The Diagnosis and Evaluation of Dilated Cardiomyopathy

Japp, Alan G.; Gulati, Ankur; Cook, Stuart A.; Cowie, Martin R.; Prasad, Sanjay K.

doi:10.1016/j.jacc.2016.03.590

Cited by 370 publications

(287 citation statements)

References 69 publications

(32 reference statements)

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“…Heart rate was significantly decreased in Med12cKO mice by P7 and remained lower throughout adulthood ( Figure 1F ) in females significantly decreased cardiac function to nearly the same degree as in male Med12cKO mice (Supplemental Figure 1, B and C, and Supplemental Table 1). DCM is characterized by ventricular chamber enlargement and cardiac dysfunction with no heart wall hypertrophy. In some cases, prominent fibrosis accompanies late-stage DCM (27). Masson's trichrome staining of adult male Med12cKO hearts demonstrated an increase in interstitial cardiac fibrosis (Figure 2A).…”

Section: Med12mentioning

confidence: 99%

MED12 regulates a transcriptional network of calcium-handling genes in the heart

Baskin¹,

Makarewich²,

DeLeon³

et al. 2017

JCI Insight

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IntroductionHeart failure is the leading cause of death in the Western world (1). Defective calcium (Ca 2+ ) cycling, such as decreased Ca 2+ uptake in the sarcoplasmic reticulum (SR) or SR calcium leak occurs in failing hearts (2, 3), and genetic mutations in calcium-handling genes cause arrhythmias and dilated cardiomyopathy (DCM) (4). Altered expression of calcium-handling genes perturbs contractility (5-9), but relatively little is known about how the expression of these genes is coordinated in the heart.Mediator is a multiprotein complex of about 30 subunits that form the core and kinase submodules (10, 11). The kinase submodule, containing MED12, MED13, CDK8, and Cyclin C (12), can repress transcription through allosteric inhibition of RNA Pol II binding to the core submodule (13) but can also activate transcription by promoting Pol II recruitment to target genes via specific transcription factors (14). We previously demonstrated that cardiac MED13 regulates systemic energy homeostasis through signaling to extracardiac tissues (15,16), but the roles of the other kinase components in the heart have not been investigated.MED12, a component of the Mediator kinase submodule, is encoded on the X chromosome, and missense mutations are associated with a variety of X-linked disorders (17)(18)(19). Developmental signaling pathways and transcription factors converge on MED12, which acts as a transcriptional hub required to coordinate development (20)(21)(22)(23). Deletion of Med12 in Drosophila decreases expression of sonic hedgehog target genes and leads to defects in eye development (20), and mutations in Med12 in zebrafish disrupt SOX-mediated transcription during endoderm development (22). MED12 is also required for neuron development through its regulation of TBX2B in zebrafish (23). Med12 hypomorphic mutant mice die in utero due to various developmental defects (24, 25), but the function of MED12 in the heart has not yet been investigated.The Mediator complex regulates gene transcription by linking basal transcriptional machinery with DNA-bound transcription factors. The activity of the Mediator complex is mainly controlled by a kinase submodule that is composed of 4 proteins, including MED12. Although ubiquitously expressed, Mediator subunits can differentially regulate gene expression in a tissue-specific manner. Here, we report that MED12 is required for normal cardiac function, such that mice with conditional cardiac-specific deletion of MED12 display progressive dilated cardiomyopathy. Loss of MED12 perturbs expression of calcium-handling genes in the heart, consequently altering calcium cycling in cardiomyocytes and disrupting cardiac electrical activity. We identified transcription factors that regulate expression of calcium-handling genes that are downregulated in the heart in the absence of MED12, and we found that MED12 localizes to transcription factor consensus sequences within calcium-handling genes. We showed that MED12 interacts with one such transcription factor, MEF2, in cardiomyocytes an...

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Section: Med12mentioning

confidence: 99%

MED12 regulates a transcriptional network of calcium-handling genes in the heart

Baskin¹,

Makarewich²,

DeLeon³

et al. 2017

JCI Insight

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“…58,59 Doing genetic tests in family members of patients with DCM or muscular dystrophy may help to make an early diagnosis and eventually administer treatment to prevent myocardial fibrosis and remodeling. 5 The high cost of a transplant makes it necessary to look for other alternatives. In this regard, the use of stem cells has been proposed as a potential and innovative approach that promotes cardiac regeneration by replacing injured tissue.…”

Section: E) New Therapiesmentioning

confidence: 99%

Dilated cardiomyopathy and severe heart failure. An update for pediatricians

Bottner¹,

Fernández²,

Valenzuela³

et al. 2018

Arch Argent Pediatr

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Dilated cardiomyopathy is the main cause of heart failure leading to heart transplant. Its prognosis is variable and depends on the etiology, the patient's age at onset, and the severity. The management of dilated cardiomyopathy is aimed at minimizing symptoms and preventing disease progression; it requires a comprehensive screening for comorbidities and the prevention of complications to improve the overall status of these children and mitigate their prognosis. Here we present a review oriented at the multidisciplinary management that pediatricians should consider when seeing these patients.

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“…3,48,49,60 Some laboratory tests may help in differential diagnosis of genetic and nongenetic causes of DCM (Table 2). 3,48,49,60 Usually the diagnostic pathway is completed, at least, by the execution of a cardiac magnetic resonance (CMR) with late gadolinium enhancement (LGE) and 48-h ECG Holter monitoring.…”

Section: Dilated Phenotypementioning

confidence: 99%

Diagnosis of Cardiomyopathies: Tips and Tricks for Internists and General Practitioners

2017

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Cardiomyopathies are little known to internists and general practitioners (GPs), and not always able to arouse the interest of cardiologists. Probably, this happens because cardiomyopathies are perceived as rare and complex disorders, a prerogative of a few dedicated centers. This may partly explain why the diagnosis of cardiomyopathy is often missed and, consequently, why cardiomyopathies are largely underdiagnosed. Internists and general practitioners should have an interest in these conditions, because cardiomyopathies are not as rare as generally perceived, and because their complexity can be unravelled with knowledge and methodology. Cardiomyopathies are defined as myocardial disorders in which the heart is structurally and functionally abnormal in the absence of coronary artery disease or abnormal loading conditions. Irrespective of the cardiac imaging technique used, a limited number of phenotypes are defined based on ventricular morphology and function. These basic phenotypes include hypertrophic, dilated, restrictive and right ventricular arrhythmogenic cardiomyopathies. Aim of this review is to describe a simplified approach to the detection of the underlying causes of specific phenotypes. We will focus our attention on the basic phenotypes, presenting a diagnostic work-up and a suggestive clinical case for each phenotype.

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The Diagnosis and Evaluation of Dilated Cardiomyopathy

Cited by 370 publications

References 69 publications

MED12 regulates a transcriptional network of calcium-handling genes in the heart

MED12 regulates a transcriptional network of calcium-handling genes in the heart

Dilated cardiomyopathy and severe heart failure. An update for pediatricians

Diagnosis of Cardiomyopathies: Tips and Tricks for Internists and General Practitioners

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