MedWire News: Cardiac resynchronization therapy (CRT) reverses molecular stress response and cell survival abnormalities that accompany cardiac dyssynchrony, preliminary study findings indicate.
David Kass and colleagues from Johns Hopkins University School of Medicine in Baltimore, Maryland, USA, looked at how CRT affects regional and global molecular protein signaling abnormalities induced by dyssynchronous heart failure (DHF).
Previous studies exploring the mechanisms underlying CRT's benefits have focused on its effects on chamber mechanics and energetics in patients, they explain. To look more closely at the molecular biologic effects of CRT, the researchers developed a novel canine model of cardiac dyssynchrony.
The researchers performed radiofrequency ablation of the left bundle branch, prolonging the QRS 100%, in 22 adult dogs. The dogs then underwent 3 weeks of atrial tachypacing (200 beats per minute) to induce dyssynchronous heart failure (DHF) followed by either another 3 weeks of atrial tachypacing or 3 weeks of biventricular tachypacing (CRT).
Both groups of dogs developed similar left ventricular (LV) dysfunction after 3 weeks of atrial tachypacing, with LV ejection fractions (LVEFs) of 30.1% in the DHF group and 28.1% in the CRT group compared with 66.7% in a control group of dogs that did not undergo pacing. At 6 weeks, LVEF declined by a further 4.7% in the DHF group but rose slightly, by 2.8%, in the CRT animals.
Both groups of dogs that underwent pacing remained in HF at 6 weeks, however, with similarly elevated diastolic pressures and reduced dP/dtmax.
Biochemical analyses of myocardial tissue taken from the dogs at the end of the study showed that mitogen-activated kinase p38 and calcium-calmodulin-dependent kinase expression and activation, and tumor necrosis factor-a levels, were increased in the late-contracting (higher-stress) lateral versus septal wall in DHF dogs.
No such disproportionate expression or activation of these molecular stress pathway proteins was observed in the CRT group, the authors report in an advance online publication by the journal Circulation.
Apoptosis, as measured by terminal deoxynucleotide transferase-mediated dUTP labeling, caspase 3 activity, and nuclear poly ADP-ribose polymerase cleavage, was less evident in CRT than in DHF myocardial tissue, accompanied by increased activation of the cell survival molecule Akt.
Furthermore, levels of the anti-apoptotic proteins Bcl-2 and phospho-Bcl 2 antagonist of cell death (pBAD) were reduced in DHF hearts, but were normal and accompanied by marked BAD phosphorylation and binding of its downstream anti-apoptosis partner 14-3-3 in CRT hearts.
"We are learning that pacemaker therapy does profoundly more than just mechanically correct how the heart beats; in fact, it produces major chemical changes that benefit the muscle," commented first author Khalid Chakir.
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