32 research outputs found

    Altered Chromosomal Positioning, Compaction, and Gene Expression with a Lamin A/C Gene Mutation

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    Lamins A and C, encoded by the LMNA gene, are filamentous proteins that form the core scaffold of the nuclear lamina. Dominant LMNA gene mutations cause multiple human diseases including cardiac and skeletal myopathies. The nuclear lamina is thought to regulate gene expression by its direct interaction with chromatin. LMNA gene mutations may mediate disease by disrupting normal gene expression.To investigate the hypothesis that mutant lamin A/C changes the lamina's ability to interact with chromatin, we studied gene misexpression resulting from the cardiomyopathic LMNA E161K mutation and correlated this with changes in chromosome positioning. We identified clusters of misexpressed genes and examined the nuclear positioning of two such genomic clusters, each harboring genes relevant to striated muscle disease including LMO7 and MBNL2. Both gene clusters were found to be more centrally positioned in LMNA-mutant nuclei. Additionally, these loci were less compacted. In LMNA mutant heart and fibroblasts, we found that chromosome 13 had a disproportionately high fraction of misexpressed genes. Using three-dimensional fluorescence in situ hybridization we found that the entire territory of chromosome 13 was displaced towards the center of the nucleus in LMNA mutant fibroblasts. Additional cardiomyopathic LMNA gene mutations were also shown to have abnormal positioning of chromosome 13, although in the opposite direction.These data support a model in which LMNA mutations perturb the intranuclear positioning and compaction of chromosomal domains and provide a mechanism by which gene expression may be altered

    Cardiovascular health and particulate vehicular emissions: a critical evaluation of the evidence

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    A major public health goal is to determine linkages between specific pollution sources and adverse health outcomes. This paper provides an integrative evaluation of the database examining effects of vehicular emissions, such as black carbon (BC), carbonaceous gasses, and ultrafine PM, on cardiovascular (CV) morbidity and mortality. Less than a decade ago, few epidemiological studies had examined effects of traffic emissions specifically on these health endpoints. In 2002, the first of many studies emerged finding significantly higher risks of CV morbidity and mortality for people living in close proximity to major roadways, vs. those living further away. Abundant epidemiological studies now link exposure to vehicular emissions, characterized in many different ways, with CV health endpoints such as cardiopulmonary and ischemic heart disease and circulatory-disease-associated mortality; incidence of coronary artery disease; acute myocardial infarction; survival after heart failure; emergency CV hospital admissions; and markers of atherosclerosis. We identify numerous in vitro, in vivo, and human panel studies elucidating mechanisms which could explain many of these cardiovascular morbidity and mortality associations. These include: oxidative stress, inflammation, lipoperoxidation and atherosclerosis, change in heart rate variability (HRV), arrhythmias, ST-segment depression, and changes in vascular function (such as brachial arterial caliber and blood pressure). Panel studies with accurate exposure information, examining effects of ambient components of vehicular emissions on susceptible human subjects, appear to confirm these mechanisms. Together, this body of evidence supports biological mechanisms which can explain the various CV epidemiological findings. Based upon these studies, the research base suggests that vehicular emissions are a major environmental cause of cardiovascular mortality and morbidity in the United States. As a means to reduce the public health consequences of such emissions, it may be desirable to promulgate a black carbon (BC) PM2.5 standard under the National Ambient Air Quality Standards, which would apply to both on and off-road diesels. Two specific critical research needs are identified. One is to continue research on health effects of vehicular emissions, gaseous as well as particulate. The second is to utilize identical or nearly identical research designs in studies using accurate exposure metrics to determine whether other major PM pollutant sources and types may also underlie the specific health effects found in this evaluation for vehicular emissions

    [Value of tomoscintigraphy with Fourier analysis in the diagnosis of arrhythmogenic right ventricular cardiomyopathy].

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    International audienceECG gated blood pool tomography has been performed in sixteen patients with right ventricular arrhythmias in whom the diagnosis of arrhythmogenic right ventricular cardiomyopathy was made based on the finding of abnormalities on contrast angiography. They were compared both to control subjects and to patients with primary dilated cardiomyopathy. Thick slices of ventricles were obtained throughout the cardiac cycle in three orthogonal planes: horizontal long axis and short axis thick slices for analysis of right and left ventricular regional wall motion abnormalities and analysis of the spread of the contraction by means of Fourier phase imaging, vertical long axis slices (one for each ventricle) for ejection fractions, because of easy and reproducible determination of valvular planes and analysis of all right ventricular segments, especially the pulmonary infundibulum. Five typical right ventricular abnormalities were seen: decreased ejection fraction (32 +/- 15% vs 55 +/- 3% in control; p < 0.001), increased diameter (ratio of right to left diameters = 1.2 +/- 0.3 vs 0.9 +/- 0.1; p < 0.01), global delayed contraction versus that of the left ventricle (22 +/- 20 degrees vs -2 +/- 6%; p < 0.01), increased dispersion of contraction (32 +/- 16 degrees vs 13 +/- 4 degrees; p < 0.01) and presence of segments with decreased and/or delayed contraction. Right ventricular disease was observed in all the patients: localized form (56%), diffused form (44%). This method provides accurate functional data for diagnosis and follow-up of patients. In future, this wall motion evaluation method may replace planar nuclear angiography as myocardial SPECT have replaced myocardial planar scintigraphy

    [Evaluation after 20 years of a case of Takayasu's disease that presented with aortic regurgitation].

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    International audienceTakayasu's disease is a segmental multifocal affection of medium and large arteries. The diagnosis is based on the association of stenotic and aneurismal lesions of the aorta and its branches secondary to an inflammatory infiltration of the media and adventitia. Cases of aortic regurgitation associated with aneurismal dilatation of the ascending aorta as the presenting features of Takayasu's disease, as in this case, are rare. Histological examination of the aortic wall may help establish the diagnosis by showing signs of aortitis. The other usual arterial lesions are sometimes missing at the initial phase of the disease. A late histological diagnosis may be difficult as the inflammatory lesions tend to be progressively replaced by fibrotic lesions or a banal atheroma

    [Conduction defects as the presenting feature of sarcoidosis or observed during the course of the disease: regression with corticoid steroid therapy].

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    International audienceCardiac sarcoidosis is often unrecognised because of the absence of specific clinical and electrical signs. The consequences are serious, the main risk being sudden death due to conduction defects (24 to 31% of cases) or ventricular arrhythmias. Any conduction defect without an obvious cause in a young patient should suggest a possible diagnosis of sarcoidosis. The confirmation is histological when giant cell non-caseuting epithelioid granuloma is demonstrated but myocardial biopsies are only positive in 20% of cases. Therefore, biopsy of accessible organs such as salivary glands is recommended. Diagnostic strategy consists in searching for signs of systemic sarcoidosis, and, when the diagnosis has been established, perform a complete work-up with echocardiography, dipyridamole myocardial scintigraphy, cardiac MRI and 24 hour ambulatory ECG recordings (Holter). The only proven treatment is steroid therapy with occasional spectacular observations of reversibility of arrhythmias or conduction defects

    Expanding the phenotype of LMNA mutations in dilated cardiomyopathy and functional consequences of these mutations

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    Aims: Mutations in the lamin A/C gene (LMNA) have been reported to be involved in dilated cardiomyopathy (DCM) associated with conduction system disease and/or skeletal myopathy. The aim of this study was to perform a mutational analysis of LMNA in a large white population of patients affected by dilated cardiomyopathy with or without associated symptoms. Methods: We performed screening of the coding sequence of LMNA on DNA samples from 66 index cases, and carried out cell transfection experiments to examine the functional consequences of the mutations identified. Results: A new missense (E161K) mutation was identified in a family with early atrial fibrillation and a previously described (R377H) mutation in another family with a quadriceps myopathy associated with DCM. A new mutation (28insA) leading to a premature stop codon was identified in a family affected by DCM with conduction defects. No mutation in LMNA was found in cases with isolated dilated cardiomyopathy. Functional analyses have identified potential physiopathological mechanisms involving identified mutations, such as haploinsufficiency (28insA) or intermediate filament disorganisation (E161K, R377H). Conclusion: For the first time, a specific phenotype characterised by early atrial fibrillation is associated with LMNA mutation. Conversely, mutations in LMNA appear as a rare cause of isolated dilated cardiomyopathy. The variable phenotypes observed in LMNA-DCM might be explained by the variability of functional consequences of LMNA mutations
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