Electrophysiological consequences of dyssynchronous heart failure and its restoration by resynchronization therapy

Takeshi Aiba, Geoffrey G. Hesketh, Andreas S. Barth, Ting Liu, Samantapudi Daya, Khalid Chakir, Veronica Lea Dimaano, Theodore P. Abraham, Brian O'Rourke, Fadi G. Akar, David A. Kass, Gordon F. Tomaselli

Research output: Contribution to journalArticle

151 Citations (Scopus)

Abstract

Background-Cardiac resynchronization therapy (CRT) is widely applied in patients with heart failure and dyssynchro- nous contraction (DHF), but the electrophysiological consequences of CRT in heart failure remain largely unexplored. Methods and Results-Adult dogs underwent left bundle-branch ablation and either right atrial pacing (190 to 200 bpm) for 6 weeks (DHF) or 3 weeks of right atrial pacing followed by 3 weeks of resynchronization by biventricular pacing at the same pacing rate (CRT). Isolated left ventricular anterior and lateral myocytes from nonfailing (control), DHF, and CRT dogs were studied with the whole-cell patch clamp. Quantitative polymerase chain reaction and Western blots were performed to measure steady state mRNA and protein levels. DHF significantly reduced the inward rectifier K + current (I K1), delayed rectifier K + current (I K), and transient outward K + current (I to) in both anterior and lateral cells. CRT partially restored the DHF-induced reduction of I K1 and I K but not I to, consistent with trends in the changes in steady state K + channel mRNA and protein levels. DHF reduced the peak inward Ca 2+ current (I Ca) density and slowed I Ca decay in lateral compared with anterior cells, whereas CRT restored peak /Ca amplitude but did not hasten decay in lateral cells. Calcium transient amplitudes were depressed and the decay was slowed in DHF, especially in lateral myocytes. CRT hastened the decay in both regions and increased the calcium transient amplitude in lateral but not anterior cells. No difference was found in Ca v1.2 (αlC) mRNA or protein expression, but reduced Ca vβ2 mRNA was found in DHF cells. DHF reduced phospholamban, ryanodine receptor, and sarcoplasmic reticulum Ca 2+ ATPase and increased Na +-Ca 2+ exchanger mRNA and protein. CRT did not restore the DHF-induced molecular remodeling, except for sarcoplasmic reticulum Ca 2+ ATPase. Action potential durations were significantly prolonged in DHF, especially in lateral cells, and CRT abbreviated action potential duration in lateral but not anterior cells. Early afterdepolarizations were more frequent in DHF than in control cells and were reduced with CRT. Conclusions-CRT partially restores DHF-induced ion channel remodeling and abnormal Ca + homeostasis and attenuates the regional heterogeneity of action potential duration. The electrophysiological changes induced by CRT may suppress ventricular arrhythmias, contribute to the survival benefit of this therapy, and improve the mechanical performance of the heart.

Original languageEnglish (US)
Pages (from-to)1220-1230
Number of pages11
JournalCirculation
Volume119
Issue number9
DOIs
StatePublished - Mar 10 2009
Externally publishedYes

Fingerprint

Cardiac Resynchronization Therapy
Heart Failure
Therapeutics
Messenger RNA
Sarcoplasmic Reticulum Calcium-Transporting ATPases
Action Potentials
Muscle Cells
Proteins
Sodium-Calcium Exchanger
Dogs
Calcium
Ryanodine Receptor Calcium Release Channel
Ion Channels
Cardiac Arrhythmias

Keywords

  • Heart failure
  • Ion channels
  • Remodeling
  • Resynchronization, electrophysiology

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Electrophysiological consequences of dyssynchronous heart failure and its restoration by resynchronization therapy. / Aiba, Takeshi; Hesketh, Geoffrey G.; Barth, Andreas S.; Liu, Ting; Daya, Samantapudi; Chakir, Khalid; Dimaano, Veronica Lea; Abraham, Theodore P.; O'Rourke, Brian; Akar, Fadi G.; Kass, David A.; Tomaselli, Gordon F.

In: Circulation, Vol. 119, No. 9, 10.03.2009, p. 1220-1230.

Research output: Contribution to journalArticle

Aiba, T, Hesketh, GG, Barth, AS, Liu, T, Daya, S, Chakir, K, Dimaano, VL, Abraham, TP, O'Rourke, B, Akar, FG, Kass, DA & Tomaselli, GF 2009, 'Electrophysiological consequences of dyssynchronous heart failure and its restoration by resynchronization therapy', Circulation, vol. 119, no. 9, pp. 1220-1230. https://doi.org/10.1161/CIRCULATIONAHA.108.794834
Aiba, Takeshi ; Hesketh, Geoffrey G. ; Barth, Andreas S. ; Liu, Ting ; Daya, Samantapudi ; Chakir, Khalid ; Dimaano, Veronica Lea ; Abraham, Theodore P. ; O'Rourke, Brian ; Akar, Fadi G. ; Kass, David A. ; Tomaselli, Gordon F. / Electrophysiological consequences of dyssynchronous heart failure and its restoration by resynchronization therapy. In: Circulation. 2009 ; Vol. 119, No. 9. pp. 1220-1230.
@article{da372ba0f88d47399b67f26bcbade58b,
title = "Electrophysiological consequences of dyssynchronous heart failure and its restoration by resynchronization therapy",
abstract = "Background-Cardiac resynchronization therapy (CRT) is widely applied in patients with heart failure and dyssynchro- nous contraction (DHF), but the electrophysiological consequences of CRT in heart failure remain largely unexplored. Methods and Results-Adult dogs underwent left bundle-branch ablation and either right atrial pacing (190 to 200 bpm) for 6 weeks (DHF) or 3 weeks of right atrial pacing followed by 3 weeks of resynchronization by biventricular pacing at the same pacing rate (CRT). Isolated left ventricular anterior and lateral myocytes from nonfailing (control), DHF, and CRT dogs were studied with the whole-cell patch clamp. Quantitative polymerase chain reaction and Western blots were performed to measure steady state mRNA and protein levels. DHF significantly reduced the inward rectifier K + current (I K1), delayed rectifier K + current (I K), and transient outward K + current (I to) in both anterior and lateral cells. CRT partially restored the DHF-induced reduction of I K1 and I K but not I to, consistent with trends in the changes in steady state K + channel mRNA and protein levels. DHF reduced the peak inward Ca 2+ current (I Ca) density and slowed I Ca decay in lateral compared with anterior cells, whereas CRT restored peak /Ca amplitude but did not hasten decay in lateral cells. Calcium transient amplitudes were depressed and the decay was slowed in DHF, especially in lateral myocytes. CRT hastened the decay in both regions and increased the calcium transient amplitude in lateral but not anterior cells. No difference was found in Ca v1.2 (αlC) mRNA or protein expression, but reduced Ca vβ2 mRNA was found in DHF cells. DHF reduced phospholamban, ryanodine receptor, and sarcoplasmic reticulum Ca 2+ ATPase and increased Na +-Ca 2+ exchanger mRNA and protein. CRT did not restore the DHF-induced molecular remodeling, except for sarcoplasmic reticulum Ca 2+ ATPase. Action potential durations were significantly prolonged in DHF, especially in lateral cells, and CRT abbreviated action potential duration in lateral but not anterior cells. Early afterdepolarizations were more frequent in DHF than in control cells and were reduced with CRT. Conclusions-CRT partially restores DHF-induced ion channel remodeling and abnormal Ca + homeostasis and attenuates the regional heterogeneity of action potential duration. The electrophysiological changes induced by CRT may suppress ventricular arrhythmias, contribute to the survival benefit of this therapy, and improve the mechanical performance of the heart.",
keywords = "Heart failure, Ion channels, Remodeling, Resynchronization, electrophysiology",
author = "Takeshi Aiba and Hesketh, {Geoffrey G.} and Barth, {Andreas S.} and Ting Liu and Samantapudi Daya and Khalid Chakir and Dimaano, {Veronica Lea} and Abraham, {Theodore P.} and Brian O'Rourke and Akar, {Fadi G.} and Kass, {David A.} and Tomaselli, {Gordon F.}",
year = "2009",
month = "3",
day = "10",
doi = "10.1161/CIRCULATIONAHA.108.794834",
language = "English (US)",
volume = "119",
pages = "1220--1230",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "9",

}

TY - JOUR

T1 - Electrophysiological consequences of dyssynchronous heart failure and its restoration by resynchronization therapy

AU - Aiba, Takeshi

AU - Hesketh, Geoffrey G.

AU - Barth, Andreas S.

AU - Liu, Ting

AU - Daya, Samantapudi

AU - Chakir, Khalid

AU - Dimaano, Veronica Lea

AU - Abraham, Theodore P.

AU - O'Rourke, Brian

AU - Akar, Fadi G.

AU - Kass, David A.

AU - Tomaselli, Gordon F.

PY - 2009/3/10

Y1 - 2009/3/10

N2 - Background-Cardiac resynchronization therapy (CRT) is widely applied in patients with heart failure and dyssynchro- nous contraction (DHF), but the electrophysiological consequences of CRT in heart failure remain largely unexplored. Methods and Results-Adult dogs underwent left bundle-branch ablation and either right atrial pacing (190 to 200 bpm) for 6 weeks (DHF) or 3 weeks of right atrial pacing followed by 3 weeks of resynchronization by biventricular pacing at the same pacing rate (CRT). Isolated left ventricular anterior and lateral myocytes from nonfailing (control), DHF, and CRT dogs were studied with the whole-cell patch clamp. Quantitative polymerase chain reaction and Western blots were performed to measure steady state mRNA and protein levels. DHF significantly reduced the inward rectifier K + current (I K1), delayed rectifier K + current (I K), and transient outward K + current (I to) in both anterior and lateral cells. CRT partially restored the DHF-induced reduction of I K1 and I K but not I to, consistent with trends in the changes in steady state K + channel mRNA and protein levels. DHF reduced the peak inward Ca 2+ current (I Ca) density and slowed I Ca decay in lateral compared with anterior cells, whereas CRT restored peak /Ca amplitude but did not hasten decay in lateral cells. Calcium transient amplitudes were depressed and the decay was slowed in DHF, especially in lateral myocytes. CRT hastened the decay in both regions and increased the calcium transient amplitude in lateral but not anterior cells. No difference was found in Ca v1.2 (αlC) mRNA or protein expression, but reduced Ca vβ2 mRNA was found in DHF cells. DHF reduced phospholamban, ryanodine receptor, and sarcoplasmic reticulum Ca 2+ ATPase and increased Na +-Ca 2+ exchanger mRNA and protein. CRT did not restore the DHF-induced molecular remodeling, except for sarcoplasmic reticulum Ca 2+ ATPase. Action potential durations were significantly prolonged in DHF, especially in lateral cells, and CRT abbreviated action potential duration in lateral but not anterior cells. Early afterdepolarizations were more frequent in DHF than in control cells and were reduced with CRT. Conclusions-CRT partially restores DHF-induced ion channel remodeling and abnormal Ca + homeostasis and attenuates the regional heterogeneity of action potential duration. The electrophysiological changes induced by CRT may suppress ventricular arrhythmias, contribute to the survival benefit of this therapy, and improve the mechanical performance of the heart.

AB - Background-Cardiac resynchronization therapy (CRT) is widely applied in patients with heart failure and dyssynchro- nous contraction (DHF), but the electrophysiological consequences of CRT in heart failure remain largely unexplored. Methods and Results-Adult dogs underwent left bundle-branch ablation and either right atrial pacing (190 to 200 bpm) for 6 weeks (DHF) or 3 weeks of right atrial pacing followed by 3 weeks of resynchronization by biventricular pacing at the same pacing rate (CRT). Isolated left ventricular anterior and lateral myocytes from nonfailing (control), DHF, and CRT dogs were studied with the whole-cell patch clamp. Quantitative polymerase chain reaction and Western blots were performed to measure steady state mRNA and protein levels. DHF significantly reduced the inward rectifier K + current (I K1), delayed rectifier K + current (I K), and transient outward K + current (I to) in both anterior and lateral cells. CRT partially restored the DHF-induced reduction of I K1 and I K but not I to, consistent with trends in the changes in steady state K + channel mRNA and protein levels. DHF reduced the peak inward Ca 2+ current (I Ca) density and slowed I Ca decay in lateral compared with anterior cells, whereas CRT restored peak /Ca amplitude but did not hasten decay in lateral cells. Calcium transient amplitudes were depressed and the decay was slowed in DHF, especially in lateral myocytes. CRT hastened the decay in both regions and increased the calcium transient amplitude in lateral but not anterior cells. No difference was found in Ca v1.2 (αlC) mRNA or protein expression, but reduced Ca vβ2 mRNA was found in DHF cells. DHF reduced phospholamban, ryanodine receptor, and sarcoplasmic reticulum Ca 2+ ATPase and increased Na +-Ca 2+ exchanger mRNA and protein. CRT did not restore the DHF-induced molecular remodeling, except for sarcoplasmic reticulum Ca 2+ ATPase. Action potential durations were significantly prolonged in DHF, especially in lateral cells, and CRT abbreviated action potential duration in lateral but not anterior cells. Early afterdepolarizations were more frequent in DHF than in control cells and were reduced with CRT. Conclusions-CRT partially restores DHF-induced ion channel remodeling and abnormal Ca + homeostasis and attenuates the regional heterogeneity of action potential duration. The electrophysiological changes induced by CRT may suppress ventricular arrhythmias, contribute to the survival benefit of this therapy, and improve the mechanical performance of the heart.

KW - Heart failure

KW - Ion channels

KW - Remodeling

KW - Resynchronization, electrophysiology

UR - http://www.scopus.com/inward/record.url?scp=63649086323&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=63649086323&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.108.794834

DO - 10.1161/CIRCULATIONAHA.108.794834

M3 - Article

C2 - 19237662

AN - SCOPUS:63649086323

VL - 119

SP - 1220

EP - 1230

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 9

ER -