non-compaction cardiomyopathy and HFrEF. Case report: 55-year-old Macedonian male patient with HFrEF, Left bundle branch block (LBBB) remained symptomatic (NYHA III) despite optimal medical treatment (OMT). Echocardiography and CMR findings were in addition to dilated and left ventricular non-compaction cardiomyopathy. Cardiac resynchronization therapy was indicated and 18 months after implantation of CRT-P device we have achieved complete and utter reversibility of systolic myocardial function (EF from 23% to 53%), left ventricular internal diameter was reduced from 90mm to 64mm, left ventricular end systolic volume (LVESV) was reduced from 319ml to 98ml and patient quality of life significantly improved. Conclusion: Cardiac resynchronization therapy is a safe and valuable method of treatment for patients with HFrEF due to dilated left ventricular non-compaction cardiomyopathy.

Titin: The Missing Link in Cardiac Physiology

Titin, an extraordinary protein known for its colossal size and multifaceted roles, is a cornerstone in the structural and functional dynamics of striated muscle tissues, including the heart and skeletal muscles. Its sheer enormity, with a molecular weight exceeding 3000 kDa, is paralleled only by the immense influence it exerts on muscle physiology. This review will delve into the remarkable structural organization of Titin and the genetics of this molecule, including the common mutations resulting in various cardiomyopathies. We will delve deeper into its role in dilated cardiomyopathy, familial restrictive cardiomyopathy, hypertrophic cardiomyopathy, and left ventricular noncompaction cardiomyopathy. This review culminates by discussing the prospects of therapeutic strategies targeting Titin. While these interventions remain primarily theoretical, the possibilities are intriguing. Patients with Titin truncation mutations present unique challenges, but innovative approaches like gene therapy or preemptive treatments with drugs such as angiotensin-converting enzyme inhibitors or beta-blockers offer hope. This multi-pronged approach highlights the significance of understanding Titin’s multifaceted role and its potential as a target for future therapeutic interventions.

Kiosk 2Q-TA-09 - Cardiac Magnetic Resonance (CMR) in the Diagnosis of Left Ventricular Noncompaction Cardiomyopathy: A Complex Clinical Presentation

Kiosk 2Q-TA-09 - Cardiac Magnetic Resonance (CMR) in the Diagnosis of Left Ventricular Noncompaction Cardiomyopathy: A Complex Clinical Presentation

Kiosk 3R-TC-09 - Differentiating Excessive Trabeculations FBom Left Ventricular Non-compaction Cardiomyopathy Utilizing Cardiovascular Magnetic Resonance

Kiosk 3R-TC-09 - Differentiating Excessive Trabeculations FBom Left Ventricular Non-compaction Cardiomyopathy Utilizing Cardiovascular Magnetic Resonance

Myocardial Mechanics and Associated Valvular and Vascular Abnormalities in Left Ventricular Noncompaction Cardiomyopathy.

Left ventricular (LV) non-compaction (LVNC) is a rare genetic cardiomyopathy due to abnormal intra-uterine arrest of compaction of the myocardial fibers during endomyocardial embryogenesis. Due to the partial or complete absence of LV compaction, the structure of the LV wall shows characteristic abnormalities, including a thin compacted epicardium and a thick non-compacted endocardium with prominent trabeculations and deep intertrabecular recesses. LVNC is frequently associated with chronic heart failure, life-threatening ventricular arrhythmias, and systemic embolic events. According to recent findings, in the presence of LVNC, dysfunctional LV proved to be associated with left atrial volumetric and functional abnormalities and consequential dilated and functionally impaired mitral annulus, partly explaining the higher prevalence of regurgitation. Although the non-compaction process morphologically affects only the LV, signs of remodeling of the right heart were also detected. Moreover, dilation and stiffening of the aorta were present. The aim of the present detailed review was to summarize findings regarding changes in cardiac mechanics, valvular abnormalities, and vascular remodeling detected in patients with LVNC.

Concealed Inherited Cardiomyopathies Detected in Cardio-Oncology Screening.

Basal cardiovascular risk assessment in cardio-oncology is essential. Integrating clinical information, ECG and transthoracic echocardiogram can identify concealed inherited cardiomyopathies (ICMPs) with potential added risk of cardiotoxicity. We aimed to evaluate the impact of our Cardio-Oncology Unit design in detecting concealed ICMPs. We carried out a retrospective study of all consecutive breast cancer patients referred to the Cardio-Oncology Unit for cardiac evaluation (2020-2022). ICMPs diagnosis was provided according to ESC guidelines and underwent genetic testing. ICMPs prevalence in this cohort was compared to the highest and lowest frequency reported in the general population. Among 591 breast cancer patients, we identified eight patients with ICMPs: one arrhythmogenic cardiomyopathy (ACM), three familial non-ischemic dilated cardiomyopathy (DCM), three hypertrophic cardiomyopathy (HCM) and one left ventricular non-compaction cardiomyopathy (LVNC), which has now been reclassified as non-dilated left ventricular cardiomyopathy. The number of ICMPs identified was within the expected range (neither overdiagnosed nor overlooked): ACM 0.0017 vs. 0.0002-0.001 (p 0.01-0.593); DCM 0.0051 vs. 0.002-0.0051 (p 0.094-0.676); HCM 0.005 vs. 0.0002-0.002 (p < 0.001-0.099); LVCN 0.0017 vs. 0.00014-0.013 (p 0.011-0.015). Genetic testing identified a pathogenic FLNC variant and two pathogenic TTN variants. Opportunistic screening of ICMPs during basal cardiovascular risk assessment can identify high-risk cancer patients who benefit from personalized medicine and enables extension of prevention strategies to all available relatives at concealed high cardiovascular risk.

Generation of an RBM20-mutation-associated left-ventricular non-compaction cardiomyopathy iPSC line (UMGi255-A) into a DCM genetic background to investigate monogenetic cardiomyopathies

RBM20 mutations account for 3 % of genetic cardiomypathies and manifest with high penetrance and arrhythmogenic effects. Numerous mutations in the conserved RS domain have been described as causing dilated cardiomyopathy (DCM), whereas a particular mutation (p.R634L) drives development of a different cardiac phenotype: left-ventricular non-compaction cardiomyopathy. We generated a mutation-induced pluripotent stem cell (iPSC) line in which the RBM20-LVNC mutation p.R634L was introduced into a DCM patient line with rescued RBM20-p.R634W mutation. These DCM-634L-iPSC can be differentiated into functional cardiomyocytes to test whether this RBM20 mutation induces development of the LVNC phenotype within the genetic context of a DCM patient.

Improving a Deep Learning Model to Accurately Diagnose LVNC.

Accurate diagnosis of Left Ventricular Noncompaction Cardiomyopathy (LVNC) is critical for proper patient treatment but remains challenging. This work improves LVNC detection by improving left ventricle segmentation in cardiac MR images. Trabeculated left ventricle indicates LVNC, but automatic segmentation is difficult. We present techniques to improve segmentation and evaluate their impact on LVNC diagnosis. Three main methods are introduced: (1) using full 800 × 800 MR images rather than 512 × 512; (2) a clustering algorithm to eliminate neural network hallucinations; (3) advanced network architectures including Attention U-Net, MSA-UNet, and U-Net++.Experiments utilize cardiac MR datasets from three different hospitals. U-Net++ achieves the best segmentation performance using 800 × 800 images, and it improves the mean segmentation Dice score by 0.02 over the baseline U-Net, the clustering algorithm improves the mean Dice score by 0.06 on the images it affected, and the U-Net++ provides an additional 0.02 mean Dice score over the baseline U-Net. For LVNC diagnosis, U-Net++ achieves 0.896 accuracy, 0.907 precision, and 0.912 F1-score outperforming the baseline U-Net. Proposed techniques enhance LVNC detection, but differences between hospitals reveal problems in improving generalization. This work provides validated methods for precise LVNC diagnosis.

Multidisciplinary approach in cardiomyopathies: From genetics to advanced imaging.

Cardiomyopathies are myocardial diseases characterized by mechanical and electrical dysfunction of the heart muscle which could lead to heart failure and life-threatening arrhythmias. Certainly, an accurate anamnesis, a meticulous physical examination, and an ECG are cornerstones in raising the diagnostic suspicion. However, cardiovascular imaging techniques are indispensable to diagnose a specific cardiomyopathy, to stratify the risk related to the disease and even to track the response to the therapy. Echocardiography is often the first exam that the patient undergoes, because of its non-invasiveness, wide availability, and cost-effectiveness. Cardiac magnetic resonance imaging allows to integrate and implement the information obtained with the echography. Furthermore, cardiomyopathies' genetic basis has been investigated over the years and the list of genetic mutations deemed potentially pathogenic is expected to grow further. The aim of this review is to show echocardiographic, cardiac magnetic resonance imaging, and genetic features of several cardiomyopathies: dilated cardiomyopathy (DMC), hypertrophic cardiomyopathy (HCM), arrhythmogenic cardiomyopathy (ACM), left ventricular noncompaction cardiomyopathy (LVNC), myocarditis, and takotsubo cardiomyopathy.

Nonsense Variant PRDM16-Q187X Causes Impaired Myocardial Development and TGF-β Signaling Resulting in Noncompaction Cardiomyopathy in Humans and Mice.

PRDM16 plays a role in myocardial development through TGF-β (transforming growth factor-beta) signaling. Recent evidence suggests that loss of PRDM16 expression is associated with cardiomyopathy development in mice, although its role in human cardiomyopathy development is unclear. This study aims to determine the impact of PRDM16 loss-of-function variants on cardiomyopathy in humans. Individuals with PRDM16 variants were identified and consented. Induced pluripotent stem cell-derived cardiomyocytes were generated from a proband hosting a Q187X nonsense variant as an in vitro model and underwent proliferative and transcriptional analyses. CRISPR (clustered regularly interspaced short palindromic repeats)-mediated knock-in mouse model hosting the Prdm16Q187X allele was generated and subjected to ECG, histological, and transcriptional analysis. We report 2 probands with loss-of-function PRDM16 variants and pediatric left ventricular noncompaction cardiomyopathy. One proband hosts a PRDM16-Q187X variant with left ventricular noncompaction cardiomyopathy and demonstrated infant-onset heart failure, which was selected for further study. Induced pluripotent stem cell-derived cardiomyocytes prepared from the PRDM16-Q187X proband demonstrated a statistically significant impairment in myocyte proliferation and increased apoptosis associated with transcriptional dysregulation of genes implicated in cardiac maturation, including TGF-β-associated transcripts. Homozygous Prdm16Q187X/Q187X mice demonstrated an underdeveloped compact myocardium and were embryonically lethal. Heterozygous Prdm16Q187X/WT mice demonstrated significantly smaller ventricular dimensions, heightened fibrosis, and age-dependent loss of TGF-β expression. Mechanistic studies were undertaken in H9c2 cardiomyoblasts to show that PRDM16 binds TGFB3 promoter and represses its transcription. Novel loss-of-function PRDM16 variant impairs myocardial development resulting in noncompaction cardiomyopathy in humans and mice associated with altered TGF-β signaling.