The sinoatrial node (SAN) is the pacemaker region of the heart that initiates each heartbeat. In 1 in 600 adults over the age of 65, there is a loss of SAN function, leading to decreased cardiac output and hypoperfusion of various organs including the brain. This commonly presents as syncope and near‐fainting, but can also lead to fatigue, palpitations, angina and congestive heart failure among other symptoms. The broad collection of disorders marked by loss of SAN function is known as sick sinus syndrome (SSS). In over 50% of SSS patients, bradycardia is complicated by atrial flutter or atrial fibrillation, significantly increasing stroke risk. Typically SSS is diagnosed by the occurrence of symptoms along with electrocardiogram evidence of bradycardia, which may or may not be accompanied by periods of tachycardia (Semelka et al. 2013).
Currently, the sole therapy for SSS is placement of a permanent pacemaker. The type of pacemaker is dependent on whether atrioventricular defects or atrial fibrillation is present. If neither is present, atrial pacemakers are indicated while patients with atrioventricular defects require dual atrial and ventricular pacing and those with atrial fibrillation should only have ventricular pacing. Generally pacemakers are well tolerated and are an effective therapeutic option for patients with brady‐arrhythmias. However, pacemaker placement has not been found to increase survival, but is instead used for symptom alleviation. Furthermore, limitations of electronic pacemakers include cost of pacemaker placement, complications such as myocardial perforation that occur in a small subset of patients, need for battery replacements, and challenges in programming electronic pacemakers to respond to increased cardiac demands required during exercise (Adan & Crown, 2003). Such limitations could potentially be overcome by the use of biological pacemakers (biopacemakers), sparking great interest in their development.
Biopacemakers, gene and cell therapies to restore pacemaking ability at the SAN or create new pacemaker regions in the heart, are an emerging strategy to combat the limitations of implantable pacemakers. An initial success in biopacemaking was the discovery that pacemaker ability in adult non‐SAN myocardial cells was suppressed by inward rectifier potassium current, encoded by Kir2.1. Thus removal of Kir2.1 activity was able to restore pacemaking ability in ventricular cardiomyocytes. This demonstrated the possibility of using gene therapy to create pacemaking regions in the heart outside of the SAN. While some cells developed pacemaking ability when Kir2.1 was removed, others did not, but instead developed a prolonged action potential (Miake et al. 2002), which increases the likelihood for early after depolarizations, a trigger for atrial fibrillation. Consequently, the search began for alternative gene targets that could produce pacemaking ability without prolonging the action potential.
Hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels were of particular interest because they open upon hyperpolarization and the inward current only begins to increase after the cardiomyocyte has completed repolarization. Thus, it would not contribute to a prolonged action potential. Further, HCN is found in the SAN and conducting system. Viral delivery of HCN2 and HCN2 mutants optimized to shift the voltage dependence of activation in large animals showed success imparting pacemaking ability. However, the basal and maximum pacemaker rate was slower than optimal. Further, pacemaker activity was chamber dependent, and was not always cAMP responsive, which is critical for regulation of cardiac output to meet oxygen demands (Bucchi et al. 2006; Rosen et al. 2011).
In an article in this issue of The Journal of Physiology, Choudhury et al. (2018) aimed to address the limitations of the HCN gene therapies by targeting Tbx18, a transcription factor important for the development of the SAN. Tbx18 is required for the development of the head portion of the SAN, but is not expressed following birth. Delivery of Tbx18 into ventricular cardiomyocytes converts them into SAN cells. They are not only capable of automaticity, but also exhibit the same morphology and express the same epigenetic changes found in SAN cells (Kapoor et al. 2013). However, the efficacy of Tbx18 gene delivery into non‐ventricular cells has not been studied. Choudhury et al. address this gap in knowledge and demonstrate the proof‐of‐concept of Tbx18 gene therapy as an effective dual chamber or atrial pacemaker.
In their study, Choudhury et al. demonstrate that Tbx18 overexpression in rat subsidiary atrial pacemaker (SAP) tissue accelerated pacemaker activity, improved heart rate stability and increased β‐adrenergic responsiveness to that of control SAN tissue. The authors use SAP tissue as a model of SSS because the SAP is an extension of the SAN and displays automaticity, but is bradycardic, exhibiting a high degree of overdrive suppression and decreased sensitivity to β‐adrenoceptor agonist, catecholamine. Three gene targets were tested: the sodium–calcium exchanger (NCX1), which is important for the calcium cycling that promotes automaticity; Tbx3, a transcription factor that acts concurrently with Tbx18 during SAN development; and Tbx18. Only Tbx18 overexpression was able to restore pacemaker rate, stability and responsiveness to β‐adrenergic stimulation.
The authors then demonstrate that Tbx18‐induced changes in HCN isoform ratio and upregulation of ryanodine receptor (RyR2) may underlie the pacemaker changes. The predominant isoforms in the SAN and SAP are HCN4 and HCN2, respectively. Following Tbx18 over‐expression, mRNA for HCN2 and RyR2 is significantly upregulated, while mRNA for HCN4 and HCN1 is not significantly increased. These proteins contribute to calcium cycling important for pacemaker activity, and therefore it will be interesting to further investigate their function at the protein level. Finally, the authors used computational modelling of the SAN to show that the observed upregulation of HCN2 could produce the observed changes in SAP pacemaking rates.
Overall, the authors provide a proof‐of‐concept that gene therapy targeting Tbx18 can be a therapeutic strategy for SSS and offer an analysis of the mechanism for this biopacemaker. While the results of this study need to be assessed in large animals, the study offers significant insight into the use of biopacemakers for SSS.
Additional information
Competing interests
None declared.
Author contributions
Both authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.
Funding
Funding sources for Wenli Dai are: T32HL007381 and T32GM007281.
Edited by: Ole Petersen & Don Bers
Linked articles This Perspective highlights an article by Choudhury et al. To read this article, visit https://doi.org/10.1113/JP276508.
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