Implantation of Sinoatrial Node Cells Into Canine Right Ventricle: Biological Pacing Appears Limited by the Substrate

Abstract

Biological pacing has been proposed as a physiologic counterpart to electronic pacing, and the sinoatrial node (SAN) is the general standard for biological pacemakers. We tested the expression of SAN pacemaker cell activity when implanted autologously in the right ventricle (RV). We induced complete heart block and implanted electronic pacemakers in the RV of adult mongrel dogs. Autologous SAN cells isolated enzymatically were studied by patch clamp to confirm SAN identity. SAN cells (400,000) were injected into the RV subepicardial free wall and dogs were monitored for 2 weeks. Pacemaker function was assessed by overdrive pacing and IV epinephrine challenge. SAN cells expressed a time-dependent inward current (If) activating on hyperpolarization: density = 4.3 ± 0.6 pA/pF at −105 mV. Four of the six dogs demonstrated >50% of beats originating from the implant site at 24 h. Biological pacemaker rates on days 7–14 = 45–55 bpm and post-overdrive escape times = 1.5–2.5 s. Brisk catecholamine responsiveness occurred. Dogs implanted with autologous SAN cells manifest biological pacing properties dissimilar from those of the anatomic SAN. This highlights the importance of cell and substrate interaction in generating biological pacemaker function.

Lipopolysaccharide Impaired the Functional Activity of Endothelial Colony-Forming Cells

“…In an animal model of ALI, Yamada et al [24] have shown that administration of LPS to murine lungs induced rapid release of EPCs into the circulation, which contributed to lung repair after LPS-induced lung injury in mice. Furthermore, transplantation of circulating EPCs or mesenchymal stem cells attenuated ALI induced by oleic acid, hyperoxia and Escherichia coli or pancreatitis-associated lung injury [25,26,27,28,29,30], and improved survival in rats with LPS-induced lung injury [31]. These studies suggest that EPCs are important for lung repair in lung injury.…”

Stem Cells for the Prevention of Neonatal Lung Disease

“…Similar to the therapeutic benefit reported for bone marrow-derived MSCs, studies utilizing UCB-derived MSCs report comparable effects in the hyperoxia-induced model of neonatal lung injury [29,31,32,33,36] - improved alveolar structure/restoration of alveolar growth, attenuation of lung fibrosis, reduced lung inflammation, prevention of impaired lung angiogenesis, and improved exercise capacity. Furthermore, the beneficial long-term effects of UCB-derived MSC administration were also demonstrated, with no evidence of adverse effects in adulthood [29,36].…”

“…Furthermore, the beneficial long-term effects of UCB-derived MSC administration were also demonstrated, with no evidence of adverse effects in adulthood [29,36]. Studies utilizing UCB-derived MSCs have also assessed the differences between the route of administration [31], dose of MSCs [32] and timing of the dose [33], with more favorable outcomes occurring with intratracheal administration with a minimum of 5 × 10 4 MSCs and optimal protective effects with 5 × 10 5 MSCs. Furthermore, administration in the early stages of lung development (prealveolar stage) was more beneficial than in the later stages (postalveolar stage).…”

“…Together, these studies have provided compelling evidence for the use of stem cells in preterm infants. Although the majority of studies utilized the hyperoxia-induced neonatal lung injury model of experimental BPD [16,19,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39], other models have also been explored, including ventilation-induced [40], LPS-induced [41] and bleomycin-induced neonatal lung injury [42]. As demonstrated in those studies, numerous mechanisms of neonatal lung injury, each contributing to BPD, have been ameliorated with the help of stem cell therapy such as lung inflammation, vascular damage, alveolar growth impairment, lung fibrosis, and poor exercise capacity.…”

Human Biological Pacemakers

“…Conversely, the lack of such power-law behavior should not necessarily exclude candidate cell types. Recent work by Zhang et al 12 demonstrated that even when a large number of SAN cells are autologously transplanted to the right ventricle of canine hearts, the range and success of pacemaking activity of the SAN cells are limited in the ventricle compared with their normal atrial environment. This underscores the importance of the host environment in influencing the resultant pacemaker activity and is likely attributable to the local anatomy, cell-cell coupling, and source-sink interactions, meaning that the resulting pacemaking activity is highly dependent on the amount of depolarizing current produced by the pacemaker cells relative to the amount of this current absorbed by the surrounding ventricular myocardium.…”