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


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-alpha 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 PP1alpha, consistent with antiapoptotic effects. Other Akt-coupled modulators of apoptosis (FOXO-3alpha and GSK3beta) 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.
Chakir
Khalid
K
Division of Cardiology, School of Medicine, Department of Biomedical Engineering, Johns Hopkins University Medical Institutions, Baltimore, MD 21205, USA.
Daya
Samantapudi K
SK
Tunin
Richard S
RS
Helm
Robert H
RH
Byrne
Melissa J
MJ
Dimaano
Veronica L
VL
Lardo
Albert C
AC
Abraham
Theodore P
TP
Tomaselli
Gordon F
GF
Kass
David A
DA
D048948:14-3-3 Proteins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002037:Bundle-Branch Block / Q000150:complications; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002304:Cardiac Pacing, Artificial / Q000379:methods*; D004285:Dogs; D004789:Enzyme Activation; D051858:Forkhead Transcription Factors / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006333:Heart Failure / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000628:therapy*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011897:Random Allocation; D013318:Stroke Volume; D013612:Tachycardia, Ectopic Atrial / Q000150:complications / Q000201:enzymology / Q000473:pathology / Q000628:therapy; D017180:Tachycardia, Ventricular / Q000150:complications / Q000201:enzymology / Q000473:pathology / Q000628:therapy; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D051025:bcl-Associated Death Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D048948:14-3-3 Proteins; D051858:Forkhead Transcription Factors; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D051025:bcl-Associated Death Protein; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3