Biological Pacemaker Implanted in Canine Left Bundle Branch Provides Ventricular Escape Rhythms That Have Physiologically Acceptable Rates

Abstract

Background-We hypothesized that administration of the HCN2 gene to the left bundle-branch (LBB) system of intact dogs would provide pacemaker function in the physiological range of heart rates. Methods and Results-An adenoviral construct incorporating HCN2 and green fluorescent protein (GFP) as a marker was injected via catheter under fluoroscopic control into the posterior division of the LBB. Controls were injected with an adenoviral construct of GFP alone or saline. Animals were monitored electrocardiographically for up to 7 days after surgery, at which time they were anesthetized and subjected to vagal stimulation to permit emergence of escape pacemakers. Hearts were then removed and injection sites visually identified and removed for microelectrode study of action potentials, patch clamp studies of pacemaker current, and/or immunohistochemical studies of HCN2. For 48 hours postoperatively, 7 of 7 animals subjected to 24-hour ECG monitoring showed multiple ventricular premature depolarizations and/or ventricular tachycardia attributable to injection-induced injury. Thereafter, sinus rhythm prevailed. During vagal stimulation, HCN2-injected dogs showed rhythms originating from the left ventricle, the rate of which was significantly more rapid than in the controls. Excised posterior divisions of the LBB from HCN2-injected animals manifested automatic rates significantly greater than the controls. Isolated tissues showed immunohistochemical and biophysical evidence of overexpressed HCN2. Conclusions-A gene-therapy approach for induction of biological pacemaker activity within the LBB system provides ventricular escape rhythms that have physiologically acceptable rates. Long-term stability and feasibility of the approach remain to be tested.

Gene Therapy for Cardiac Arrhythmias

“…19,20 The adenoviral gene transduction of HCN2 channel induced pacemaker ac- tivity in the atrium 21 and the left bundle branch. 22 These initial trials revealed that a gene transfer into cardiomyocytes evoked spontaneous activity, but the heart rate as a result of these biological pacemakers was relatively low. The optimal biological pacemaker has phenotypes with: 1) an adequate basal beating rate similar to normal sinus rhythm, and 2) appropriate heart rate response by autonomic regulation.…”

Biological Pacemakers – A Review

“…Qu et al reported increased spontaneous beating rate in neonatal rat ventricular myocytes infected with adenoviral HCN2. Increased escape rate was demonstrated by injection of adenovirus carrying HCN2 in canine left atrium [44] and in the canine left bundle branch [34]. In a canine model of International Journal of Cardiovascular Practice atrioventricular block, implanted with a pacemaker set at a rate of 45 beats per minute, requirement of pacing was reduced after injection of the wild-type HCN2 [45].…”

“…Two other experimental studies confirmed [31,32] these findings. As with other approaches using stem cells, concerns have been raised about the risk of infection, neoplasia, and further differentiation over time [33,34]. Another approach is to not use stem cells, and instead reprogram adult cells to become undifferentiated cells.…”

Cardiac gene therapy in large animals: bridge from bench to bedside

“…This is most advantageous for some gene therapies with focused target regions, such as induction of angiogenesis at the infarct border and biological pacemakers. Whereas catheter-based endocardial injection provides a less invasive delivery with imaging guidance, 56,74,89 surgical approach provides secure injection at the target site under direct real-time confirmation. Because some of the studies delivered the vectors at the time of model creation, a surgical approach was more commonly used.…”