Dataset Information

Novel role for vinculin in ventricular myocyte mechanics and dysfunction.

ABSTRACT: Vinculin (Vcl) plays a key structural role in ventricular myocytes that, when disrupted, can lead to contractile dysfunction and dilated cardiomyopathy. To investigate the role of Vcl in myocyte and myocardial function, cardiomyocyte-specific Vcl knockout mice (cVclKO) and littermate control wild-type mice were studied with transmission electron microscopy (TEM) and in vivo magnetic resonance imaging (MRI) tagging before the onset of global ventricular dysfunction. MRI revealed significantly decreased systolic strains transverse to the myofiber axis in vivo, but no changes along the muscle fibers or in fiber tension in papillary muscles from heterozygous global Vcl null mice. Myofilament lattice spacing from TEM was significantly greater in cVclKO versus wild-type hearts fixed in the unloaded state. AFM in Vcl heterozygous null mouse myocytes showed a significant decrease in membrane cortical stiffness. A multiscale computational model of ventricular mechanics incorporating cross-bridge geometry and lattice mechanics showed that increased transverse systolic stiffness due to increased lattice spacing may explain the systolic wall strains associated with Vcl deficiency, before the onset of ventricular dysfunction. Loss of cardiac myocyte Vcl may decrease systolic transverse strains in vivo by decreasing membrane cortical tension, which decreases transverse compression of the lattice thereby increasing interfilament spacing and stress transverse to the myofibers.

SUBMITTER: Tangney JR

PROVIDER: S-EPMC3617425 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Novel role for vinculin in ventricular myocyte mechanics and dysfunction.

Tangney Jared R JR Chuang Joyce S JS Janssen Matthew S MS Krishnamurthy Adarsh A Liao Peter P Hoshijima Masahiko M Wu Xin X Meininger Gerald A GA Muthuchamy Mariappan M Zemljic-Harpf Alice A Ross Robert S RS Frank Lawrence R LR McCulloch Andrew D AD Omens Jeffrey H JH

Biophysical journal 20130401 7

Vinculin (Vcl) plays a key structural role in ventricular myocytes that, when disrupted, can lead to contractile dysfunction and dilated cardiomyopathy. To investigate the role of Vcl in myocyte and myocardial function, cardiomyocyte-specific Vcl knockout mice (cVclKO) and littermate control wild-type mice were studied with transmission electron microscopy (TEM) and in vivo magnetic resonance imaging (MRI) tagging before the onset of global ventricular dysfunction. MRI revealed significantly dec ...[more]

PMID: 23561539

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Project description:OBJECTIVES:The objective of this study was to evaluate the changes in three-dimensional (3D) speckle-tracking echocardiography-derived measures of mechanics and their associations with systolic and diastolic dysfunction after anthracyclines. BACKGROUND:An improved understanding of the changes in 3D cardiac mechanics with anthracyclines may provide important mechanistic insight and identify new metrics to detect cardiac dysfunction. METHODS:A total of 142 women with breast cancer receiving doxorubicin (240 mg/m2) with or without trastuzumab underwent 3D speckle-tracking echocardiography at standardized intervals prior to, during, and annually after chemotherapy. Left ventricular ejection fraction (LVEF), global circumferential strain (GCS), global longitudinal strain (GLS), principal strain, twist, and torsion were quantified. Linear regression analyses defined the associations between clinical factors and 3D parameters. Linear regression models with cluster robust variance estimators determined the associations between 3D measures and 2-dimensional (2D) LVEF and Doppler-derived E/e' over time. RESULTS:There were significant abnormalities in 3D LVEF, GCS, GLS, and principal strain post-doxorubicin compared with control subjects (p < 0.001). The 3D parameters worsened post-anthracyclines, and only partially recovered to baseline over a median of 2.1 years (interquartile range: 1 to 4 years). Higher blood pressure and body mass index were associated with worse post-anthracycline 3D GCS and GLS, respectively. All 3D measures were associated with 2D LVEF at the same visit; only 3D LVEF, GCS, GLS, and principal strain were associated with 2D LVEF at subsequent visits (p < 0.05). In exploratory analyses, 3D LVEF and GCS were associated with subsequent systolic function independent of their corresponding 2D measures. The 3D LVEF, GCS, principal strain, and twist were significantly associated with concurrent, but not subsequent, E/e'. CONCLUSIONS:Anthracyclines result in early and persistent abnormalities in 3D mechanics. The 3D LVEF and strain measures are associated with concurrent and subsequent systolic dysfunction, and concurrent diastolic dysfunction. Future research is needed to define the mechanisms and clinical relevance of abnormal 3D mechanics.

Project description:Early afterdepolarizations (EADs) are spontaneous depolarizations during the repolarization phase of an action potential in cardiac myocytes. It is widely known that EADs are promoted by increasing inward currents and/or decreasing outward currents, a condition called reduced repolarization reserve. Recent studies based on bifurcation theories show that EADs are caused by a dual Hopf-homoclinic bifurcation, bringing in further mechanistic insights into the genesis and dynamics of EADs. In this study, we investigated the EAD properties, such as the EAD amplitude, the inter-EAD interval, and the latency of the first EAD, and their major determinants. We first made predictions based on the bifurcation theory and then validated them in physiologically more detailed action potential models. These properties were investigated by varying one parameter at a time or using parameter sets randomly drawn from assigned intervals. The theoretical and simulation results were compared with experimental data from the literature. Our major findings are that the EAD amplitude and takeoff potential exhibit a negative linear correlation; the inter-EAD interval is insensitive to the maximum ionic current conductance but mainly determined by the kinetics of ICa,L and the dual Hopf-homoclinic bifurcation; and both inter-EAD interval and latency vary largely from model to model. Most of the model results generally agree with experimental observations in isolated ventricular myocytes. However, a major discrepancy between modeling results and experimental observations is that the inter-EAD intervals observed in experiments are mainly between 200 and 500 ms, irrespective of species, while those of the mathematical models exhibit a much wider range with some models exhibiting inter-EAD intervals less than 100 ms. Our simulations show that the cause of this discrepancy is likely due to the difference in ICa,L recovery properties in different mathematical models, which needs to be addressed in future action potential model development.

Dataset Information

Novel role for vinculin in ventricular myocyte mechanics and dysfunction.

Publications

Novel role for vinculin in ventricular myocyte mechanics and dysfunction.

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