Reversal of global apoptosis and regional stress kinase activation by cardiac resynchronization

Khalid Chakir, Samantapudi K. Daya, Richard S. Tunin, Robert H. Helm, Melissa J. Byrne, Veronica L. Dimaano, Albert C. Lardo, Theodore P. Abraham, Gordon F. Tomaselli, David A Kass

Research output: Contribution to journalArticle

Abstract

BACKGROUND - Cardiac dyssynchrony in the failing heart worsens global function and efficiency and generates regional loading disparities that may exacerbate stress-response molecular signaling and worsen cell survival. We hypothesized that cardiac resynchronization (CRT) from biventricular stimulation reverses such molecular abnormalities at the regional and global levels. METHODS AND RESULTS - Adult dogs (n=27) underwent left bundle-branch radiofrequency ablation, prolonging the QRS by 100%. Dogs were first subjected to 3 weeks of atrial tachypacing (200 bpm) to induce dyssynchronous heart failure (DHF) and then randomized to either 3 weeks of additional atrial tachypacing (DHF) or biventricular tachypacing (CRT). At 6 weeks, ejection fraction improved in CRT (2.8±1.8%) compared with DHF (-4.4±2.7; P=0.02 versus CRT) dogs, although both groups remained in failure with similarly elevated diastolic pressures and reduced dP/dtmax. In DHF, mitogen-activated kinase p38 and calcium-calmodulin-dependent kinase were disproportionally expressed/activated (50% to 150%), and tumor necrosis factor-α increased in the late-contracting (higher-stress) lateral versus septal wall. These disparities were absent with CRT. Apoptosis assessed by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling staining, caspase-3 activity, and nuclear poly ADP-ribose polymerase cleavage was less in CRT than DHF hearts and was accompanied by increased Akt phosphorylation/activity. Bcl-2 and BAD protein diminished with DHF but were restored by CRT, accompanied by marked BAD phosphorylation, enhanced BAD-14-3-3 interaction, and reduced phosphatase PP1α, consistent with antiapoptotic effects. Other Akt-coupled modulators of apoptosis (FOXO-3α and GSK3β) were more phosphorylated in DHF than CRT and thus less involved. CONCLUSIONS - CRT reverses regional and global molecular remodeling, generating more homogeneous activation of stress kinases and reducing apoptosis. Such changes are important benefits from CRT that likely improve cardiac performance and outcome.

Original languageEnglish (US)
Pages (from-to)1369-1377
Number of pages9
JournalCirculation
Volume117
Issue number11
DOIs
StatePublished - Mar 2008

Fingerprint

Cardiac Resynchronization Therapy
Phosphotransferases
Apoptosis
Heart Failure
Dogs
Calcium-Calmodulin-Dependent Protein Kinase Kinase
Phosphorylation
Poly(ADP-ribose) Polymerases
Transferases
Mitogens
Phosphoric Monoester Hydrolases
Caspase 3
Cell Survival
Tumor Necrosis Factor-alpha
Staining and Labeling
Blood Pressure

Keywords

  • Apoptosis
  • Cardiac pacing, artificial
  • Heart failure
  • Molecular biology
  • Pacing

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Reversal of global apoptosis and regional stress kinase activation by cardiac resynchronization. / Chakir, Khalid; Daya, Samantapudi K.; Tunin, Richard S.; Helm, Robert H.; Byrne, Melissa J.; Dimaano, Veronica L.; Lardo, Albert C.; Abraham, Theodore P.; Tomaselli, Gordon F.; Kass, David A.

In: Circulation, Vol. 117, No. 11, 03.2008, p. 1369-1377.

Research output: Contribution to journalArticle

Chakir, K, Daya, SK, Tunin, RS, Helm, RH, Byrne, MJ, Dimaano, VL, Lardo, AC, Abraham, TP, Tomaselli, GF & Kass, DA 2008, 'Reversal of global apoptosis and regional stress kinase activation by cardiac resynchronization', Circulation, vol. 117, no. 11, pp. 1369-1377. https://doi.org/10.1161/CIRCULATIONAHA.107.706291
Chakir, Khalid ; Daya, Samantapudi K. ; Tunin, Richard S. ; Helm, Robert H. ; Byrne, Melissa J. ; Dimaano, Veronica L. ; Lardo, Albert C. ; Abraham, Theodore P. ; Tomaselli, Gordon F. ; Kass, David A. / Reversal of global apoptosis and regional stress kinase activation by cardiac resynchronization. In: Circulation. 2008 ; Vol. 117, No. 11. pp. 1369-1377.
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AU - Chakir, Khalid

AU - Daya, Samantapudi K.

AU - Tunin, Richard S.

AU - Helm, Robert H.

AU - Byrne, Melissa J.

AU - Dimaano, Veronica L.

AU - Lardo, Albert C.

AU - Abraham, Theodore P.

AU - Tomaselli, Gordon F.

AU - Kass, David A

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N2 - BACKGROUND - Cardiac dyssynchrony in the failing heart worsens global function and efficiency and generates regional loading disparities that may exacerbate stress-response molecular signaling and worsen cell survival. We hypothesized that cardiac resynchronization (CRT) from biventricular stimulation reverses such molecular abnormalities at the regional and global levels. METHODS AND RESULTS - Adult dogs (n=27) underwent left bundle-branch radiofrequency ablation, prolonging the QRS by 100%. Dogs were first subjected to 3 weeks of atrial tachypacing (200 bpm) to induce dyssynchronous heart failure (DHF) and then randomized to either 3 weeks of additional atrial tachypacing (DHF) or biventricular tachypacing (CRT). At 6 weeks, ejection fraction improved in CRT (2.8±1.8%) compared with DHF (-4.4±2.7; P=0.02 versus CRT) dogs, although both groups remained in failure with similarly elevated diastolic pressures and reduced dP/dtmax. In DHF, mitogen-activated kinase p38 and calcium-calmodulin-dependent kinase were disproportionally expressed/activated (50% to 150%), and tumor necrosis factor-α increased in the late-contracting (higher-stress) lateral versus septal wall. These disparities were absent with CRT. Apoptosis assessed by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling staining, caspase-3 activity, and nuclear poly ADP-ribose polymerase cleavage was less in CRT than DHF hearts and was accompanied by increased Akt phosphorylation/activity. Bcl-2 and BAD protein diminished with DHF but were restored by CRT, accompanied by marked BAD phosphorylation, enhanced BAD-14-3-3 interaction, and reduced phosphatase PP1α, consistent with antiapoptotic effects. Other Akt-coupled modulators of apoptosis (FOXO-3α and GSK3β) were more phosphorylated in DHF than CRT and thus less involved. CONCLUSIONS - CRT reverses regional and global molecular remodeling, generating more homogeneous activation of stress kinases and reducing apoptosis. Such changes are important benefits from CRT that likely improve cardiac performance and outcome.

AB - BACKGROUND - Cardiac dyssynchrony in the failing heart worsens global function and efficiency and generates regional loading disparities that may exacerbate stress-response molecular signaling and worsen cell survival. We hypothesized that cardiac resynchronization (CRT) from biventricular stimulation reverses such molecular abnormalities at the regional and global levels. METHODS AND RESULTS - Adult dogs (n=27) underwent left bundle-branch radiofrequency ablation, prolonging the QRS by 100%. Dogs were first subjected to 3 weeks of atrial tachypacing (200 bpm) to induce dyssynchronous heart failure (DHF) and then randomized to either 3 weeks of additional atrial tachypacing (DHF) or biventricular tachypacing (CRT). At 6 weeks, ejection fraction improved in CRT (2.8±1.8%) compared with DHF (-4.4±2.7; P=0.02 versus CRT) dogs, although both groups remained in failure with similarly elevated diastolic pressures and reduced dP/dtmax. In DHF, mitogen-activated kinase p38 and calcium-calmodulin-dependent kinase were disproportionally expressed/activated (50% to 150%), and tumor necrosis factor-α increased in the late-contracting (higher-stress) lateral versus septal wall. These disparities were absent with CRT. Apoptosis assessed by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling staining, caspase-3 activity, and nuclear poly ADP-ribose polymerase cleavage was less in CRT than DHF hearts and was accompanied by increased Akt phosphorylation/activity. Bcl-2 and BAD protein diminished with DHF but were restored by CRT, accompanied by marked BAD phosphorylation, enhanced BAD-14-3-3 interaction, and reduced phosphatase PP1α, consistent with antiapoptotic effects. Other Akt-coupled modulators of apoptosis (FOXO-3α and GSK3β) were more phosphorylated in DHF than CRT and thus less involved. CONCLUSIONS - CRT reverses regional and global molecular remodeling, generating more homogeneous activation of stress kinases and reducing apoptosis. Such changes are important benefits from CRT that likely improve cardiac performance and outcome.

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