Characterization of a right atrial subsidiary pacemaker and acceleration of the pacing rate by HCN over-expression

Morris, Gwilym M.; D’Souza, Alicia; Dobrzynski, Halina; Lei, Ming; Choudhury, Moinuddin; Billeter, Rudi; Kryukova, Yelena; Robinson, Richard B.; Kingston, Paul A.; Boyett, Mark R.

doi:10.1093/cvr/cvt164

Cited by 25 publications

(43 citation statements)

References 47 publications

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“…92 The concept has also been applied to SND by overexpression of HCN channels to accelerate pacemaker activity of the caudal SAN pacemaker complex in a model of SND. 93 Clearly, significant challenges remain before this treatment can become a clinical reality. 90,94…”

Section: San Dysfunction and Diabetes Mellitusmentioning

confidence: 99%

Fibrosis, Electrics and Genetics

Morris

Kalman

2014

Circ J

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The sinoatrial node (SAN) is the normal pacemaker of the heart. During a human lifetime it must initiate approximately 2 billion heartbeats and coordinate the cardiovascular response to our physiological and emotional demands. Disease of the SAN is common, and one of the leading indications for electronic pacemaker implantation. Advances in understanding the genetics and molecular mechanisms determining normal SAN function, and of the pathways controlling remodeling are revealing SAN disease to be heterogeneous. We review the contemporary concepts of SAN function, heart rate adaptation and SAN disease from the molecular level to clinical application. (Circ J 2014; 78: 1272 -1282

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Section: San Dysfunction and Diabetes Mellitusmentioning

confidence: 99%

Fibrosis, Electrics and Genetics

Morris

Kalman

2014

Circ J

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“…13 However, nodal tissue capable of supporting pacemaker activity can be detected inferiorly as far as the most inferior aspect of the CT and the Eustacian ridge. 14,15 The main body is crescent-shaped with a thinner tail of tissue extending below it. 13 Nodal cells are densely packed within fibrous connective tissue.…”

Section: Sinoatrial Node Structurementioning

confidence: 99%

“…I K,1 knockout or HCN channel upregulation using adenoviral vectors. 14,81,82 However, pacing was often either too slow or unreliable for direct translation into humans. In an attempt to reproduce the complexity of the SAN, groups are now either modulating multiple features simultaneously or using transcription factors.…”

Section: Future Prospects In Sinoatrial Node Researchmentioning

confidence: 99%

Biology of the Sinus Node and its Disease

Choudhury

Boyett

Morris

2015

Arrhythmia &Amp; Electrophysiology Review

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The sinoatrial or sinus node (SAN) is the heart's natural pacemaker.Located in the superior right atrium, it automatically produces cyclical electrical activity to initiate each heartbeat in normal sinus rhythm. SAN dysfunction (SND) in humans, also known as 'sick sinus syndrome', can manifest as pathological bradycardia and asystolic pauses. As a result, SND can lead to symptoms of reduced cerebral perfusion such as dizziness and syncope.However, early SND may be latent and individuals may remain asymptomatic. Implantable electronic pacemakers are currently the only effective treatment. SND is the most common reason to have a pacemaker implanted, the indication for 27.5 % of all pacemakers implanted in the UK. 1 The prevalence of SND in the UK is around 0.03 % affecting all ages, but it is much more common in the elderly population. The aetiology of SND can be intrinsic, extrinsic or often a mixture of the two. One retrospective study of 277 patients presenting to the emergency department with compromising bradycardia showed that 51 % of cases were attributable to a treatable extrinsic cause such as an adverse drug reaction, electrolyte imbalance or acute myocardial infarction. The other 49 % were assumed to be intrinsic or 'idiopathic'. The pathophysiology of 'idiopathic' SND is still not clearly understood.Historically it is attributed to fibrosis and cell senescence and this is often still quoted today. 4,5 However, contemporary evidence suggests that electrical remodelling of molecular pacemaking mechanisms such as membrane ion channels and intracellular Ca 2+ cycling are important factors in SND. 6 In this article we summarise the mechanisms of SAN function and review the current evidence surrounding the pathophysiology of SND. Development of the Sinoatrial NodeThe SAN is the uppermost part of the cardiac conduction system (CCS), a chain of specialised tissue that directs electrical impulses through the heart and thus co-ordinates the way it contracts. The CCS is defined by a specific pattern of gene expression, differing to the surrounding 'working myocardium'. During early embryogenesis as the heart tube forms, mesodermal cells quickly multiply and differentiate into working cardiomyocytes capable of contraction and fast conduction.7 However, the CCS is derived from primary myocardium that is instead led down a different lineage directed by specific transcription factors (Figure 1). 7Tbx3 is a T-box transcription factor found selectively within the CCS.Transgenic mice have been used to demonstrate its role in repressing working myocardial development and promoting a pacemaker programme of genes.8 These include key pacemaker genes, such as those encoding the low conductance gap junction connexin (Cx)45 and the hyperpolarisation-activated cyclic nucleotide-gated (HCN) membrane ion channel. 8,9 The function of HCN channels within the SAN is discussed below.The SAN is derived from an area of the developing CCS called the sinus venosus. The sinus venosus expresses a homeobox regulatory gene named Shox2.10 Sho...

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“…Injection into such areas could generate atrial demand pacing to patients with symptomatic sinus bradycardia. 51 What is the likelihood that some of the approaches to biological pacing will reach clinical testing?…”

Section: From Experimental Study To Clinical Trial?mentioning

confidence: 99%