Evolution of viral myocarditis to dilated cardiomyopathy (DCM)represents a delicate balance between host innate immunity and T-cell acquired immunity. IRF-9 is a key member of a transcription factor family that regulates type I interferon (IFN) production, critical for innate antiviral protection. RESULTS: IRF9-/- mice showed dramatically increased mortality compared to the wildtype littermates (0% WT vs 72% IRF-9-/- on day 14, P<0.0001). On day 42, there was less cardiac hypertrophy and inflammation in IRF-9-/- mice compared to WT controls (p<0.05). Onn day 42 there was a dramatic increase in the number of cytotoxic and helper T-Cells in the wild-type mice that was not observed in the IRF-9-/- spleens (p<0.05). CONCLUSIONS: These data suggest a novel dual role of IRF-9 in not only regulating interferon in acute stage of viral infection in myocarditis, but also late acquired immunity activation, including CD4/8 populations, contributing to the development of chronic cardiomyopathy.

Thesis (Ph.D. in Human Medical Genetics) -- University of Colorado Denver, 2008. / Typescript. Includes bibliographical references (leaves 140-146).

Thesis (Ph.D. in Clinical Sciences) -- University of Colorado at Denver and Health Sciences Center, 2005. / Typescript. Includes bibliographical references (leaves 134-149). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;

Abstract Hereditary hemochromatosis (HH) is a common autosomal recessive disorder estimated to affect one out of every 250–400 Caucasian individuals. It is a disorder of iron metabolism, in which excessive iron accumulation in the body may induce serious clinical manifestations (e.g. liver cirrhosis, hepatocellular carcinoma, diabetes, and cardiomyopathy). HH is caused by mutations in the HFE gene, and HFE genotyping thus enables early diagnosis of the disease and detection of the individuals at risk for HH. HFE mutations have also been proposed to predispose to certain other diseases, such as various hematological malignancies and cardiomyopathy. The present evaluation of the clinical utility and outcome of HFE genotyping in search for HH was based on data obtained from 137 subjects referred for HFE mutation analysis during the years 1999–2001. The C282Y and H63D mutations were determined for each subject. HFE genotyping was also used to examine the association between HFE mutations with various hematological disorders and idiopathic dilated cardiomyopathy (IDCM). The C282Y and H63D mutations were determined from 232 patients with various hematological disorders and the C282Y, H63D, and S65C mutations from 91 patients with IDCM and 102 control subjects. High frequencies of C282Y homozygotes (16.8%) and C282Y/H63D compound heterozygotes (5.1%) were found among the subjects referred for HFE genotyping, and the rate of positive findings for HH increased steadily over the years 1999–2001. The frequencies of HFE mutations did not differ significantly in patients with various hematological disorders and IDCM compared to controls. At the end of the follow-up period, left ventricular end-diastolic diameter (LVEDD) was significantly higher in IDCM patients carrying the C282Y mutation than in those without this mutation (p = 0.037). The present study supports active testing for the HFE gene mutations C282Y and H63D in public health care. Serum transferrin saturation is considered the most useful test for selecting subjects for such analysis. Although increasing numbers of HH cases are recognized by physicians, it may still be an underdiagnosed disease. HFE mutations do not seem to significantly increase the risk for various hematological disorders or IDCM. The C282Y mutation may, nevertheless, mediate the progression of IDCM by modifying LV dilation and remodeling.

The E2F family of transcription factors regulate cellular growth, death and differentiation, but their role in cardiac biology remains to be fully explored. We hypothesized that the balance of the E2F pathway would determine cardiac development and function. We provide evidence for this via modulation of the E2F6 repressor, in a transgenic (Tg) mouse model. Targeted expression of E2F6 in the heart led to dilated cardiomyopathy (DCM) and death. Microarray analysis revealed that E2F responsive pathways were activated in Tg mice. Furthermore, we found that E2F6 and YY1 (E2F-co-factor) were translocated to the nucleus in Tg mice, providing a potential mechanism for the observed transcriptional activation. We also observed a marked decrease of Connexin43 protein in the myocardium, and reduced atrial conductivity in Tg mice which may lead to reduced cardiac function. The data demonstrates a novel role for E2F pathway outside of cell cycle control in the heart.

Cardiomyopathies are the most common form of genetic disorders featuring primary abnormalities in the structure and function of the heart. Over the past few decades, tremendous progress has been made in elucidating the genetic basis of cardiac disorders. However, the development of specific and effective therapies remains largely limited due to the lack of suitable therapeutic targets. Nucleoli are polyfunctional subnuclear domains that are heavily involved in ribosomal RNA production. Recent studies have identified nucleolar structure perturbations and functional defects associated with different types of cardiomyopathies. Additionally, several mutations have been identified in several ribosomal genes that are linked to cardiomyopathy in human patients. We previously identified a nucleolar DEAD-box RNA helicase, DDX27, as a critical regulator of myogenesis. This study aimed to investigate the role of ddx27 deficiency in cardiac muscle and expand the understanding of DDX27 mediated pathways that are involved in myopathies. In this study, we used zebrafish models to investigate ddx27 deficiency in cardiac muscle. Phenotype characterization, cardiac function testing, transmission electron microscopy and histological analysis of ddx27 mutants revealed corresponding dilated cardiomyopathy and skeletal muscle hypotrophy. Furthermore, knockdown of DDX27 ortholog, Rs1, in cardiac muscle was fatal for Drosophila larvae. However, other tissues (i.e., neural or gastrointestinal) were unaffected suggesting that abnormalities caused by Ddx27 deficiency are specific to cardiac and skeletal muscle. Immunofluorescence, northern blotting and polysomal profiling of ddx27 zebrafish myofibers revealed that DDX27 is necessary for preserving nucleolar architecture and ribosome biogenesis. Here we have shown that DDX27 is essential for normal function of cardiac and skeletal myogenic processes due to its critical role in ribosomal regulation. Additionally, we provide novel evidence for DdX27 deficiency contributing to dilated cardiomyopathy. Overall, the findings of this study provide further evidence for the role of RNA helicases, specifically DDX27, in cardiac and skeletal muscle pathogenesis as well as provide novel insight into the molecular pathways of therapeutic benefit for afflicted patients of these diseases. / 2022-06-04T00:00:00Z

Objectives: We sought to identify a novel gene for dilated cardiomyopathy (DCM). Background: DCM is a heritable, genetically heterogeneous disorder that remains idiopathic in the majority of patients. Familial cases provide an opportunity to discover unsuspected molecular bases of DCM, enabling pre-clinical risk detection. Methods: Two large families with autosomal-dominant DCM were studied. Genome-wide linkage analysis was used to identify a disease locus, followed by fine mapping and positional candidate gene sequencing. Mutation scanning was then performed in 278 unrelated subjects with idiopathic DCM, prospectively identified at the Mayo Clinic. Results: Overlapping loci for DCM were independently mapped to chromosome 10q25-q26. Deoxyribonucleic acid sequencing of affected individuals in each family revealed distinct heterozygous missense mutations in exon 9 of RBM20, encoding ribonucleic acid (RNA) binding motif protein 20. Comprehensive coding sequence analyses identified missense mutations clustered within this same exon in 6 additional DCM families. Mutations segregated with DCM (peak composite logarithm of the odds score >11.49), were absent in 480 control samples, and altered residues within a highly conserved arginine/serine (RS)-rich region. Expression of RBM20 messenger RNA was confirmed in human heart tissue. Conclusions: Our findings establish RBM20 as a DCM gene and reveal a mutation hotspot in the RS domain. RBM20 is preferentially expressed in the heart and encodes motifs prototypical of spliceosome proteins that regulate alternative pre-messenger RNA splicing, thus implicating a functionally distinct gene in human cardiomyopathy. RBM20 mutations are associated with young age at diagnosis, end-stage heart failure, and high mortality.

No description available.

No description available.

Introduction: Takotsubo cardiomyopathy or stress cardiomyopathy is a syndrome of transient left ventricular (LV) dysfunction mimicking myocardial infarction, but lacking obstruction of coronary artery disease (CAD) or acute plaque rupture. A characteristic differentiation from CAD is that regional motional abnormality extends beyond a territory perfused with a single epicardial coronary artery. Clinically, it is characterized by apical ballooning of the LV due to due to depression of mid and apical segments, with hyperkinesis of cardiac basal walls. Women are affected more than men, predominantly in the postmenopausal age. Case Report: A 54-year-old Caucasian female with a history of COPD, hypertension, uncontrolled diabetes mellitus, hyperlipidemia, depression and ongoing tobacco use presented with complaints of worsening shortness of breath two days prior to admission. She denied chest pain, worsened cough, palpitations, nausea or vomiting. On examination, she was in distress and anxious, with labored breathing. Upon examining the chest, decreased air entry was present in both lung fields with bibasilar wheezing. Initial lab tests showed mild respiratory acidosis, with pH of 7.24, pCO2 of 47.4 and pO2 of 65. Troponins on the day of admission was Soon after admission, she started complaining of severe right neck pain. Repeat EKG revealed localized lateral J point, anteroseptal q waves and 4mm ST-segment elevation in leads V3 and V4 reciprocal changes and without chest pain. Repeat troponins were slightly elevated to 0.42 ng/ml and CK-MB was elevated to 20.2 ng/ml. A transthoracic echocardiogram showed regional abnormalities in left ventricle with the apex, mid to distal septum and the anterior part of septum was akinetic. Discussion: Takotsubo cardiomyopathy presents in 1 to 2 percent of troponin-positive acute coronary syndrome (ACS) with various clinical manifestations and various outcomes. Some patients have favorable outcomes based on their clinical performance and extent of cardiac muscle involvement. As in the case we presented, this syndrome can be entirely idiopathic, without a definitive underlying cause. Supportive management while hospitalized and early identification of complications improve the prognosis.