Hypertrophic cardiomyopathy (HCM) is a complex disease characterized by thickening of the cardiac muscle. Common symptoms include chest pain, shortness of breath, palpitations, fatigue and syncope ...(fainting), which are often confused for other conditions. Clinical treatment focuses on the relief of symptoms with medical therapies, which provide adequate to more variable symptomatic relief. Patients may experience more severe complications that require surgical intervention, such as implantable cardioverter-defibrillator therapy or septal myectomy. Despite the potential impact on quality of life, the humanistic burden of HCM is not well established. Here, we present four patient testimonials that highlight challenges faced by patients and clinicians in diagnosing HCM and managing symptoms. These testimonials provide valuable information on the spectrum and expression of HCM across generations. Such testimonials can better inform disease diagnosis and monitoring, maximizing quality of life and improving disease outcome.
This study shows that mutations in genes previously implicated in adult-onset cardiomyopathy cause 49% of presumed sporadic cases and 64% of familial cases of childhood-onset cardiac hypertrophy. ...These findings indicate that genetic analyses and family evaluations are warranted when childhood-onset hypertrophy is diagnosed.
Mutations in genes previously implicated in adult-onset cardiomyopathy cause 49% of presumed sporadic cases and 64% of familial cases of childhood-onset cardiac hypertrophy.
The diagnosis of childhood cardiomyopathies can be prompted by abnormal physical findings that occur without symptoms or by life-threatening events, including sudden death, which is the presenting manifestation in 3.5% of affected children.
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Despite sophisticated medical management, rates of death and cardiac transplantation among children with symptomatic childhood-onset cardiomyopathy approach 40%.
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The early age at diagnosis and the striking differences in morbidity and mortality that distinguish childhood cardiomyopathies from adult-onset cardiomyopathies have been interpreted to indicate distinct causes of these pathologic conditions.
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Adult-onset hypertrophic cardiomyopathy is a prevalent genetic condition caused by inherited or new mutations in . . .
We report a 5‐generation family with phenotypically diverse neurodegenerative disease including relentlessly progressive choreoathetoid movements, dysarthria, dysphagia, spastic paralysis, and ...behavioral dementia in descendants of a 67‐year‐old woman with amyotrophic lateral sclerosis. Disease onset varied with gender, occurring in male children and adult women. Exome sequence analyses revealed a novel mutation (c.1490C>T, p.P497L) in the ubiquilin‐2 gene (UBQLN2) with X‐linked inheritance in all studied affected individuals. As ubiquilin‐2–positive inclusions were identified in brain, we suggest that mutant peptide predisposes to protein misfolding and accumulation. Our findings expand the spectrum of neurodegenerative phenotypes caused by UBQLN2 mutations. ANN NEUROL 2014;75:793–798
Dilated cardiomyopathy, a myocardial disorder characterized by dilatation of the cardiac chambers and impaired systolic contraction, is a major cause of congestive heart failure worldwide. Despite ...advances in therapy, mortality due to dilated cardiomyopathy remains high.
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Dilated cardiomyopathy can result from coronary artery disease, myocarditis, or systemic diseases but can also result from a primary (idiopathic) disorder of the myocyte's contractile apparatus, cytoskeleton, or both.
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The cellular and molecular basis of primary dilated cardiomyopathy remains poorly understood.
Approximately one third of cases of idiopathic dilated cardiomyopathy are inherited.
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Although this disorder can be transmitted as a recessive or . . .
Dilated cardiomyopathy is a relatively common but poorly understood group of disorders that result in heart failure and premature death.
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Epidemiologic data indicate that 36.5 in 100,000 people have ...dilated cardiomyopathy. Although ischemic, toxic, metabolic, or infectious causes are recognized, inherited gene defects account for 25 to 30 percent of cases.
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Of the five mutated genes known to cause dilated cardiomyopathy, four are often associated with additional clinical manifestations. Among these, defects in the cytoskeletal proteins dystrophin,
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desmin,
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and tafazzin
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produce both myocardial and skeletal-muscle dysfunction, whereas lamin A/C mutations
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cause ventricular dysfunction with conduction-system disease. Familial . . .
Sarcomere mutations cause both dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM); however, the steps leading from mutation to disease are not well described. By studying mutation ...carriers before a clinical diagnosis develops, we characterize the early manifestations of sarcomere mutations in DCM and investigate how these manifestations differ from sarcomere mutations associated with HCM.
Sixty-two genotyped individuals in families with sarcomeric DCM underwent clinical evaluation including strain echocardiography. The group included 12 subclinical DCM mutation carriers with normal cardiac dimensions and left ventricular ejection fraction (LVEF ≥55%), 21 overt DCM subjects, and 29 related mutation (-) normal controls. Results were compared with a previously characterized cohort of 60 subclinical HCM subjects (sarcomere mutation carriers without left ventricular hypertrophy). Systolic myocardial tissue velocity, longitudinal, circumferential, and radial strain, and longitudinal and radial strain rate were reduced by 10%-23% in subclinical DCM mutation carriers compared with controls (P<0.001 for all comparisons), after adjusting for age and family relations. No significant differences in diastolic parameters were identified comparing the subclinical and control cohorts. The opposite pattern of contractile abnormalities with reduced diastolic but preserved systolic function was seen in subclinical HCM.
Subtle abnormalities in systolic function are present in subclinical DCM mutation carriers, despite normal left ventricular size and ejection fraction. In contrast, impaired relaxation and preserved systolic function appear to be the predominant early manifestations of sarcomere mutations that lead to HCM. These findings support the theory that the mutation's intrinsic impact on sarcomere function influences whether a dilated or hypertrophic phenotype develops.
The Ser358Leu mutation in TMEM43, encoding an inner nuclear membrane protein, has been implicated in arrhythmogenic right ventricular cardiomyopathy (ARVC). The pathogenetic mechanisms of this ...mutation are poorly understood.
To determine the frequency of TMEM43 mutations as a cause of ARVC, we screened 11 ARVC families for mutations in TMEM43 and five desmosomal genes previously implicated in the disease. Functional studies were performed in COS-7 cells transfected with wildtype, mutant, and 1:2 wildtype:mutant TMEM43 to determine the effect of the Ser358Leu mutation on the stability and cellular localization of TMEM43 and other nuclear envelope and desmosomal proteins, assessed by solubility assays and immunofluorescence imaging. mRNA expression was assessed of genes potentially affected by dysfunction of the nuclear lamina.
Three novel mutations in previously documented desmosomal genes, but no mutations in TMEM43, were identified. COS-7 cells transfected with mutant TMEM43 exhibited no change in desmosomal stability. Stability and nuclear membrane localization of mutant TMEM43 and of lamin B and emerin were normal. Mutant TMEM43 did not alter the expression of genes located on chromosome 13, previously implicated in nuclear envelope protein mutations leading to skeletal muscular dystrophies.
Mutant TMEM43 exhibits normal cellular localization and does not disrupt integrity and localization of other nuclear envelope and desmosomal proteins. The pathogenetic role of TMEM43 mutations in ARVC remains uncertain.
Cells of the adult human heart Litviňuková, Monika; Talavera-López, Carlos; Maatz, Henrike ...
Nature,
12/2020, Letnik:
588, Številka:
7838
Journal Article
Recenzirano
Odprti dostop
Cardiovascular disease is the leading cause of death worldwide. Advanced insights into disease mechanisms and therapeutic strategies require a deeper understanding of the molecular processes involved ...in the healthy heart. Knowledge of the full repertoire of cardiac cells and their gene expression profiles is a fundamental first step in this endeavour. Here, using state-of-the-art analyses of large-scale single-cell and single-nucleus transcriptomes, we characterize six anatomical adult heart regions. Our results highlight the cellular heterogeneity of cardiomyocytes, pericytes and fibroblasts, and reveal distinct atrial and ventricular subsets of cells with diverse developmental origins and specialized properties. We define the complexity of the cardiac vasculature and its changes along the arterio-venous axis. In the immune compartment, we identify cardiac-resident macrophages with inflammatory and protective transcriptional signatures. Furthermore, analyses of cell-to-cell interactions highlight different networks of macrophages, fibroblasts and cardiomyocytes between atria and ventricles that are distinct from those of skeletal muscle. Our human cardiac cell atlas improves our understanding of the human heart and provides a valuable reference for future studies.
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