Dataset Information

Plasticity of surface structures and ?(2)-adrenergic receptor localization in failing ventricular cardiomyocytes during recovery from heart failure.

ABSTRACT: BACKGROUND:Cardiomyocyte surface morphology and T-tubular structure are significantly disrupted in chronic heart failure, with important functional sequelae, including redistribution of sarcolemmal ?(2)-adrenergic receptors (?(2)AR) and localized secondary messenger signaling. Plasticity of these changes in the reverse remodeled failing ventricle is unknown. We used AAV9.SERCA2a gene therapy to rescue failing rat hearts and measured z-groove index, T-tubule density, and compartmentalized ?(2)AR-mediated cAMP signals, using a combined nanoscale scanning ion conductance microscopy-Förster resonance energy transfer technique. METHODS AND RESULTS:Cardiomyocyte surface morphology, quantified by z-groove index and T-tubule density, was normalized in reverse-remodeled hearts after SERCA2a gene therapy. Recovery of sarcolemmal microstructure correlated with functional ?(2)AR redistribution back into the z-groove and T-tubular network, whereas minimal cAMP responses were initiated after local ?(2)AR stimulation of crest membrane, as observed in failing cardiomyocytes. Improvement of ?(2)AR localization was associated with recovery of ?AR-stimulated contractile responses in rescued cardiomyocytes. Retubulation was associated with reduced spatial heterogeneity of electrically stimulated calcium transients and recovery of myocardial BIN-1 and TCAP protein expression but not junctophilin-2. CONCLUSIONS:In summary, abnormalities of sarcolemmal structure in heart failure show plasticity with reappearance of z-grooves and T-tubules in reverse-remodeled hearts. Recovery of surface topology is necessary for normalization of ?(2)AR location and signaling responses.

SUBMITTER: Lyon AR

PROVIDER: S-EPMC4886822 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Plasticity of surface structures and β(2)-adrenergic receptor localization in failing ventricular cardiomyocytes during recovery from heart failure.

Lyon Alexander R AR Nikolaev Viacheslav O VO Miragoli Michele M Sikkel Markus B MB Paur Helen H Benard Ludovic L Hulot Jean-Sebastien JS Kohlbrenner Erik E Hajjar Roger J RJ Peters Nicholas S NS Korchev Yuri E YE Macleod Ken T KT Harding Sian E SE Gorelik Julia J

Circulation. Heart failure 20120328 3

<h4>Background</h4>Cardiomyocyte surface morphology and T-tubular structure are significantly disrupted in chronic heart failure, with important functional sequelae, including redistribution of sarcolemmal β(2)-adrenergic receptors (β(2)AR) and localized secondary messenger signaling. Plasticity of these changes in the reverse remodeled failing ventricle is unknown. We used AAV9.SERCA2a gene therapy to rescue failing rat hearts and measured z-groove index, T-tubule density, and compartmentalized ...[more]

PMID: 22456061

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Project description:Heart failure is a leading cause of death, yet its underlying electrophysiological (EP) mechanisms are not well understood. In this study, we use a multiscale approach to analyze a model of heart failure and connect its results to features of the electrocardiogram (ECG). The heart failure model is derived by modifying a previously validated electrophysiology model for a healthy rabbit heart. Specifically, in accordance with the heart failure literature, we modified the cell EP by changing both membrane currents and calcium handling. At the tissue level, we modeled the increased gap junction lateralization and lower conduction velocity due to downregulation of Connexin 43. At the biventricular level, we reduced the apex-to-base and transmural gradients of action potential duration (APD). The failing cell model was first validated by reproducing the longer action potential, slower and lower calcium transient, and earlier alternans characteristic of heart failure EP. Subsequently, we compared the electrical wave propagation in one dimensional cables of healthy and failing cells. The validated cell model was then used to simulate the EP of heart failure in an anatomically accurate biventricular rabbit model. As pacing cycle length decreases, both the normal and failing heart develop T-wave alternans, but only the failing heart shows QRS alternans (although moderate) at rapid pacing. Moreover, T-wave alternans is significantly more pronounced in the failing heart. At rapid pacing, APD maps show areas of conduction block in the failing heart. Finally, accelerated pacing initiated wave reentry and breakup in the failing heart. Further, the onset of VF was not observed with an upregulation of SERCA, a potential drug therapy, using the same protocol. The changes introduced at the cell and tissue level have increased the failing heart's susceptibility to dynamic instabilities and arrhythmias under rapid pacing. However, the observed increase in arrhythmogenic potential is not due to a steepening of the restitution curve (not present in our model), but rather to a novel blocking mechanism.

Dataset Information

Plasticity of surface structures and ?(2)-adrenergic receptor localization in failing ventricular cardiomyocytes during recovery from heart failure.

Publications

Plasticity of surface structures and β(2)-adrenergic receptor localization in failing ventricular cardiomyocytes during recovery from heart failure.

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