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

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 (nϭ27) 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 (2.8Ϯ1.8%) compared with DHF (Ϫ4.4Ϯ2.7; Pϭ0.02 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-␣ increased in the late-contracting (higher-stress) lateral versus septal wall. These disparities were absent with CRT. Apoptosis assessed by terminal deoxynucleotide transferasemediated 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 PP1␣, consistent with antiapoptotic effects. Other Akt-coupled modulators of apoptosis (FOXO-3␣ and GSK3␤) 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.

Cellular and Molecular Aspects of Dyssynchrony and Resynchronization

“…Treating cells from dyssynchronous HF dogs with ranolazine, a relatively selective I Na-L inhibitor significantly reduces APD (Figure 3), but has little impact on myocytes from non-failing or CRT dogs [61]. It is known that Ca 2+ /Calmodulin protein Kinase II (CaMKII) increases I Na-L [62], and dyssynchrony is associated with an increase in CaMKII activity in the late-activated lateral wall, while CRT decreases this activity [61,63].…”

“…Annexin A5 decreases in CRT responders, and is unchanged in non-responders [109]. Annexin A5 is a pro-apoptotic protein [110,111], and resynchronization has been shown to have anti-apoptotic effects [63,112]. The neutrophilto-lymphocyte ratio decreases in responders and increases in non-responders, and while there were no baseline differences, there was a trend (p=0.20) towards lower levels in responders [113].…”

Speckle-Tracking Echocardiography Elucidates the Effect of Pacing Site on Left Ventricular Synchronization in the Normal and Infarcted Rat Myocardium

“…Animal studies have shown that DHF is associated with regional molecular changes (collectively termed 'molecular polarization'), including downregulation of Ca 2+ handling proteins and connexin 43, activation of stress response kinases and increased expression of tumor necrosis factor in the lateral LV wall. Most of these changes can be reversed by CRT [11]. Additional studies identifying regional changes in ionic channels and multiple gene transcripts [12,13] have revealed a highly complicated picture in which multiple players are involved.…”

Cardiac resynchronization therapy: a breakthrough in heart failure management

“…Prolonged electrical activation resulting in a compromised sequence of activation is present within the atria (intra-atrial dyssynchrony), between atria and ventricles [atrioventricular (AV) dyssynchrony], within the LV (intraventricu- Activated [34] Reduced activation [34] Apoptotic cell death Activated [38] Reduced activation [37,38] ß-adrenergic signalling Reduced [43] Increased [43] Cellular-regional LV Decreased hypertrophy in late-activated regions [40] Metabolic Overall myocardial oxygen consumption Unchanged [46,48] Unchanged [46,48] Cardiac efficiency Decreased [46,48] Improved [46,48] Regional differences in myocardial blood flow Present [23] Ameliorated by CRT [40] Haemodynamic Diastolic filling time Shortened [32] Prolonged [45] Functional mitral regurgitation Increased [19] Decreased [44] Systolic pump function Decreased [32] Improved [43] Clinial events Hospitalization rates for heart failure (HF)…”

“…In recent years, evidence has accumulated from several studies to suggest that dyssynchrony not only adds to disorder of gene expression on a global ventricular level that is typical of HF (even in the absence of dyssynchrony) [34][35][36][37][38], but also promotes regional differences in gene expression within the LV (between early-and late-activated regions) [39][40][41].…”