Reversal of Global Apoptosis and Regional Stress Kinase Activation by Cardiac Resynchronization

• Published in: Circulation (New York, N.Y.) Vol. 117; no. 11; pp. 1369 - 1377
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 18.03.2008
• Subjects: 14-3-3 Proteins - metabolism; Animals; Apoptosis; Associated diseases and complications; bcl-Associated Death Protein - metabolism; Biological and medical sciences; Blood and lymphatic vessels; Bundle-Branch Block - complications; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cardiac Pacing, Artificial - methods; Cardiology. Vascular system; Diabetes. Impaired glucose tolerance; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Dogs; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme Activation; Forkhead Transcription Factors - metabolism; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Heart Failure - enzymology; Heart Failure - etiology; Heart Failure - pathology; Heart Failure - therapy; Medical sciences; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism; Random Allocation; Stroke Volume; Tachycardia, Ectopic Atrial - complications; Tachycardia, Ectopic Atrial - enzymology; Tachycardia, Ectopic Atrial - pathology; Tachycardia, Ectopic Atrial - therapy; Tachycardia, Ventricular - complications; Tachycardia, Ventricular - enzymology; Tachycardia, Ventricular - pathology; Tachycardia, Ventricular - therapy; Tumor Necrosis Factor-alpha - biosynthesis; Heart failure; Bradycardia; Arrhythmia; pacing; Heart disease; Cardiovascular disease; Molecular biology; Excitability disorder; Stress; cardiac pacing, artificial; Apoptosis
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.107.706291

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. 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. 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.