Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is a genetic disease caused by mutations in desmosomal proteins. The phenotypic hallmark of ARVC is fibroadipocytic replacement of cardiac myocytes, which is a unique phenotype with a yet-to-be-defined molecular mechanism. We established atrial myocyte cell lines expressing siRNA against desmoplakin (DP), responsible for human ARVC. We show suppression of DP expression leads to nuclear localization of the desmosomal protein plakoglobin and a 2-fold reduction in canonical Wnt/b-catenin signaling through Tcf/Lef1 transcription factors. The ensuing phenotype is increased expression of adipogenic and fibrogenic genes and accumulation of fat droplets. We further show that cardiac-restricted deletion of Dsp, encoding DP, impairs cardiac morphogenesis and leads to high embryonic lethality in the homozygous state. Heterozygous DP-deficient mice exhibited excess adipocytes and fibrosis in the myocardium, increased myocyte apoptosis, cardiac dysfunction, and ventricular arrhythmias, thus recapitulating the phenotype of human ARVC. We believe our results provide for a novel molecular mechanism for the pathogenesis of ARVC and establish cardiac-restricted DP-deficient mice as a model for human ARVC. These findings could provide for the opportunity to identify new diagnostic markers and therapeutic targets in patients with ARVC.
LV longitudinal and radial strains are reduced, but circumferential deformation and twist are normal in DHF patients. On the other hand, in patients with SHF, longitudinal, radial, and circumferential deformation, and twist are all reduced. Multivariable regression analysis suggests that preserved LV twist and circumferential strain may contribute to normal EF in patients with DHF.
Left ventricular relaxation, minimal pressure and preload determine Ea while late diastolic velocity determinants include LA dP/dt, LA relaxation and LV end-diastolic pressure.
Background-Diastolic strain rate (SR) measurements that comprise all left ventricular (LV) segments are advantageous over myocardial velocity for assessment of diastolic function. Mitral early diastolic velocity (E)/SR ratio during the isovolumetric relaxation (IVR) period can be used to estimate LV filling pressures. Methods and Results-Simultaneous echocardiographic imaging and LV pressure measurements (7F catheters) were performed in 7 adult dogs. Loading conditions were altered by saline infusion and caval occlusion, and lusitropic state was changed by dobutamine and esmolol infusion. A curve depicting global SR was derived from each of the 3 apical views, and SR was measured during IVR (SR IVR ) and early LV filling (SR E ). SR IVR had a strong correlation with time constant of LV pressure decay during the IVR period () (rϭϪ0.83, PϽ0.001), whereas SR E was significantly related to LV end-diastolic pressure (rϭ0.52, Pϭ0.005) in the experimental stages where was Ͻ40 ms. In 50 patients with simultaneous right heart catheterization and echocardiographic imaging, mitral E/SR IVR ratio had the best correlation with mean wedge pressure (rϭ0.79, PϽ0.001), as well as in 24 prospective patients (rϭ0.84, Pϭ0.001). E/SR IVR was most useful in patients with ratio of E to mitral annulus early diastolic velocity (E/Ea ratio) 8 to 15 and was more accurate than E/Ea in patients with normal ejection fraction and regional dysfunction (both PϽ0.01). Conclusions-Global SR IVR by 2-dimensional speckle tracking is strongly dependent on LV relaxation. E/SR IVR can predict LV filling pressures with reasonable accuracy, particularly in patients with normal ejection fraction and in those with regional dysfunction.
TGF--activated kinase-1 (TAK1), also known as MAPKK kinase-7 (MAP3K7), is a candidate effector of multiple circuits in cardiac biology and disease. Here, we show that inhibition of TAK1 in mice by a cardiac-specific dominant-negative mutation evokes electrophysiological and biochemical properties reminiscent of human Wolff-Parkinson-White syndrome, arising from mutations in AMPactivated protein kinase (AMPK), most notably, accelerated atrioventricular conduction and impaired AMPK activation. To test conclusively the biochemical connection from TAK1 to AMPK suggested by this phenotype, we disrupted TAK1 in mouse embryos and embryonic fibroblasts by Cre-mediated recombination. In TAK1-null embryos, the activating phosphorylation of AMPK at T172 was blocked, accompanied by defective AMPK activity. However, loss of endogenous TAK1 causes midgestation lethality, with defective yolk sac and intraembryonic vasculature. To preclude confounding lethal defects, we acutely ablated floxed TAK1 in culture by viral delivery of Cre. In culture, endogenous TAK1 was activated by oligomycin, the antidiabetic drug metformin, 5-aminoimidazole-4-carboxamide riboside (AICAR), and ischemia, well established triggers of AMPK activity. Loss of TAK1 in culture blocked T172 phosphorylation induced by all three agents, interfered with AMPK activation, impaired phosphorylation of the endogenous AMPK substrate acetyl CoA carboxylase, and also interfered with activation of the AMPK kinase LKB1. Thus, by disrupting the endogenous TAK1 locus, we prove a pivotal role for TAK1 in the LKB1͞AMPK signaling axis, an essential governor of cell metabolism. APKs, MAPKKs (MAP2Ks), and MAP2K kinases (MAP3Ks) comprise a multitiered signaling cascade that couples extracellular cues and intracellular stresses to diverse effector pathways controlling cell growth, survival, transcription, and function (1). Among upstream members of this superfamily, TGF--activated kinase-1 (TAK1)͞MA PKK kinase-7 (MAP3K7) first was identified as a mammalian kinase that complements the lack of Ste11, a MAP3K, in yeast and is activated by TGF- and the relative, bone morphogenetic protein (2). Within the MAPK family, TAK1 is coupled preferentially to JNK and p38. Additional inputs for TAK1 activation include cytokine signaling and innate immunity, and additional outputs include I B kinase  (3). Disruption of TAK1 by saturation mutagenesis in ES cells substantiated that TAK1 is indeed essential for a subset of TGF- effects and also exerts essential functions in signaling by cytokine and Toll-like receptors (3), as proposed on earlier grounds. Additionally, the early-lethal phenotype of TAK1-null embryos, with intraembryonic and yolk sac vascular patterning defects, resembles that of mice devoid of other TGF- signaling proteins, the type I receptor Alk1 and type III receptor endoglin (4).A recognized limitation of germ-line deletions is that potential gene functions may be obscured by early lethality, indirect effects, or secondary adaptations, fueling interest in lineagerestr...
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