Search Results (84)

Background: Left ventricular non-compaction cardiomyopathy (LVNC) is a congenital heart disease characterized by abnormal prenatal development of the left ventricle that has an aberrantly thick trabecular layer and a thinner compacted myocardial layer. However, the underlying molecular mechanisms of LVNC regulated by mitochondrial phosphatase genes remain largely unresolved. Methods: We generated a mouse model with cardiac-specific deletion (CKO) of Ptpmt1, a type of mitochondrial phosphatase gene, using the αMHC-Cre, and investigated the effects of cardiac-specific Ptpmt1 deficiency on cardiac development. Morphological, histological, and immunofluorescent analyses were conducted in Ptpmt1 CKO and littermate controls. A transcriptional atlas was identified by RNA sequencing (RNA-seq) analysis. Results: We found that CKO mice were born at the Mendelian ratio with normal body weights. However, most of the CKO mice died within 24 h after birth, developing spontaneous ventricular tachycardia. Morphological and histological analysis further revealed that newborn CKO mice developed an LVNC phenotype, evidenced by a thicker trabecular layer and a thinner myocardium layer, when compared with the littermate control. We then examined the embryonic hearts and found that such an LVNC phenotype could also be observed in CKO hearts at E15.5 but not at E13.5. We also performed the EdU incorporation assay and demonstrated that cardiac cell proliferation in both myocardium and trabecular layers was significantly reduced in CKO hearts at E15.5, which is also consistent with the dysregulation of genes associated with heart development and cardiomyocyte proliferation in CKO hearts at the same stage, as revealed by both the transcriptome analysis and the quantitative real-time PCR. Deletion of Ptpmt1 in mouse cardiomyocytes also induced an increase in phosphorylated eIF2α and ATF4 levels, indicating a mitochondrial stress response in CKO hearts. Conclusions: Our results demonstrated that Ptpmt1 may play an essential role in regulating left ventricular compaction during mouse heart development. Full article

Ventricular chamber development involves the coordinated maturation of diverse cardiomyocyte cell populations. In the human fetal heart, single-cell and single-nucleus RNA sequencing technologies and spatial transcriptomics reveal marked regional gene expression differences. In contrast, the mouse ventricular wall appears more homogeneous, except for a transient hybrid cardiomyocyte population co-expressing compact (Hey2) and trabecular (Irx3, Nppa, Bmp10) markers, indicating a transitional lineage state. To further investigate this, we used in situ hybridization (ISH) to examine the expression of a selected set of cardiomyocyte markers in normal and left ventricular non-compaction cardiomyopathy (LVNC) mouse models. In developing mouse ventricles, the expression of key marker genes was largely restricted to two wide myocardial domains, compact and trabecular myocardium, suggesting a less complex regional organization than the human fetal heart. Other markers labeled endocardial and coronary endothelial cells rather than cardiomyocytes, differing from patterns observed in the human heart. In the LVNC model, various markers exhibited altered spatial expression, indicating that the precise regional organization of gene expression is critical for normal ventricular wall maturation. These findings underscore the critical role of spatially regulated gene programs in ventricular chamber development and point to their potential involvement in cardiomyopathy pathogenesis. Full article

Barth syndrome (BTHS) is inherited through an X-linked pattern. The gene is located on Xq28. Male individuals who inherit the TAFAZZIN pathogenic variant will have the associated condition, while female individuals who inherit the TAFAZZIN pathogenic variant generally do not experience the condition. There are several organs that may be affected, but striking is the cardiological involvement. Cardiovascular disease, which may be the trigger starting the diagnostic procedure in a proband, may include a range of diseases from a severely dilated heart to a hypertrophic heart in the spectrum of anomalies encountered. Left ventricular non-compaction of the heart is also occasionally encountered. This cardiac event may reveal the prognosis of the affected patients. In this narrative review, we highlight the gene’s characteristics, the reactome, the cardiological features of the cardiovascular disease observed in patients affected with BTHS, emphasize the most current studies on BTHS cardiomyopathy, and delineate the biological underlying mechanisms supporting the proposal of new therapeutic options. Full article

A biopsy involves the removal of a piece or an entire organ from a living patient. The former began with open heart surgery (surgical pathology) and the latter with the recipient heart in cardiac transplantation. Transvenous or transarterial catheterization is the current procedure to performed endomyocardial biopsy with bioptome from the ventricles. This manoeuvre was first carried out by Werner Forssmann through a urological catheter in 1929, which he introduced into his radial left vein until it reached the RV. Then, in London in 1974, Richardson invented a new technique with a catheter via the right femoral vein, which he applied with success in patients with multiple myocardial diseases, both inflammatory and non-inflammatory. Subsequently, a transjugular endomyocardial biopsy was accomplished by Margaret Billingham to monitor heart rejection during cardiac transplantation. In the beginning, only histology for a light microscope, and rarely during electron microscopy, was employed. With the advent of molecular techniques and the discovery of polymerase chain reaction (PCR), molecular investigation became part of the gold standard for diagnosis involving EMB: histology, immunohistochemistry and molecular investigation, the latter in search of a viral cause. Nowadays, EMB is frequently employed in infiltrative (amyloidosis) and storage diseases (e.g., hemochromatosis and Fabry diseases). Diagnosis of myocarditis is now possible through Magnetic Cardiac Resonance (MCR), in place of BEM histology, thanks to oedema. With the help of ECMO, it is possible to allow the heart to rest, supporting its recovery from ejection fraction even in fulminant myocarditis. Cardiac transplantation with the pathological study of the recipient heart offers the opportunity to discover and study new diseases, like restrictive cardiomyopathy and a non-compacted left ventricle. Full article

Genetically determined left ventricular excessive trabeculation (LVET) has a wide clinical spectrum ranging from asymptomatic subjects to severe heart failure with arrhythmias and thromboembolic events. Unlike other cardiomyopathies, the relatives of LVET patients never reach the spotlight of guidelines and clinical practice, although these family members can be often affected by these conditions. Thus, we aimed to investigate the relatives of LVET by multidimensional analysis, such as genetic testing, ECG and cardiac ultrasound (ECHO). We included 55 blood relatives from the family of 18 LVET patients (male = 27, age = 44 ± 20.8y), who underwent anamnesis registration. With Sanger sequencing, the relatives were classified into genetically positive (GEN-pos) and unaffected (GEN-neg) subgroups. In addition to regular ECG parameters, Sokolow-Lyon Index (SLI) values were calculated. 2D ECHO images were analysed with TomTec Arena, evaluating LV volumetric, functional (EF) and strain parameters. Individuals were categorized into JENNI-pos and JENNI-neg morphological subgroups according to the Jenni LVET ECHO criteria. Family history showed frequent involvement (arrhythmia 61%, stroke 56%, syncope 39%, sudden cardiac death 28%, implanted device 28%), as well as personal anamnesis (subjective symptoms 75%, arrhythmias 44%). ECG and ECHO parameters were within the normal range. In terms of genetics, 78% of families and 38% of relatives carried the index mutation. LV_SLI and QT duration were lower in the GEN-pos group; ECHO parameters were comparable in the subgroups. Morphologically, 33% of the relatives met Jenni-LVET criteria were genetically affected and showed lower LV_EF values. The frequently found genetic, morphological and clinical involvement may indicate the importance of screening and, if necessary, regular follow-up of relatives in the genetically affected LVET population. Full article

Left ventricular hypertrabeculation is one of the most debated conditions in modern cardiology. Many studies have tried to characterise this disease by addressing the various clinical risks and diagnostic tools, but its very nosological existence is currently being challenged. The latest ESC guidelines on cardiomyopathies state that it should be addressed as a morphologic trait rather than an intrinsic disease of the cardiac muscle. Despite the huge number of diagnostic criteria and possible phenocopies, no specific consensus identifies a specific flowchart regarding the management of patients with suspected hypertrabeculation. This review aims to provide a clinical approach for patients with a phenotypical appearance of excessive trabeculation. Full article

Background/Objectives: The microtubule-associated scaffold protein 1 (MTUS1) gene affects the microtubule stability and cell polarity in the heart and could thus lead to the development of left ventricular noncompaction (LVNC). Pathological gene variants in MTUS1 are associated with pathological phenotypes in both cell cultures and animal models. However, the literature lacks human studies on the specific effects of the MTUS1 gene in heart disease, particularly in congenital LVNC. Methods: We present a case of a male infant, diagnosed with LVNC, who passed away at the age of 8 months due to end-stage heart failure. In the investigation process of the etiology of LVNC, whole-genome sequencing using next-generation sequencing was performed in the patient and his first-degree family members. Results: Genetic analysis identified two heterozygous variants in the MTUS1 gene (NM_001363059.2:c.87C>G and NM_001363059.2:c.2449+421_2288-425del) in the presented patient. The first variant introduced an early stop codon, while the second caused the deletion of an entire exon, both of which significantly altered the protein structure. The older brother of the patient, at the age of 5 years, was a carrier of both variants; however, he was asymptomatic and without signs of heart disease on cardiac ultrasonography. Conclusions: Although, in theory, defects in the MTUS1 gene may contribute to the development of LVNC, our observations indicate that MTUS1 variants alone are not sufficient to cause LVNC or lead to any significant developmental disorder. Additional factors, whether genetic or environmental, are likely necessary for the clinical manifestation of LVNC. Full article

Background: Accurate segmentation of the left ventricular myocardium in cardiac MRI is essential for developing reliable deep learning models to diagnose left ventricular non-compaction cardiomyopathy (LVNC). This work focuses on improving the segmentation database used to train these models, enhancing the quality of myocardial segmentation for more precise model training. Methods: We present a semi-automatic framework that refines segmentations through three fundamental approaches: (1) combining neural network outputs with expert-driven corrections, (2) implementing a blob-selection method to correct segmentation errors and neural network hallucinations, and (3) employing a cross-validation process using the baseline U-Net model. Results: Applied to datasets from three hospitals, these methods demonstrate improved segmentation accuracy, with the blob-selection technique boosting the Dice coefficient for the Trabecular Zone by up to 0.06 in certain populations. Conclusions: Our approach enhances the dataset’s quality, providing a more robust foundation for future LVNC diagnostic models. Full article

Background: Myocardial disease is an important component of the wide field of cardiovascular disease. However, the phenomenon of multiple myocardial diseases in a single patient remains understudied. Aim: To investigate the prevalence and impact of myocarditis in patients with genetic cardiomyopathies and to evaluate the outcomes of myocarditis treatment in the context of cardiomyopathies. Methods: A total of 342 patients with primary cardiomyopathies were enrolled. The study cohort included 125 patients with left ventricular non-compaction (LVNC), 100 with primary myocardial hypertrophy syndrome, 70 with arrhythmogenic right ventricular cardiomyopathy (ARVC), 60 with dilated cardiomyopathy (DCM), and 30 with restrictive cardiomyopathy (RCM). The diagnosis of myocarditis was based on data from myocardial morphological examination or a non-invasive diagnostic algorithm consisting of an analysis of clinical presentation, anti-cardiac antibody (Ab) titres, and cardiac MRI. Results: The prevalence of myocarditis was 74.3% in ARVC, 56.7% in DCM, 54.4% in LVNC, 37.5% in RCM, and 30.9% in HCM. Myocarditis had a primary viral or secondary autoimmune nature and manifested with the onset or worsening of chronic heart failure (CHF) and arrhythmias. Treatment of myocarditis in cardiomyopathies has been shown to stabilise or improve patient condition and reduce the risk of adverse outcomes. Conclusions: In cardiomyopathies, the genetic basis and inflammation are components of a single continuum, which forms a complex phenotype. In genetic cardiomyopathies, myocarditis should be actively diagnosed and treated as it is an important therapeutic target. Full article

Left ventricular hypertrabeculation (LVHT) used to be a rare phenotypic trait. With advances in diagnostic imaging techniques, LVHT is being recognised in an increasing number of people. The scientific data show the possibility of the overdiagnosis of this cardiomyopathy in a population of people who have very high levels of physical activity. We describe the case of a young athlete with no medical history, who presented with syncope during a marathon running race. Initial evaluation showed elevated troponin I; transthoracic echocardiography showed a trabeculated ventricle and subsequent cardiac magnetic resonance (CMR) revealed left ventricular hypertrabeculation (LVHT). During subsequent evaluation by tilt table testing, vasovagal syncope was identified as the likely aetiology of the syncope. The patient was advised to cease sports and stimulants like caffeine use. At the 29-month follow-up, CMR showed the normalisation of the non-compacted to compacted myocardial ratio and an improvement in left ventricular function, with no further syncopal episodes reported. This is an example of the physiological hypertrabeculation of the LV apex in a recreational endurance athlete, with the normalisation of the non-compacted to compacted myocardial layer ratio after detraining. Physiological hypertrabeculation, a benign component of exercise-induced cardiac remodelling, must be differentiated from non-compaction cardiomyopathy and other pathologies causing syncope. This case underscores the importance of distinguishing physiological hypertrabeculation from pathological LVHT in athletes, highlighting that exercise-induced cardiac remodelling can normalise with detraining. Full article

Pediatric dilated cardiomyopathy (DCM) is a rare heart muscle disorder leading to the enlargement of all chambers and systolic dysfunction. We identified a novel de novo variant, c.88A>G (p.Lys30Glu, K30E), in the TPM1 gene encoding the major cardiac muscle tropomyosin (Tpm) isoform, Tpm1.1. The variant was found in a proband with DCM and left ventricular non-compaction who progressed to terminal heart failure at the age of 3 years and 8 months. To study the properties of the mutant protein, we produced recombinant K30E Tpm and used various biochemical and biophysical methods to compare its properties with those of WT Tpm. The K30E substitution decreased the thermal stability of Tpm and its complex with actin and significantly reduced the sliding velocity of the regulated thin filaments over a surface covered by ovine cardiac myosin in an in vitro motility assay across the entire physiological range of Ca²⁺ concentration. Our molecular dynamics simulations suggest that the charge reversal of the 30th residue of Tpm alters the actin monomer to which it is bound. We hypothesize that this rearrangement of the actin–Tpm interaction may hinder the transition of a myosin head attached to a nearby actin from a weakly to a strongly bound, force-generating state, thereby reducing myocardial contractility. The impaired myosin interaction with regulated actin filaments and the decreased thermal stability of the actin–Tpm complex at a near physiological temperature likely contribute to the pathogenicity of the variant and its causative role in progressive DCM. Full article

Dilated cardiomyopathy (DCM) is characterized by reduced systolic function and cardiac dilation. Cases without an identified secondary cause are classified as idiopathic dilated cardiomyopathy (IDC). Over the last 35 years, many cases of IDC have increasingly been recognized to be genetic in etiology with a core set of definitively causal genes in up to 40% of cases. While over 200 genes have been associated with DCM, the evidence supporting pathogenicity for most remains limited. Further, rapid advances in sequencing and bioinformatics have recently revealed a complex genetic spectrum ranging from monogenic to polygenic in DCM. These advances have also led to the discovery of causal and modifier genetic variants in secondary forms of DCM (e.g., alcohol-induced cardiomyopathy). Current guidelines recommend genetic counseling and screening, as well as endorsing a handful of genotype-specific therapies (e.g., device placement in LMNA cardiomyopathy). The future of genetics in DCM will likely involve polygenic risk scores, direct-to-consumer testing, and pharmacogenetics, requiring providers to have a thorough understanding of this rapidly developing field. Herein we outline three decades of genetics in DCM, summarize recent advances, and project possible future avenues for the field. Full article

The discovery of hypertrophic cardiomyopathy (HCM) dates back to 1958, when the pathologist Donald Teare of the St. George’s Hospital in London performed autopsies in eight cases with asymmetric hypertrophy of the ventricular septum and bizarre disorganization (disarray) at histology, first interpreted as hamartoma. Seven had died suddenly. The cardiac specimens were cut along the long axis, similar to the 2D echo. In the same year, at the National Institute of Health U.S.A., Eugene Braunwald, a hemodynamist, and Andrew Glenn Morrow, a cardiac surgeon, clinically faced a patient with an apparently similar morbid entity, with a systolic murmur and subaortic valve gradient. “Discrete” subaortic stenosis was postulated. However, at surgery, Dr. Morrow observed only hypertrophy and performed myectomy to relieve the obstruction. This first Braunwald–Morrow patient underwent a successful cardiac transplant later at the disease end stage. The same Dr. Morrow was found to be affected by the familial HCM and died suddenly in 1992. The term “functional subaortic stenosis” was used in 1959 and “idiopathic hypertrophic subaortic stenosis” in 1960. Years before, in 1957, Lord Brock, a cardiac surgeon at the Guy’s Hospital in London, during alleged aortic valve surgery in extracorporeal circulation, did not find any valvular or discrete subaortic stenoses. In 1980, John F. Goodwin of the Westminster Hospital in London, the head of an international WHO committee, put forward the first classification of heart muscle diseases, introducing the term cardiomyopathy (dilated, hypertrophic, and endomyocardial restrictive). In 1995, the WHO classification was revisited, with the addition of two new entities, namely arrhythmogenic and purely myocardial restrictive, the latter a paradox of a small heart accounting for severe congestive heart failure by ventricular diastolic impairment. A familial occurrence was noticed earlier in HCM and published by Teare and Goodwin in 1960. In 1989–1990, the same family underwent molecular genetics investigation by the Seidman team in Boston, and a missense mutation of the β-cardiac myosin heavy chain in chromosome 14 was found. Thus, 21 years elapsed from HCM gross discovery to molecular discoveries. The same original family was the source of both the gross and genetic explanations of HCM, which is now named sarcomere disease. Restrictive cardiomyopathy, characterized grossly without hypertrophy and histologically by myocardial disarray, was found to also have a sarcomeric genetic mutation, labeled “HCM without hypertrophy”. Sarcomere missense mutations have also been reported in dilated cardiomyopathy (DCM) and non-compaction cardiomyopathy. Moreover, sarcomeric gene defects have been detected in some DNA non-coding regions of HCM patients. The same mutation in the family may express different phenotypes (HCM, DCM, and RCM). Large ischemic scars have been reported by pathologists and are nowadays easily detectable in vivo by cardiac magnetic resonance with gadolinium. The ischemic arrhythmic substrate enhances the risk of sudden death. Full article

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. Full article

The aim of this study was to evaluate the clinical course and outcomes of post-COVID myocarditis in patients with cardiomyopathies (CMP). This case series includes 10 patients with different CMPs who had COVID-19 (seven men; 48.4 ± 11.4 yr.): left ventricular non-compaction (n = 2), arrhythmogenic right ventricular CMP in combination with a heterozygous form of hemochromatosis (n = 1, HFE), restrictive CMP (n = 1, MyBPC3), laminopathy (n = 1, LMNA), dilated cardiomyopathy (n = 1, MYH7 + MyBPC3), Danon’s disease (n = 1, LAMP2) and AL cardiac amyloidosis (n = 3). Myocardial morphological examination with immunohistochemical staining and PCR for SARS-CoV-2 and cardiotropic viruses was performed in six patients, while cardiac MRI and anti-cardiac antibody titres were evaluated in all patients. Post-COVID lymphocytic myocarditis was confirmed morphologically in six patients (with LVNC, RCM, ARCV, Danon’s disease, and AL amyloidosis). Spike and nucleocapsid coronavirus proteins were detected in cell infiltrates, endothelium and cardiomyocytes in all biopsies; SARS-CoV-2 RNA was found in five out of six. In four patients, the diagnosis of myocarditis was based on MRI, high titres of anti-cardiac antibodies and clinical data. The mean time from COVID-19 to the diagnosis of myocarditis was 7 (5; 10.5) months. Myocarditis manifested with the onset/increase of arrhythmias and heart failure. Immunosuppressive therapy with corticosteroids was administered to six patients and led to an increase in ejection fraction and improvement of heart failure symptoms in five of them. CMPs are a favourable background for the development of post-COVID myocarditis. The onset or deterioration of heart failure and/or arrhythmias in patients with CMPs after COVID-19 requires the exclusion of myocarditis and, if present, the administration of immunosuppressive therapy. Full article