Electrical remodeling in dyssynchrony and resynchronization

Takeshi Aiba, Gordon F. Tomaselli

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Heart failure (HF) is associated with anatomic and functional remodeling of cardiac tissues in both animal models and humans,which alters Ca2+ homeostasis, protein phosphorylation, excitation-contraction coupling, results in arrhythmias. Indeed, the electrophysiological hallmark of cells and tissues isolated from failing hearts is prolongation of action potential duration (APD) and conduction slowing. The changes in cellular and tissue function are regionally heterogenous particularly in the dyssynchronously contracting heart. Cardiac resynchronization therapy (CRT) is widely applied in patients with HF and dyssynchronous left ventricular (LV) contraction (DHF), but the electrophysiological consequences of CRT are not fully understood.We demonstrated the molecular and cellular basis of excitability, conduction, and electrical remodeling in DHF and its restoration by CRT using a canine tachypacing HF model. CRT partially reversed the DHFinduced downregulation of K+ current and improved Na+ channel gating and abbreviated persistent (late) Na+ current. CRT reduced Ca2+/ calmodulin protein kinase II activity and restored transverse tubular system and spatial distribution of ryanodine receptor, thus it significantly improved Ca2+ homeostasis especially in myocytes from late-activated, lateral wall and restored the DHF-induced blunted β-adrenergic receptor responsiveness. CRT abbreviated DHF-induced prolongation of APD in the lateral wall myocytes and reduced the LV regional gradient of APD and suppressed the development of early afterdepolarizations. In conclusion, CRT partially restores the DHF-induced ion channel remodeling, abnormal Ca2+ homeostasis, blunted β-adrenergic response, and regional heterogeneity of APD, thus it may suppress ventricular arrhythmias and contribute to the mortality benefit of CRT as well as improve mechanical performance of the heart.

Original languageEnglish (US)
Pages (from-to)170-179
Number of pages10
JournalJournal of Cardiovascular Translational Research
Volume5
Issue number2
DOIs
StatePublished - Apr 1 2012
Externally publishedYes

Fingerprint

Atrial Remodeling
Cardiac Resynchronization Therapy
Action Potentials
Homeostasis
Heart Failure
Muscle Cells
Cardiac Arrhythmias
Excitation Contraction Coupling
Calcium-Calmodulin-Dependent Protein Kinases
Ryanodine Receptor Calcium Release Channel
Ion Channels
Adrenergic Agents
Adrenergic Receptors
Protein Kinases
Canidae
Down-Regulation
Animal Models
Phosphorylation
Mortality

Keywords

  • Cardiac resynchronization therapy
  • Dyssynchrony
  • Electrophysiology
  • Heart failure
  • Ion channels

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Genetics
  • Genetics(clinical)
  • Molecular Medicine
  • Pharmaceutical Science

Cite this

Electrical remodeling in dyssynchrony and resynchronization. / Aiba, Takeshi; Tomaselli, Gordon F.

In: Journal of Cardiovascular Translational Research, Vol. 5, No. 2, 01.04.2012, p. 170-179.

Research output: Contribution to journalArticle

@article{c8d679d7abcd45ceb297a5d75683499b,
title = "Electrical remodeling in dyssynchrony and resynchronization",
abstract = "Heart failure (HF) is associated with anatomic and functional remodeling of cardiac tissues in both animal models and humans,which alters Ca2+ homeostasis, protein phosphorylation, excitation-contraction coupling, results in arrhythmias. Indeed, the electrophysiological hallmark of cells and tissues isolated from failing hearts is prolongation of action potential duration (APD) and conduction slowing. The changes in cellular and tissue function are regionally heterogenous particularly in the dyssynchronously contracting heart. Cardiac resynchronization therapy (CRT) is widely applied in patients with HF and dyssynchronous left ventricular (LV) contraction (DHF), but the electrophysiological consequences of CRT are not fully understood.We demonstrated the molecular and cellular basis of excitability, conduction, and electrical remodeling in DHF and its restoration by CRT using a canine tachypacing HF model. CRT partially reversed the DHFinduced downregulation of K+ current and improved Na+ channel gating and abbreviated persistent (late) Na+ current. CRT reduced Ca2+/ calmodulin protein kinase II activity and restored transverse tubular system and spatial distribution of ryanodine receptor, thus it significantly improved Ca2+ homeostasis especially in myocytes from late-activated, lateral wall and restored the DHF-induced blunted β-adrenergic receptor responsiveness. CRT abbreviated DHF-induced prolongation of APD in the lateral wall myocytes and reduced the LV regional gradient of APD and suppressed the development of early afterdepolarizations. In conclusion, CRT partially restores the DHF-induced ion channel remodeling, abnormal Ca2+ homeostasis, blunted β-adrenergic response, and regional heterogeneity of APD, thus it may suppress ventricular arrhythmias and contribute to the mortality benefit of CRT as well as improve mechanical performance of the heart.",
keywords = "Cardiac resynchronization therapy, Dyssynchrony, Electrophysiology, Heart failure, Ion channels",
author = "Takeshi Aiba and Tomaselli, {Gordon F.}",
year = "2012",
month = "4",
day = "1",
doi = "10.1007/s12265-012-9348-9",
language = "English (US)",
volume = "5",
pages = "170--179",
journal = "Journal of Cardiovascular Translational Research",
issn = "1937-5387",
publisher = "Springer New York",
number = "2",

}

TY - JOUR

T1 - Electrical remodeling in dyssynchrony and resynchronization

AU - Aiba, Takeshi

AU - Tomaselli, Gordon F.

PY - 2012/4/1

Y1 - 2012/4/1

N2 - Heart failure (HF) is associated with anatomic and functional remodeling of cardiac tissues in both animal models and humans,which alters Ca2+ homeostasis, protein phosphorylation, excitation-contraction coupling, results in arrhythmias. Indeed, the electrophysiological hallmark of cells and tissues isolated from failing hearts is prolongation of action potential duration (APD) and conduction slowing. The changes in cellular and tissue function are regionally heterogenous particularly in the dyssynchronously contracting heart. Cardiac resynchronization therapy (CRT) is widely applied in patients with HF and dyssynchronous left ventricular (LV) contraction (DHF), but the electrophysiological consequences of CRT are not fully understood.We demonstrated the molecular and cellular basis of excitability, conduction, and electrical remodeling in DHF and its restoration by CRT using a canine tachypacing HF model. CRT partially reversed the DHFinduced downregulation of K+ current and improved Na+ channel gating and abbreviated persistent (late) Na+ current. CRT reduced Ca2+/ calmodulin protein kinase II activity and restored transverse tubular system and spatial distribution of ryanodine receptor, thus it significantly improved Ca2+ homeostasis especially in myocytes from late-activated, lateral wall and restored the DHF-induced blunted β-adrenergic receptor responsiveness. CRT abbreviated DHF-induced prolongation of APD in the lateral wall myocytes and reduced the LV regional gradient of APD and suppressed the development of early afterdepolarizations. In conclusion, CRT partially restores the DHF-induced ion channel remodeling, abnormal Ca2+ homeostasis, blunted β-adrenergic response, and regional heterogeneity of APD, thus it may suppress ventricular arrhythmias and contribute to the mortality benefit of CRT as well as improve mechanical performance of the heart.

AB - Heart failure (HF) is associated with anatomic and functional remodeling of cardiac tissues in both animal models and humans,which alters Ca2+ homeostasis, protein phosphorylation, excitation-contraction coupling, results in arrhythmias. Indeed, the electrophysiological hallmark of cells and tissues isolated from failing hearts is prolongation of action potential duration (APD) and conduction slowing. The changes in cellular and tissue function are regionally heterogenous particularly in the dyssynchronously contracting heart. Cardiac resynchronization therapy (CRT) is widely applied in patients with HF and dyssynchronous left ventricular (LV) contraction (DHF), but the electrophysiological consequences of CRT are not fully understood.We demonstrated the molecular and cellular basis of excitability, conduction, and electrical remodeling in DHF and its restoration by CRT using a canine tachypacing HF model. CRT partially reversed the DHFinduced downregulation of K+ current and improved Na+ channel gating and abbreviated persistent (late) Na+ current. CRT reduced Ca2+/ calmodulin protein kinase II activity and restored transverse tubular system and spatial distribution of ryanodine receptor, thus it significantly improved Ca2+ homeostasis especially in myocytes from late-activated, lateral wall and restored the DHF-induced blunted β-adrenergic receptor responsiveness. CRT abbreviated DHF-induced prolongation of APD in the lateral wall myocytes and reduced the LV regional gradient of APD and suppressed the development of early afterdepolarizations. In conclusion, CRT partially restores the DHF-induced ion channel remodeling, abnormal Ca2+ homeostasis, blunted β-adrenergic response, and regional heterogeneity of APD, thus it may suppress ventricular arrhythmias and contribute to the mortality benefit of CRT as well as improve mechanical performance of the heart.

KW - Cardiac resynchronization therapy

KW - Dyssynchrony

KW - Electrophysiology

KW - Heart failure

KW - Ion channels

UR - http://www.scopus.com/inward/record.url?scp=84866085303&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84866085303&partnerID=8YFLogxK

U2 - 10.1007/s12265-012-9348-9

DO - 10.1007/s12265-012-9348-9

M3 - Article

C2 - 22271011

AN - SCOPUS:84866085303

VL - 5

SP - 170

EP - 179

JO - Journal of Cardiovascular Translational Research

JF - Journal of Cardiovascular Translational Research

SN - 1937-5387

IS - 2

ER -