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Articles by E Aikawa
Total Records ( 5 ) for E Aikawa
  J. P Dal Bianco , E Aikawa , J Bischoff , J. L Guerrero , M. D Handschumacher , S Sullivan , B Johnson , J. S Titus , Y Iwamoto , J Wylie Sears , R. A Levine and A. Carpentier

Background— In patients with left ventricular infarction or dilatation, leaflet tethering by displaced papillary muscles frequently induces mitral regurgitation, which doubles mortality. Little is known about the biological potential of the mitral valve (MV) to compensate for ventricular remodeling. We tested the hypothesis that MV leaflet surface area increases over time with mechanical stretch created by papillary muscle displacement through cell activation, not passive stretching.

Methods and Results— Under cardiopulmonary bypass, the papillary muscle tips in 6 adult sheep were retracted apically short of producing mitral regurgitation to replicate tethering without confounding myocardial infarction or turbulence. Diastolic leaflet area was quantified by 3-dimensional echocardiography over 61±6 days compared with 6 unstretched sheep MVs. Total diastolic leaflet area increased by 2.4±1.3 cm2 (17±10%) from 14.3±1.9 to 16.7±1.9 cm2 (P=0.006) with stretch with no change in the unstretched valves despite sham open heart surgery. Stretched MVs were 2.8 times thicker than normal (1.18±0.14 versus 0.42±0.14 mm; P<0.0001) at 60 days with an increased spongiosa layer. Endothelial cells (CD31+) coexpressing -smooth muscle actin were significantly more common by fluorescent cell sorting in tethered versus normal leaflets (41±19% versus 9±5%; P=0.02), indicating endothelial-mesenchymal transdifferentiation. -Smooth muscle actin–positive cells appeared in the atrial endothelium, penetrating into the interstitium, with increased collagen deposition. Thickened chordae showed endothelial and subendothelial -smooth muscle actin. Endothelial-mesenchymal transdifferentiation capacity also was demonstrated in cultured MV endothelial cells.

Conclusions— Mechanical stresses imposed by papillary muscle tethering increase MV leaflet area and thickness, with cellular changes suggesting reactivated embryonic developmental pathways. Understanding such actively adaptive mechanisms can potentially provide therapeutic opportunities to augment MV area and reduce ischemic mitral regurgitation.

  D. E Sosnovik , R Wang , G Dai , T Wang , E Aikawa , M Novikov , A Rosenzweig , R. J Gilbert and V. J. Wedeen

Background— Changes in myocardial microstructure are important components of the tissue response to infarction but are difficult to resolve with current imaging techniques. A novel technique, diffusion spectrum MRI tractography (DSI tractography), was thus used to image myofiber architecture in normal and infarcted myocardium. Unlike diffusion tensor imaging, DSI tractography resolves multiple myofiber populations per voxel, thus generating accurate 3D tractograms, which we present in the myocardium for the first time.

Methods and Results— DSI tractography was performed at 4.7 T in excised rat hearts 3 weeks after left coronary artery ligation (n=4) and in 4 age-matched controls. Fiber architecture in the control hearts varied smoothly from endocardium to epicardium, producing a symmetrical array of crossing helical structures in which orthogonal myofibers were separated by fibers with intermediate helix angles. Fiber architecture in the infarcted hearts was severely perturbed. The infarct boundary in all cases was highly irregular and punctuated repeatedly by residual myofibers extending from within the infarct to the border zones. In all infarcts, longitudinal myofibers extending toward the basal-anterior wall and transversely oriented myofibers extending toward the septum lay in direct contact with each other, forming nodes of orthogonal myofiber intersection or contact.

Conclusions— DSI tractography resolves 3D myofiber architecture and reveals a complex network of orthogonal myofibers within infarcted myocardium. Meshlike networks of orthogonal myofibers in infarcted myocardium may resist mechanical remodeling but also probably increase the risk for lethal reentrant arrhythmias. DSI tractography thus provides a new and important readout of tissue injury after myocardial infarction.

  D. E Sosnovik , E Garanger , E Aikawa , M Nahrendorf , J. L Figuiredo , G Dai , F Reynolds , A Rosenzweig , R Weissleder and L. Josephson

Background— A novel dual-contrast molecular MRI technique to image both cardiomyocyte apoptosis and necrosis in vivo within 4 to 6 hours of ischemia is presented. The technique uses the annexin-based nanoparticle AnxCLIO-Cy5.5 (apoptosis) and simultaneous delayed-enhancement imaging with a novel gadolinium chelate, Gd-DTPA-NBD (necrosis).

Methods and Results— Mice with transient coronary ligation were injected intravenously at the onset of reperfusion with AnxCLIO-Cy5.5 (n=7) or the control probe Inact_CLIO-Cy5.5 (n=6). T2*-weighted MR images (9.4 T) were acquired within 4 to 6 hours of reperfusion. The contrast-to-noise ratio between injured and uninjured myocardium was measured. The mice were then injected with Gd-DTPA-NBD, and delayed-enhancement imaging was performed within 10 to 30 minutes. Uptake of AnxCLIO-Cy5.5 was most prominent in the midmyocardium and was significantly greater than that of Inact_CLIO-Cy5.5 (contrast-to-noise ratio, 8.82±1.5 versus 3.78±1.1; P<0.05). Only 21±3% of the myocardium with accumulation of AnxCLIO-Cy5.5 showed delayed-enhancement of Gd-DTPA-NBD. Wall thickening was significantly reduced in segments with delayed enhancement and/or transmural accumulation of AnxCLIO-Cy5.5 (P<0.001). Fluorescence microscopy of AnxCLIO-Cy5.5 and immunohistochemistry of Gd-DTPA-NBD confirmed the presence of large numbers of apoptotic but potentially viable cardiomyocytes (AnxCLIO-Cy5.5 positive, Gd-DTPA-NBD negative) in the midmyocardium.

Conclusions— A novel technique to image cardiomyocyte apoptosis and necrosis in vivo within 4 to 6 hours of injury is presented and reveals large areas of apoptotic but viable myocardium in the midmyocardium. Strategies to salvage the numerous apoptotic but potentially viable cardiomyocytes in the midmyocardium in acute ischemia should be investigated.

  D. E Sosnovik , M Nahrendorf , P Panizzi , T Matsui , E Aikawa , G Dai , L Li , F Reynolds , G. W Dorn , R Weissleder , L Josephson and A. Rosenzweig

Background— The ability to image cardiomyocyte (CM) apoptosis in heart failure could facilitate more accurate diagnostics and optimize targeted therapeutics. We thus aimed to develop a platform to image CM apoptosis quantitatively and specifically in heart failure in vivo. The myocardium in heart failure, however, is characterized by very low levels of CM apoptosis and normal vascular permeability, factors thought to preclude the use of molecular MRI.

Methods and Results— Female mice with overexpression of Gaq were studied. Two weeks postpartum, these mice develop a cardiomyopathy characterized by low levels of CM apoptosis and minimal myocardial necrosis or inflammation. The mice were injected with the annexin-labeled nanoparticle (AnxCLIO-Cy5.5) or a control probe (CLIO-Cy5.5) and imaged in vivo at 9.4 T. Uptake of AnxCLIO-Cy5.5 occurred in isolated clusters, frequently in the subendocardium. Myocardial T2* was significantly lower (7.6±1.5 versus 16.8±2.7 ms, P<0.05) in the mice injected with AnxCLIO-Cy5.5 versus CLIO-Cy5.5, consistent with the uptake of AnxCLIO-Cy5.5 by apoptotic CMs. A strong correlation (r2=0.86, P<0.05) was seen between in vivo T2* (AnxCLIO-Cy5.5 uptake) and myocardial caspase-3 activity.

Conclusions— The ability of molecular MRI to image sparsely expressed targets in the myocardium is demonstrated in this study. Moreover, a novel platform for high-resolution and specific imaging of CM apoptosis in heart failure is established. In addition to providing novel insights into the pathogenesis of CM apoptosis, the developed platform could facilitate the development of novel antiapoptotic therapies in heart failure.

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