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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,
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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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–
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Although this disorder can be transmitted as a recessive or . . .
AMP-activated protein kinase (AMPK) is a heterotrimeric enzyme that is expressed in most mammalian tissues including cardiac muscle. Among the multiple biological processes influenced by AMPK, ...regulation of fuel supply and energy-generating pathways in response to the metabolic needs of the organism is fundamental and likely accounts for the remarkable evolutionary conservation of this enzyme complex. By regulating the activity of acetyl–coenzyme A carboxylase, AMPK affects levels of malonyl–coenzyme A, a key energy regulator in the cell. AMPK is generally quiescent under normal conditions but is activated in response to hormonal signals and stresses sufficient to produce an increase in AMP/ATP ratio, such as hypoglycemia, strenuous exercise, anoxia, and ischemia. Once active, muscle AMPK enhances uptake and oxidative metabolism of fatty acids as well as increases glucose transport and glycolysis. Data from AMPK deficiency models suggest that AMPK activity might influence the pathophysiology and therapy of diabetes and increase heart tolerance to ischemia. Effects that are not as well understood include AMPK regulation of transcription. Different AMPK isoforms are found in distinct locations within the cell and have distinct functions in different tissues. A principal mode of AMPK activation is phosphorylation by upstream kinases (eg, LKB1). These kinases have a fundamental role in cell-cycle regulation and protein synthesis, suggesting involvement in a number of human disorders including cardiac hypertrophy, apoptosis, cancer, and atherosclerosis. The physiological role played by AMPK during health and disease is far from being clearly defined. Naturally occurring mutations affecting the nucleotide-sensing modules in the regulatory γ subunit of AMPK lead to enzyme dysregulation and inappropriate activation under resting conditions. Glycogen accumulation ensues, leading to human disease manifesting as cardiac hypertrophy, accessory atrioventricular connections, and degeneration of the physiological conduction system. Whether AMPK is a key participant or bystander in other disease states and whether its selective manipulation may significantly benefit these conditions remain important questions.
Dominant mutations in sarcomere proteins such as the myosin heavy chains (MHC) are the leading genetic causes of human hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy. We found that ...expression of the HCM-causing cardiac MHC gene (Myh6) R403Q mutation in mice can be selectively silenced by an RNA interference (RNAi) cassette delivered by an adeno-associated virus vector. RNAi-transduced MHC⁴⁰³ / ⁺ mice developed neither hypertrophy nor myocardial fibrosis, the pathologic manifestations of HCM, for at least 6 months. Because inhibition of HCM was achieved by only a 25% reduction in the levels of the mutant transcripts, we suggest that the variable clinical phenotype in HCM patients reflects allele-specific expression and that partial silencing of mutant transcripts may have therapeutic benefit.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Congenital heart disease (CHD) is the most common congenital anomaly in newborn babies. Cardiac malformations have been produced in multiple experimental animal models, by perturbing selected ...molecules that function in the developmental pathways involved in myocyte specification, differentiation, or cardiac morphogenesis. In contrast, the precise genetic, epigenetic, or environmental basis for these perturbations in humans remains poorly understood. Over the past few decades, researchers have tried to bridge this knowledge gap through conventional genome-wide analyses of rare Mendelian CHD families, and by sequencing candidate genes in CHD cohorts. Although yielding few, usually highly penetrant, disease gene mutations, these discoveries provided 3 notable insights. First, human CHD mutations impact a heterogeneous set of molecules that orchestrate cardiac development. Second, CHD mutations often alter gene/protein dosage. Third, identical pathogenic CHD mutations cause a variety of distinct malformations, implying that higher order interactions account for particular CHD phenotypes. The advent of contemporary genomic technologies including single nucleotide polymorphism arrays, next-generation sequencing, and copy number variant platforms are accelerating the discovery of genetic causes of CHD. Importantly, these approaches enable study of sporadic cases, the most common presentation of CHD. Emerging results from ongoing genomic efforts have validated earlier observations learned from the monogenic CHD families. In this review, we explore how continued use of these technologies and integration of systems biology is expected to expand our understanding of the genetic architecture of CHD.
Mobile genetic elements threaten genome integrity in all organisms. RDE-3 (also known as MUT-2) is a ribonucleotidyltransferase that is required for transposon silencing and RNA interference in ...Caenorhabditis elegans
. When tethered to RNAs in heterologous expression systems, RDE-3 can add long stretches of alternating non-templated uridine (U) and guanosine (G) ribonucleotides to the 3' termini of these RNAs (designated poly(UG) or pUG tails)
. Here we show that, in its natural context in C. elegans, RDE-3 adds pUG tails to targets of RNA interference, as well as to transposon RNAs. RNA fragments attached to pUG tails with more than 16 perfectly alternating 3' U and G nucleotides become gene-silencing agents. pUG tails promote gene silencing by recruiting RNA-dependent RNA polymerases, which use pUG-tailed RNAs (pUG RNAs) as templates to synthesize small interfering RNAs (siRNAs). Our results show that cycles of pUG RNA-templated siRNA synthesis and siRNA-directed pUG RNA biogenesis underlie double-stranded-RNA-directed transgenerational epigenetic inheritance in the C. elegans germline. We speculate that this pUG RNA-siRNA silencing loop enables parents to inoculate progeny against the expression of unwanted or parasitic genetic elements.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Peripartum cardiomyopathy (PPCM) occurs in ≈1:2000 deliveries in the United States and worldwide. The genetic underpinnings of PPCM remain poorly defined. Approximately 10% of women with PPCM harbor ...truncating variants in
(TTNtvs). Whether mutations in other genes can predispose to PPCM is not known. It is also not known if the presence of TTNtvs predicts clinical presentation or outcomes. Nor is it known if the prevalence of TTNtvs differs in women with PPCM and preeclampsia, the strongest risk factor for PPCM.
Women with PPCM were retrospectively identified from several US and international academic centers, and clinical information and DNA samples were acquired. Next-generation sequencing was performed on 67 genes, including
, and evaluated for burden of truncating and missense variants. The impact of TTNtvs on the severity of clinical presentation, and on clinical outcomes, was evaluated.
Four hundred sixty-nine women met inclusion criteria. Of the women with PPCM, 10.4% bore TTNtvs (odds ratio=9.4 compared with 1.2% in the reference population; Bonferroni-corrected
*=1.2×10
). We additionally identified overrepresentation of truncating variants in FLNC (odds ratio=24.8,
*=7.0×10
), DSP (odds ratio=14.9,
*=1.0×10
), and BAG3 (odds ratio=53.1,
*=0.02), genes not previously associated with PPCM. This profile is highly similar to that found in nonischemic dilated cardiomyopathy. Women with TTNtvs had lower left ventricular ejection fraction on presentation than did women without TTNtvs (23.5% versus 29%,
=2.5×10
), but did not differ significantly in timing of presentation after delivery, in prevalence of preeclampsia, or in rates of clinical recovery.
This study provides the first extensive genetic and phenotypic landscape of PPCM and demonstrates that predisposition to heart failure is an important risk factor for PPCM. The work reveals a degree of genetic similarity between PPCM and dilated cardiomyopathy, suggesting that gene-specific therapeutic approaches being developed for dilated cardiomyopathy may also apply to PPCM, and that approaches to genetic testing in PPCM should mirror those taken in dilated cardiomyopathy. Last, the clarification of genotype/phenotype associations has important implications for genetic counseling.
Cells of the adult human heart Litviňuková, Monika; Talavera-López, Carlos; Maatz, Henrike ...
Nature,
12/2020, Volume:
588, Issue:
7838
Journal Article
Peer reviewed
Open access
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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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Genome sequencing can identify individuals in the general population who harbor rare coding variants in genes for Mendelian disorders and who may consequently have increased disease risk. Previous ...studies of rare variants in phenotypically extreme individuals display ascertainment bias and may demonstrate inflated effect-size estimates. We sequenced seven genes for maturity-onset diabetes of the young (MODY) in well-phenotyped population samples (n = 4,003). We filtered rare variants according to two prediction criteria for disease-causing mutations: reported previously in MODY or satisfying stringent de novo thresholds (rare, conserved and protein damaging). Approximately 1.5% and 0.5% of randomly selected individuals from the Framingham and Jackson Heart Studies, respectively, carry variants from these two classes. However, the vast majority of carriers remain euglycemic through middle age. Accurate estimates of variant effect sizes from population-based sequencing are needed to avoid falsely predicting a substantial fraction of individuals as being at risk for MODY or other Mendelian diseases.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Precision medicine promises to dramatically improve patient outcomes and reduce health care costs through a shift in focus from disease treatment to prevention and individualized therapies. For ...families with inherited cardiomyopathies, efforts to date have been directed toward discovery and functional characterization of single disease-causing variants. With advances in sequencing, the cataloging of personal genetic variation has been expedited, providing improved insights into the key importance of the genes in which variants occur. These advances have propelled seminal opportunities for successful variant-targeted disease-reversing therapy. New challenges have also emerged-particularly interpretation of the rapidly rising numbers of "variants of unknown significance." For treatments based on patient genotype to be feasible on a wider scale, these obstacles need to be overcome. Here the authors focus on genetics of dilated cardiomyopathy and provide a roadmap for implementing genomic information into future patient management.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Variants in SCN10A, which encodes a voltage-gated sodium channel, are associated with alterations of cardiac conduction parameters and the cardiac rhythm disorder Brugada syndrome; however, it is ...unclear how SCN10A variants promote dysfunctional cardiac conduction. Here we showed by high-resolution 4C-seq analysis of the Scn10a-Scn5a locus in murine heart tissue that a cardiac enhancer located in Scn10a, encompassing SCN10A functional variant rs6801957, interacts with the promoter of Scn5a, a sodium channel-encoding gene that is critical for cardiac conduction. We observed that SCN5A transcript levels were several orders of magnitude higher than SCN10A transcript levels in both adult human and mouse heart tissue. Analysis of BAC transgenic mouse strains harboring an engineered deletion of the enhancer within Scn10a revealed that the enhancer was essential for Scn5a expression in cardiac tissue. Furthermore, the common SCN10A variant rs6801957 modulated Scn5a expression in the heart. In humans, the SCN10A variant rs6801957, which correlated with slowed conduction, was associated with reduced SCN5A expression. These observations establish a genomic mechanism for how a common genetic variation at SCN10A influences cardiac physiology and predisposes to arrhythmia.
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