Functional anatomy of the murine sinus node: high-resolution optical mapping of ankyrin-B heterozygous mice

Glukhov, Alexey V.; Fedorov, Vadim V.; Anderson, Mark E.; Mohler, Peter J.; Efimov, Igor R.

doi:10.1152/ajpheart.00756.2009

Cited by 77 publications

(82 citation statements)

References 29 publications

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“…Recently, Fedorov et al (15,17) found discrete exit points in the canine SAN but, in a study of murine hearts, did not note any (18). In our rabbit model, exit points were functional and anatomically distinct exit points were not necessary for proper physiological function.…”

Section: Discussioncontrasting

confidence: 54%

Onset of atrial arrhythmias elicited by autonomic modulation of rabbit sinoatrial node activity: a modeling study

Munoz

Kaur

Vigmond

2011

American Journal of Physiology-Heart and Circulatory Physiology

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Muñoz MA, Kaur J, Vigmond EJ. Onset of atrial arrhythmias elicited by autonomic modulation of rabbit sinoatrial node activity: a modeling study. Am J Physiol Heart Circ Physiol 301: H1974-H1983, 2011. First published August 19, 2011 doi:10.1152/ajpheart.00059.2011.-Neuronal modulation of the sinoatrial node (SAN) plays a crucial role in the initiation and maintenance of atrial arrhythmias (AF), although the exact mechanisms remain unclear. We used a computer model of a rabbit right atrium (RA) with a heterogeneous SAN and detailed ionic current descriptions for atrial and SAN myocytes to explore reentry initiation associated with autonomic activity. Heterogeneous acetylcholine (ACh)-dependent ionic responses along with L-type Ca current (ICa,L) upregulation were incorporated in the SAN only. During control, activation was typical with the leading pacemaker site located close to the superior vena cava or the intercaval region. With cholinergic stimulation, activation patterns frequently included caudal shifts of the leading pacemaker site and occasional double breakouts. The model became increasingly arrhythmogenic for the ACh concentration Ͼ20 nM and for large ICa,L conductance. Reentries obtained included counterclockwise rotors in the free wall, clockwise reentry circulating between the SAN and free wall, and typical flutter. The SAN was the cause of reentry with a common leading sequence of events: a bradycardic beat with shifting in the caudal direction, followed by a premature beat or unidirectional block within the SAN. Electrotonic loading, and not just overdrive pacing, squelches competing pacemaker sites in the SAN. Cholinergic stimulation concomitant with I Ca,L upregulation shifts leading pacemaker site and can lead to reentry. A heterogeneous response to autonomic innervation, a large myocardial load, and an extensive SAN in the intercaval region are required for neurally induced SAN-triggered reentry. electrophysiology; reentry; autonomic innervation ATRIAL FIBRILLATION (AF) is the most common and diverse cardiac arrhythmia (21). Experimental observations have illustrated the crucial role that neuronal mechanisms have in its initiation and maintenance (33). Atrial arrhythmias can be induced in dogs by localized electrical stimuli applied to nerve branches of the thoracic vagosympathetic complex (31) or mediastinal nerves (2, 31). Experiments show that acetylcholine (ACh) can trigger reentry and AF in the right atrium (RA) and that adrenergic stimulation facilitates both AF initiation and maintenance (33). Atropine completely abolishes bradycardia and subsequent tachyarrhythmias, indicating that cholinergic efferents play a predominant role in induction (33).Different studies describe a similar sequence of events for arrhythmias originating in the RA that were induced by neural stimulation: cycle length (CL) prolongation, often with leading pacemaker site (LPS) shifting, followed by an atrial premature beat (APB), and subsequent tachyarrhythmia (1, 2, 31, 33). The escape beat initiating the tachyarr...

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Section: Discussioncontrasting

confidence: 54%

Onset of atrial arrhythmias elicited by autonomic modulation of rabbit sinoatrial node activity: a modeling study

Munoz

Kaur

Vigmond

2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…Such a mechanism has been shown for SAN dysrhythmia. 36 It is quite possible that in WT mice HCN1 channel activity at the resting membrane potential increases the membrane conductance, stabilizes 1 leading pacemaker focus, and thus decreases beat-to-beat fluctuations in the heart. In addition, HCN1 channels could protect the SAN from excess hyperpolarizing electrotonic loading by the surrounding atrium, which could significantly slow pacemaking 37 and could impair sinoatrial conduction.…”

Section: Discussionmentioning

confidence: 99%

Sick Sinus Syndrome in HCN1-Deficient Mice

et al. 2013

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Among these channels, HCN (hyperpolarization-activated cyclic nucleotide-gated) channels, which are the molecular correlate of hyperpolarization-activated current (I f ), 14 are considered to be of particular importance. Three of the 4 members of the HCN channel family (HCN1, HCN2, and HCN4) have been identified in pacemaker cells. Quantitatively, in all vertebrates studied so far, HCN4 underlies the major fraction of SAN I f , amounting to ≈70% to 80% of the total I f . HCN4 is essential for the formation of mature pacemaker cells during embryogenesis.15 Moreover, analysis of human HCN4 channelopathies 16 and genetic mouse models 1,17,18 (see also the work by Herrmann et al 9 and Hoesl et al 10 ) suggests that this channel plays an important role in autonomic control of heart rate. Mice deficient in HCN2 display mild cardiac dysrhythmia, whereas autonomic control of heart rate is preserved in these mice. 11,19 In contrast to HCN4 and HCN2, the role of HCN1 in heart has not yet been examined. HCN1 was originally cloned from mouse brain. 20 Indeed, analysis of HCN1 knockout (KO) mice revealed that this channel is involved in the control of Background-Sinus node dysfunction (SND) is a major clinically relevant disease that is associated with sudden cardiac death and requires surgical implantation of electric pacemaker devices. Frequently, SND occurs in heart failure and hypertension, conditions that lead to electric instability of the heart. Although the pathologies of acquired SND have been studied extensively, little is known about the molecular and cellular mechanisms that cause congenital SND. Methods and Results-Here, we show that the HCN1 protein is highly expressed in the sinoatrial node and is colocalized with HCN4, the main sinoatrial pacemaker channel isoform. To characterize the cardiac phenotype of HCN1-deficient mice, a detailed functional characterization of pacemaker mechanisms in single isolated sinoatrial node cells, explanted beating sinoatrial node preparation, telemetric in vivo electrocardiography, echocardiography, and in vivo electrophysiology was performed. On the basis of these experiments we demonstrate that mice lacking the pacemaker channel HCN1 display congenital SND characterized by bradycardia, sinus dysrhythmia, prolonged sinoatrial node recovery time, increased sinoatrial conduction time, and recurrent sinus pauses. As a consequence of SND, HCN1-deficient mice display a severely reduced cardiac output. Conclusions-We propose that HCN1 stabilizes the leading pacemaker region within the sinoatrial node and hence is crucial for stable heart rate and regular beat-to-beat variation. Furthermore, we suggest that HCN1-deficient mice may be a valuable genetic disease model for human SND. (Circulation. 2013;128:2585-2594.)

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“…SAN and atrial optical mapping. Optical mapping of spontaneous pacemaker activity and conduction velocity was performed as described previously (57).…”

Section: Methodsmentioning

confidence: 99%

Oxidized CaMKII causes cardiac sinus node dysfunction in mice

et al. 2011

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Sinus node dysfunction (SND) is a major public health problem that is associated with sudden cardiac death and requires surgical implantation of artificial pacemakers. However, little is known about the molecular and cellular mechanisms that cause SND. Most SND occurs in the setting of heart failure and hypertension, conditions that are marked by elevated circulating angiotensin II (Ang II) and increased oxidant stress. Here, we show that oxidized calmodulin kinase II (ox-CaMKII) is a biomarker for SND in patients and dogs and a disease determinant in mice. In wild-type mice, Ang II infusion caused sinoatrial nodal (SAN) cell oxidation by activating NADPH oxidase, leading to increased ox-CaMKII, SAN cell apoptosis, and SND. p47 --mice lacking functional NADPH oxidase and mice with myocardial or SAN-targeted CaMKII inhibition were highly resistant to SAN apoptosis and SND, suggesting that ox-CaMKII-triggered SAN cell death contributed to SND. We developed a computational model of the sinoatrial node that showed that a loss of SAN cells below a critical threshold caused SND by preventing normal impulse formation and propagation. These data provide novel molecular and mechanistic information to understand SND and suggest that targeted CaMKII inhibition may be useful for preventing SND in high-risk patients. IntroductionEach normal heart beat is initiated as an electrical impulse from a small number of highly specialized sinoatrial node (SAN) pacemaker cells that reside in the lateral right atrium. There is now general agreement that physiological SAN function requires a pacemaker current (I f ) (1) and spontaneous release of sarcoplasmic reticulum (SR) intracellular Ca 2+ that triggers depolarizing current through the Na + /Ca 2+ exchanger (I NCX ) (2, 3). The multifunctional Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) is essential for increasing SR Ca 2+ release in SAN cells in response to stress to cause physiological "fight-or-flight" heart rate (HR) increases (4). Although the physiological basis for SAN behavior is increasingly understood, very little is known about SAN disease. Severe SAN dysfunction (SND) is marked by irregular prolonged pauses between heart beats, pathologically slow HRs at rest, and inadequate activity-related increases in HR. At present, surgical implantation of permanent pacemakers is required for treatment of SND and costs $2 billion annually in the United States (5). SND commonly occurs in the setting of heart failure and hypertension (6-8), conditions characterized by excessive activation of renin-Ang II signaling (9) and elevated levels of ROS (10). Ang II increases ROS in ventricular myocardium by stimulating NADPH oxidase to cause activation of CaMKII (ox-CaMKII) by oxidation of Met281/282 in the CaMKII regulatory domain (11).

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Functional anatomy of the murine sinus node: high-resolution optical mapping of ankyrin-B heterozygous mice

Cited by 77 publications

References 29 publications

Onset of atrial arrhythmias elicited by autonomic modulation of rabbit sinoatrial node activity: a modeling study

Onset of atrial arrhythmias elicited by autonomic modulation of rabbit sinoatrial node activity: a modeling study

Sick Sinus Syndrome in HCN1-Deficient Mice

Oxidized CaMKII causes cardiac sinus node dysfunction in mice

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