ExperimentalBiological pacemakers in canines exhibit positive chronotropic response to emotional arousal
Introduction
A distinct advantage of intrinsic cardiac pacemakers over their electronic replacements is their seamless response to physiologic stimuli, thereby adapting heart rate to the metabolic needs of the body. Although electronic pacing is a lifesaving technology and rate-responsive units now are in use, the nuanced input of the autonomic nervous system is difficult to replicate. Recent experiments in the engineering of biological pacemakers based on the HCN family of genes has demonstrated good responsiveness to infusion of catecholamines1 and to vagal stimulation.2 However, such testing does not provide information regarding autonomic control in a conscious animal. Specifically, whether activation of the sympathetic nervous system in response to emotional arousal would be associated with a significant increase in the activity of a genetically engineered biological pacemaker remains unknown.
The purpose of this study was to evaluate whether a stimulus that reproducibly evokes emotional arousal during sinus rhythm does so as well in dogs implanted with a biological pacemaker. A positive outcome would provide evidence of the autonomic responsiveness of these pacemakers. The paradigm is based on a standardized protocol in which we consistently observed significant cardiovascular responses to presentation of food following an overnight fast.3 To evaluate the responsiveness of the biological pacemakers to emotional arousal, we performed quantitative Poincaré analysis of heart rate variability (HRV),4 which circumvents the stationarity requirements associated with conventional time- and frequency-domain HRV techniques. RR interval was also continuously assessed.
Section snippets
Methods
Experiments were performed using protocols that were approved by the Columbia University Institutional Animal Care and Use Committee and conformed to the Guide for the Care and Use of Laboratory Animals (NIH Publication No. 85-23, revised 1996).
Results
As in previous studies from our laboratory, pacemaker function became evident within 2 to 3 days of implantation, with stabilization as a function of time after implantation.
Discussion
Among the beneficial theoretical advantages that biological pacemakers possess over electronic devices is their potential capacity to adapt to changing physiologic demands associated with mental and/or physical activity. Promising evidence already available indicates that pacemakers based on the HCN2 channel isoform respond to beta-adrenergic and muscarinic stimulation, suggesting a capacity to respond to autonomic input.2, 6, 7 We investigated autonomic response to emotional arousal in dogs
Conclusion
The present study contributes to progress in the field of biological pacemakers in the evolution from proof of concept to experimental confirmation of appropriate chronotropic response to behavioral arousal, an important step in clinical implementation.
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Cited by (31)
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2020, Emerging Technologies for Heart Diseases: Volume 2: Treatments for Myocardial Ischemia and ArrhythmiasGene Therapy and Biological Pacing
2018, Cardiac Electrophysiology: From Cell to Bedside: Seventh EditionThe past, present, and future of pacemaker therapies
2015, Trends in Cardiovascular MedicineCitation Excerpt :Yet, there are other means to quantify sensitivity to autonomic modulation. Shlapakova et al. [49] reported significantly increased sensitivity to emotional arousal in HCN2-based biological pacing as compared to controls, a property that not has been quantified for any of the other approaches. In the HCN2 and AC1 canine studies, heart rate variability was studied with Poincaré plots (Fig. 6A).
Stem cell-based biological pacemakers from proof of principle to therapy: A review
2014, CytotherapyCitation Excerpt :The dogs injected with the wild-type or mutant HCN2 (mE324A) channel had significantly fewer electronic backup beats than control dogs (GFP alone; 26% vs. 36% vs. 83%, respectively) and a greater increase in heart rate following epinephrine injection especially in the E324A group (29). Autonomic responsiveness was also revealed by the analysis of the heart rate variability after presenting food (30). Importantly, in the previous studies, the presence of the HCN protein/If expression was systematically demonstrated through histologic, immuno-histochemical or electrophysiologic analysis of the explanted heart.
Biological Pacing
2014, Cardiac Electrophysiology: From Cell to Bedside: Sixth EditionAutologous biological pacing function with adrenergic-responsiveness in porcine of complete heart block
2013, International Journal of CardiologyCitation Excerpt :However, the facts including the small number and incapability of regeneration of sinus nodal cells restrict the future application of this approach. In a recent study, Shlapakova and colleague explored the possibility of utilizing heterogeneous MSCs in a short-term attempt of biological pacing in canines [8]. Nevertheless, the possibility of delayed rejection and correlated cell loss could not be excluded due to xenograft.
Drs. Cohen, Robinson, and Rosen have received grant funding from Boston Scientific, Inc. Gerard J.J. Boink received support from the Netherlands Heart Foundation (NHF) and the Interuniversity Cardiology Institute of the Netherlands (ICIN).