The normal function of the human myocardium requires the proper generation and utilization of energy and relies on a series of complex metabolic processes to achieve this normal function. When ...metabolic processes fail to work properly or effectively, heart muscle dysfunction can occur with or without accompanying functional abnormalities of other organ systems, particularly skeletal muscle. These metabolic derangements can result in structural, functional, and infiltrative deficiencies of the heart muscle. Mitochondrial and enzyme defects predominate as disease-related etiologies. In this review, left ventricular noncompaction cardiomyopathy, which is often caused by mutations in sarcomere and cytoskeletal proteins and is also associated with metabolic abnormalities, is discussed. In addition, cardiomyopathies resulting from mitochondrial dysfunction, metabolic abnormalities, storage diseases, and inborn errors of metabolism are described.
Left ventricular non-compaction (LVNC) is a rare cardiomyopathy associated with a hypertrabeculated phenotype and a large spectrum of symptoms. It is still unclear whether LVNC results from a defect ...of ventricular trabeculae development and the mechanistic basis that underlies the varying severity of this pathology is unknown. To investigate these issues, we inactivated the cardiac transcription factor Nkx2-5 in trabecular myocardium at different stages of trabecular morphogenesis using an inducible Cx40-creERT2 allele. Conditional deletion of Nkx2-5 at embryonic stages, during trabecular formation, provokes a severe hypertrabeculated phenotype associated with subendocardial fibrosis and Purkinje fiber hypoplasia. A milder phenotype was observed after Nkx2-5 deletion at fetal stages, during trabecular compaction. A longitudinal study of cardiac function in adult Nkx2-5 conditional mutant mice demonstrates that excessive trabeculation is associated with complex ventricular conduction defects, progressively leading to strain defects, and, in 50% of mutant mice, to heart failure. Progressive impaired cardiac function correlates with conduction and strain defects independently of the degree of hypertrabeculation. Transcriptomic analysis of molecular pathways reflects myocardial remodeling with a larger number of differentially expressed genes in the severe versus mild phenotype and identifies Six1 as being upregulated in hypertrabeculated hearts. Our results provide insights into the etiology of LVNC and link its pathogenicity with compromised trabecular development including compaction defects and ventricular conduction system hypoplasia.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Fibrotic rigidification following a myocardial infarct is known to impair cardiac output, and it is also known that cardiomyocytes on rigid culture substrates show a progressive loss of rhythmic ...beating. Here, isolated embryonic cardiomyocytes cultured on a series of flexible substrates show that matrices that mimic the elasticity of the developing myocardial microenvironment are optimal for transmitting contractile work to the matrix and for promoting actomyosin striation and 1-Hz beating. On hard matrices that mechanically mimic a post-infarct fibrotic scar, cells overstrain themselves, lack striated myofibrils and stop beating; on very soft matrices, cells preserve contractile beating for days in culture but do very little work. Optimal matrix leads to a strain match between cell and matrix, and suggests dynamic differences in intracellular protein structures. A `cysteine shotgun' method of labeling the in situ proteome reveals differences in assembly or conformation of several abundant cytoskeletal proteins, including vimentin, filamin and myosin. Combined with recent results, which show that stem cell differentiation is also highly sensitive to matrix elasticity, the methods and analyses might be useful in the culture and assessment of cardiogenesis of both embryonic stem cells and induced pluripotent stem cells. The results described here also highlight the need for greater attention to fibrosis and mechanical microenvironments in cell therapy and development.
Twelve regulated cell death programs have been described. We review in detail the basic biology of nine including death receptor-mediated apoptosis, death receptor-mediated necrosis (necroptosis), ...mitochondrial-mediated apoptosis, mitochondrial-mediated necrosis, autophagy-dependent cell death, ferroptosis, pyroptosis, parthanatos, and immunogenic cell death. This is followed by a dissection of the roles of these cell death programs in the major cardiac syndromes: myocardial infarction and heart failure. The most important conclusion relevant to heart disease is that regulated forms of cardiomyocyte death play important roles in both myocardial infarction with reperfusion (ischemia/reperfusion) and heart failure. While a role for apoptosis in ischemia/reperfusion cannot be excluded, regulated forms of necrosis, through both death receptor and mitochondrial pathways, are critical. Ferroptosis and parthanatos are also likely important in ischemia/reperfusion, although it is unclear if these entities are functioning as independent death programs or as amplification mechanisms for necrotic cell death. Pyroptosis may also contribute to ischemia/reperfusion injury, but potentially through effects in non-cardiomyocytes. Cardiomyocyte loss through apoptosis and necrosis is also an important component in the pathogenesis of heart failure and is mediated by both death receptor and mitochondrial signaling. Roles for immunogenic cell death in cardiac disease remain to be defined but merit study in this era of immune checkpoint cancer therapy. Biology-based approaches to inhibit cell death in the various cardiac syndromes are also discussed.
Left ventricular non-compaction cardiomyopathy Towbin, Jeffrey A, Dr; Lorts, Angela, MD; Jefferies, John Lynn, MD
The Lancet (British edition),
08/2015, Letnik:
386, Številka:
9995
Journal Article
Recenzirano
Summary Left ventricular non-compaction, the most recently classified form of cardiomyopathy, is characterised by abnormal trabeculations in the left ventricle, most frequently at the apex. It can be ...associated with left ventricular dilation or hypertrophy, systolic or diastolic dysfunction, or both, or various forms of congenital heart disease. Affected individuals are at risk of left or right ventricular failure, or both. Heart failure symptoms can be induced by exercise or be persistent at rest, but many patients are asymptomatic. Patients on chronic treatment for compensated heart failure sometimes present acutely with decompensated heart failure. Other life-threatening risks of left ventricular non-compaction are ventricular arrhythmias or complete atrioventricular block, presenting clinically as syncope, and sudden death. Genetic inheritance arises in at least 30–50% of patients, and several genes that cause left ventricular non-compaction have been identified. These genes seem generally to encode sarcomeric (contractile apparatus) or cytoskeletal proteins, although, in the case of left ventricular non-compaction with congenital heart disease, disturbance of the NOTCH signalling pathway seems part of a final common pathway for this form of the disease. Disrupted mitochondrial function and metabolic abnormalities have a causal role too. Treatments focus on improvement of cardiac efficiency and reduction of mechanical stress in patients with systolic dysfunction. Further, treatment of arrhythmia and implantation of an automatic implantable cardioverter-defibrillator for prevention of sudden death are mainstays of therapy when deemed necessary and appropriate. Patients with left ventricular non-compaction and congenital heart disease often need surgical or catheter-based interventions. Despite progress in diagnosis and treatment in the past 10 years, understanding of the disorder and outcomes need to be improved.
Left ventricular noncompaction (LVNC) describes a ventricular wall anatomy characterized by prominent left ventricular (LV) trabeculae, a thin compacted layer, and deep intertrabecular recesses. ...Individual variability is extreme, and trabeculae represent a sort of individual "cardioprinting." By itself, the diagnosis of LVNC does not coincide with that of a "cardiomyopathy" because it can be observed in healthy subjects with normal LV size and function, and it can be acquired and is reversible. Rarely, LVNC is intrinsically part of a cardiomyopathy; the paradigmatic examples are infantile tafazzinopathies. When associated with LV dilation and dysfunction, hypertrophy, or congenital heart disease, the genetic cause may overlap. The prevalence of LVNC in healthy athletes, its possible reversibility, and increasing diagnosis in healthy subjects suggests cautious use of the term LVNC cardiomyopathy, which describes the morphology but not the functional profile of the cardiomyopathy.
Cellular senescence, a stress-induced irreversible growth arrest often characterized by expression of p16(Ink4a) (encoded by the Ink4a/Arf locus, also known as Cdkn2a) and a distinctive secretory ...phenotype, prevents the proliferation of preneoplastic cells and has beneficial roles in tissue remodelling during embryogenesis and wound healing. Senescent cells accumulate in various tissues and organs over time, and have been speculated to have a role in ageing. To explore the physiological relevance and consequences of naturally occurring senescent cells, here we use a previously established transgene, INK-ATTAC, to induce apoptosis in p16(Ink4a)-expressing cells of wild-type mice by injection of AP20187 twice a week starting at one year of age. We show that compared to vehicle alone, AP20187 treatment extended median lifespan in both male and female mice of two distinct genetic backgrounds. The clearance of p16(Ink4a)-positive cells delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects, including kidney, heart and fat, where clearance preserved the functionality of glomeruli, cardio-protective KATP channels and adipocytes, respectively. Thus, p16(Ink4a)-positive cells that accumulate during adulthood negatively influence lifespan and promote age-dependent changes in several organs, and their therapeutic removal may be an attractive approach to extend healthy lifespan.
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.
Systemic light chain amyloidosis (AL) is a life-threatening disease caused by aggregation and deposition of monoclonal immunoglobulin light chains (LC) in target organs. Severity of heart ...involvement is the most important factor determining prognosis. Here, we report the 4.0 Å resolution cryo-electron microscopy map and molecular model of amyloid fibrils extracted from the heart of an AL amyloidosis patient with severe amyloid cardiomyopathy. The helical fibrils are composed of a single protofilament, showing typical 4.9 Å stacking and cross-β architecture. Two distinct polypeptide stretches (total of 77 residues) from the LC variable domain (V
) fit the fibril density. Despite V
high sequence variability, residues stabilizing the fibril core are conserved through different cardiotoxic V
, highlighting structural motifs that may be common to misfolding-prone LCs. Our data shed light on the architecture of LC amyloids, correlate amino acid sequences with fibril assembly, providing the grounds for development of innovative medicines.
Myocardial infarction is a leading cause of death worldwide
. Although advances have been made in acute treatment, an incomplete understanding of remodelling processes has limited the effectiveness ...of therapies to reduce late-stage mortality
. Here we generate an integrative high-resolution map of human cardiac remodelling after myocardial infarction using single-cell gene expression, chromatin accessibility and spatial transcriptomic profiling of multiple physiological zones at distinct time points in myocardium from patients with myocardial infarction and controls. Multi-modal data integration enabled us to evaluate cardiac cell-type compositions at increased resolution, yielding insights into changes of the cardiac transcriptome and epigenome through the identification of distinct tissue structures of injury, repair and remodelling. We identified and validated disease-specific cardiac cell states of major cell types and analysed them in their spatial context, evaluating their dependency on other cell types. Our data elucidate the molecular principles of human myocardial tissue organization, recapitulating a gradual cardiomyocyte and myeloid continuum following ischaemic injury. In sum, our study provides an integrative molecular map of human myocardial infarction, represents an essential reference for the field and paves the way for advanced mechanistic and therapeutic studies of cardiac disease.
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