Simultaneous epicardial–endocardial mapping of the sinus node in humans with structural heart disease: Impact of overdrive suppression on sinoatrial exits

doi:10.1016/j.hrthm.2020.06.034

Heart Rhythm

Volume 17, Issue 12, December 2020, Pages 2154-2163

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https://doi.org/10.1016/j.hrthm.2020.06.034 Get rights and content

Background

The 3-dimensional (3D) nature of sinoatrial node (SAN) function has not been characterized in the intact human heart.

Objective

The purpose of this study was to characterize the 3D nature of SAN function in patients with structural heart disease (SHD) using simultaneous endocardial–epicardial (endo–epi) phase mapping.

Methods

Simultaneous intraoperative endo–epi SAN mapping was performed during sinus rhythm at baseline (SR_baseline) and postoverdrive suppression at 600 ms (SR_post-pace600) and 400 ms (SR_post-pace400) using 2 Abbott Advisor HD Grid Mapping Catheters. Unipolar and bipolar electrograms (EGMs) were exported for phase analysis to determine (1) activation exits; (2) wavefront propagation sequence; (3) endo–epi dissociation; and (4) fractionation. Comparison of these variables was made among the 3 rhythms from an endo–epi perspective.

Results

Sixteen patients with SHD were included. SR_baseline activations were unicentric and predominantly exited cranially (87.5%) with endo–epi synchrony. However, with overdrive suppression, a tendency for caudal exit shift and endo–epi asynchrony was observed: SR_post-pace600 vs SR_baseline: cranial endo 75% vs 87.5% (P = .046); cranial epi 68.8% vs 87.5% (P = 0.002); caudal endo 12.5% vs 6.2% (P = 0.215); caudal epi 25% vs 6.2% (P = .0003); and SR_post-pace400 vs SR_baseline: cranial endo 81.3% vs 87.5% (P = 0.335); cranial epi 68.7% vs 87.5% (P = 0.0034; caudal endo 12.5% vs 6.2% (P = .148); caudal epi 31.2% vs 6.2% (P = 0.0017), consistent with multicentricity. EGM fractionation was more prevalent with overdrive suppression.

Conclusion

During mapping of the intact human heart, SAN demonstrated redundancy of sinoatrial exits with postoverdrive shift in sites of earliest activation and epi–endo dissociation of sinoatrial exits.

Graphical abstract

Introduction

The sinoatrial node (SAN) is a collection of specialized cells that are situated at the junction of the superior vena cava (SVC) and right atrium (RA) in the epicardial sulcus terminalis and extend a variable distance along the long axis of the crista terminalis inferiorly.¹^,² Human mapping studies have suggested an extensive integrated sinus pacemaker complex with dynamic variation in the site of earliest activation.3, 4, 5

Recent studies using integrated intramural optical mapping combined with 3-dimensional (3D) histologic reconstruction in isolated preparations have demonstrated the 3D nature of the SAN. Multiple pacemaker sites and multiple preferential sinoatrial conduction pathways (SACPs) exist with both endocardial and epicardial exits. With suppression of 1 pacemaker or conduction pathway, activation of a subsidiary pacemaker with conduction over an alternate pathway maintains SAN function.⁶^,⁷ This redundancy of pacemakers and conduction pathways results in a robust system that is resistant to failure.

Sick sinus syndrome is the most common indication for bradycardia pacing and usually occurs in the context of advanced SAN and atrial remodeling.⁴^,8, 9, 10 In this setting, atrial arrhythmias frequently coexist, and pauses usually occur immediately after termination of atrial fibrillation (AF).¹¹ Although the 3D nature of atrial conduction has been demonstrated in isolated preparations, the relative importance of endocardial and epicardial SAN exits and how they are modified by overdrive suppression in the intact atrium has not been evaluated.

In this study, we used simultaneous endocardial and epicardial phase mapping of the SAN during sinus rhythm (SR) and after overdrive suppression to further characterize the preferential nature of sinoatrial conduction in humans with structural heart disease (SHD) undergoing cardiac surgery.

Section snippets

Study population

Patients undergoing cardiac surgery for ischemic and/or valvular heart disease at Royal Melbourne Hospital, Melbourne, Australia, were included. Patients with a history of catheter ablation for atrial arrhythmias were excluded. All patients gave written informed consent before the surgery. The study protocol was approved by the research and ethics committee of Melbourne Health.

Data acquisition

After median sternotomy and before cardiopulmonary bypass, simultaneous epicardial and endocardial mapping of the

Baseline characteristics

We studied 16 patients (12 male; age 60.5 ± 4.1 years) who underwent cardiac surgery for ischemic heart disease or valvulopathy. None of the patients had symptomatic SAN dysfunction. Mean left atrial volume of the cohort was 58 ± 12.4 mL/m². A minority of patients (n = 3) had a history of paroxysmal AF. Baseline characteristics of the study population are given in Table 1.

Sinus node exits: Baseline vs postoverdrive suppression

A total of 149 activations were analyzed (9.3 ± 1.4 per patient). Mean cycle length during SR_baseline was 902 ± 126 ms.

Discussion

Simultaneous endo–epi phase mapping of human SAN in patients with SHD at baseline and postoverdrive suppression revealed the following key findings. (1) Predominant cranial exits with symmetrical activation sites on the endocardial and epicardial surfaces during SR_baseline. (2) Postpacing caudal shift in the activation exits with marked asymmetry in endo–epi exit sites consistent with multicentricity and redundancy of sinoatrial conduction. Differential epi–endo breakout sites resulted in

Conclusion

In the current study, we performed simultaneous epi–endo mapping of the human sinus node in the intact heart to further characterize the 3D characteristics of sinus node function and the impact of overdrive suppression. After overdrive suppression there was a tendency to caudal shift in exits, differential and hence multicentric endo–epi breakthroughs, asymmetrical wavefront propagation associated with EED, and increased EGM fractionation.

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Left atrial appendage isolation in addition to pulmonary vein isolation in persistent atrial fibrillation: one-year clinical outcome after cryoballoon-based ablation
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Redundant and diverse intranodal pacemakers and conduction pathways protect the human sinoatrial node from failure
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Three-dimensional functional anatomy of the human sinoatrial node for epicardial and endocardial mapping and ablation
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Citation Excerpt :
Furthermore, ex vivo NIOM studies suggest that transmural conduction from intramural SAN pacemaker through superior and/or inferior SACP to atria can lead to differences between epicardial vs endocardial layers where exits from the SAN head could be predicted to be seen earlier on epicardium vs endocardium, whereas exits from SAN tail will be seen earlier on endocardium vs epicardium (Figure 5D).20,21 Using simultaneous endocardial and epicardial mapping of the human SAN, Parameswaran et al44 demonstrated postpacing caudal shift in SAN exits with marked asymmetry in endo–epicardial exit sites, resulting in significant postpacing endo–epicardial dissociation of activation (Figure 5E). These findings of complex intramural SAN activation and exit patterns add to the challenges of meaningful electrode mapping.
The sinoatrial node (SAN) is the primary pacemaker of the human heart. It is a single, elongated, 3-dimensional (3D) intramural fibrotic structure located at the junction of the superior vena cava intercaval region bordering the crista terminalis (CT). SAN activation originates in the intranodal pacemakers and is conducted to the atria through 1 or more discrete sinoatrial conduction pathways. The complexity of the 3D SAN pacemaker structure and intramural conduction are underappreciated during clinical multielectrode mapping and ablation procedures of SAN and atrial arrhythmias. In fact, defining and targeting SAN is extremely challenging because, even during sinus rhythm, surface-only multielectrode mapping may not define the leading pacemaker sites in intramural SAN but instead misinterpret them as epicardial or endocardial exit sites through sinoatrial conduction pathways. These SAN exit sites may be distributed up to 50 mm along the CT beyond the ∼20-mm-long anatomic SAN structure. Moreover, because SAN reentrant tachycardia beats may exit through the same sinoatrial conduction pathway as during sinus rhythm, many SAN arrhythmias are underdiagnosed. Misinterpretation of arrhythmia sources and/or mechanisms (eg, enhanced automaticity, intranodal vs CT reentry) limits diagnosis and success of catheter ablation treatments for poorly understood SAN arrhythmias. The aim of this review is to provide a state-of-the-art overview of the 3D structure and function of the human SAN complex, mechanisms of SAN arrhythmias and available approaches for electrophysiological mapping, 3D structural imaging, pharmacologic interventions, and ablation to improve diagnosis and mechanistic treatment of SAN and atrial arrhythmias.
Characterization of the pace-and-drive capacity of the human sinoatrial node: A 3D in silico study
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Citation Excerpt :
These observations highlight the importance of the SEP dimensions, which modulate the hyperpolarizing effect of the CT cells on the SAN cells. Robust SAN pace-and-drive capacity depends on the ability to shift the LPS to avoid exit block and overcome the source-sink mismatch (2,6,7,11,18,24,25,40,54), combined with the variability of the default LPS location from one patient to another (52). However, the reasons that lead to an LPS shift remained largely unclear, and Kharche et al., for instance, modeled this phenomenon by displacing the LPS arbitrarily to different locations (25).
The sinoatrial node (SAN) is a complex structure that spontaneously depolarizes rhythmically (“pacing”) and excites the surrounding non-automatic cardiac cells (“drive”) to initiate each heart beat. However, the mechanisms by which the SAN cells can activate the large and hyperpolarized surrounding cardiac tissue are incompletely understood. Experimental studies demonstrated the presence of an insulating border that separates the SAN from the hyperpolarizing influence of the surrounding myocardium, except at a discrete number of sinoatrial exit pathways (SEPs). We propose a highly detailed 3D model of the human SAN, including 3D SEPs to study the requirements for successful electrical activation of the primary pacemaking structure of the human heart. A total of 788 simulations investigate the ability of the SAN to pace and drive with different heterogeneous characteristics of the nodal tissue (gradient and mosaic models) and myocyte orientation. A sigmoidal distribution of the tissue conductivity combined with a mosaic model of SAN and atrial cells in the SEP was able to drive the right atrium (RA) at varying rates induced by gradual If block. Additionally, we investigated the influence of the SEPs by varying their number, length, and width. SEPs created a transition zone of transmembrane voltage and ionic currents to enable successful pace and drive. Unsuccessful simulations showed a hyperpolarized transmembrane voltage (−66 mV), which blocked the L-type channels and attenuated the sodium-calcium exchanger. The fiber direction influenced the SEPs that preferentially activated the crista terminalis (CT). The location of the leading pacemaker site (LPS) shifted toward the SEP-free areas. LPSs were located closer to the SEP-free areas (3.46 $\pm$ 1.42 mm), where the hyperpolarizing influence of the CT was reduced, compared with a larger distance from the LPS to the areas where SEPs were located (7.17 $\pm$ 0.98 mm). This study identified the geometrical and electrophysiological aspects of the 3D SAN-SEP-CT structure required for successful pace and drive in silico.
Inappropriate Sinus Tachycardia: Etiology, Pathophysiology, and Management: JACC Review Topic of the Week
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Historically, sinus impulse was envisioned as originating from a discrete focus at the superior vena cava (SVC)/right atrial junction and propagating through specialized atrial conducting tissue.12 However, advances in multi-electrode mapping have led to the identification of the 3-dimensional complexity of the sinus node with different exits at various heart rates.13 In addition, Brennan et al14 demonstrated the presence of spatially distinct dual sino atrial (SA) nodal sites.
Inappropriate sinus tachycardia (IST) is a clinical syndrome that generally affects young patients and is associated with distressing symptoms. Although the most common symptom is palpitations, it can be accompanied by a myriad of symptoms, including anxiety, dizziness, presyncope, and syncope. The pathogenesis of IST is not well understood and considered multifactorial, with autonomic dysfunction being the central abnormality. IST is a diagnosis of exclusion. Management presents a clinical challenge. The overall efficacy of lifestyle modifications and medical therapy may be limited. Recent advances in catheter and surgical sinus node sparing ablation techniques have led to improvement in outcomes. In addition, increased focus has led to development of multimodality team-based interventions to improve outcomes in this group of patients. In this review, we discuss the mechanistic basis of IST, review current approaches to diagnosis, and outline contemporary therapeutic approaches.
Sinus node exit, crista terminalis conduction, interatrial connection, and wavefront collision: Key features of human atrial activation in sinus rhythm
2022, Heart Rhythm
Citation Excerpt :
Considerable efforts have been invested in understanding atrial activation during sinus rhythm. However, most studies conducted over the past decades have faced one of the following pitfalls: (1) abnormal tissue remodeling, when fibrotic atria with altered wavefront propagation were included for analysis; (2) low spatial resolution, due to poor reconstruction accuracy or recording density as provided by early electroanatomic mapping systems; and (3) piecemeal electrophysiological study, when limited to 1 atrium or even 1 atrial structure.4–12 To circumvent these limitations, we sought to comprehensively characterize normal atrial activation in patients with preserved voltage using stepwise biatrial high-density mapping focused on the interplay between distinct activation sequences in sinus rhythm.
An understanding of normal atrial activation during sinus rhythm can inform catheter ablation strategies to avoid deleterious impacts of ablation lesions on atrial conduction and mechanics.
The purpose of this study was to describe how the sinus node impulse originates, propagates, and collides in right and left atria with normal voltage.
Fifty consecutive patients undergoing catheter ablation of atrial fibrillation with endocardial atrial voltage >0.5 mV during high-density 3-dimensional mapping were studied.
Sinus node exits varied among patients along a lateral oblique arc extending from the anterior aspect of the superior vena cava (SVC) to the mid-posterior wall of the right atrium (RA). Conduction slowing or block at one of the smooth components that faces the crista terminalis was observed in 54% of cases, including complete block at the SVC musculature and systemic venous sinus in 6% of cases. Depending on these 2 key features of RA activation, interatrial conduction was mediated by the Bachmann bundle (64%) and posterior bundles (54%), with an overlap of the resulting left atrial breakthrough location. Wavefront collision was consistently observed at 3 sites: the septal aspect of the cavotricuspid isthmus, and the lower aspects of the dome and of the mitral isthmus.
During sinus rhythm, atrial activation occurs via distinct sequences mediated by a complex interaction of anatomic factors.
Endo-Epicardial Mapping of In Vivo Human Sinoatrial Node Activity
2021, JACC: Clinical Electrophysiology
Citation Excerpt :
Previous research has shown that EEA in the atrial wall plays an important role in the development of atrial tachyarrhythmias and may initiate re-entry (9,19,20). A recent study by Parameswaran et al. (6) also identified EEA at SAN exit sites (4 × 4 electrodes, 3-mm interelectrode distance). EEA was determined by: 1) comparing regional differences in distribution of SAN exit sites; 2) assessing the endo-epicardial wave front propagation sequence; and 3) determining the difference in phase value ≥20 ms between opposing endo-epicardial electrodes.
The aim of the current study was to examine electrophysiological characteristics of sinoatrial node (SAN) activity from an endo-epicardial perspective.
Electrophysiological properties of the in vivo human SAN and its exit pathways remain poorly understood.
Twenty patients (75% male; median age 66 years [59 to 73 years]) with structural heart disease underwent simultaneous endo-epicardial mapping (256 unipolar electrodes, interelectrode distance 2 mm). Conduction times, endo-epicardial delays (EEDs), and R/S ratio were examined in the surrounding 10 mm of SAN activation. Areas of conduction block were defined as conduction delays ≥12 ms and endo-epicardial asynchrony as EED ≥15 m.
Three distinct activation patterns were observed in a total of 28 SAN–focal activation patterns (SAN-FAPs) (4 patients exhibited >1 different exit site), including SAN activation patterns with: 1) solely an endocardial exit site (n = 10 [36%]); 2) solely an epicardial exit site (n = 13 [46%]); and 3) simultaneously activated endo-epicardial exit sites (n = 5 [18%]). Median (interquartile range) EED at the origin of the SAN-FAP was 10 ms (6 to 14 ms) and the prevalence of endo-epicardial asynchrony in the surroundings of the SAN-FAP was 5% (2% to 18%). Electrograms at the origin of the SAN-FAPs exhibited significantly larger R-peaks in the mid right atrium (RA) compared with the superior RA (mid R/S ratio 0.15 [0.067 to 0.34] vs. superior R/S ratio 0.045 [0.026 to 0.062]; p = 0.004). Conduction velocity within a distance of 10 mm from the SAN-FAP was 125 cm/s (80 to 250 cm/s). All 6 SAN-FAPs at the mid RA were observed in patients with a history of atrial fibrillation.
Variations in activation patterns of the SAN observed in this study highlight the complex 3-dimensional SAN geometry and indicate the presence of interindividual differences in SAN exit pathways. Solely in patients with a history of atrial fibrillation, SAN activity occurred more caudally, which indicates changes in preferential SAN exit pathways.
To the Editor—Investigating sinoatrial node activation during sinus rhythm using phase mapping
2021, Heart Rhythm

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: Funding sources/Disclosures: Drs Parameswaran, Nalliah, Wong, Anderson, Voskoboinik, Sugumar, and Chieng are supported by the National Health and Medical Research Council (NHMRC) research scholarship. Drs Kalman and Sanders are supported by practitioner fellowships from the NHMRC. Dr Morris is supported by a British Heart Foundation Intermediate Fellowship; has reported receiving research support from Boston Scientific and Medtronic; and has served on the advisory board of Boston Scientific and Biosense Webster. Dr Kalman has reported receiving research support from Biosense Webster, Boston Scientific, Abbott, and Medtronic; and has served on the advisory board of Boston Scientific and Biosense Webster. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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ClinicalImaging/MappingSimultaneous epicardial–endocardial mapping of the sinus node in humans with structural heart disease: Impact of overdrive suppression on sinoatrial exits

Background

Objective

Methods

Results

Conclusion

Graphical abstract

Introduction

Section snippets

Study population

Data acquisition

Baseline characteristics

Sinus node exits: Baseline vs postoverdrive suppression

Discussion

Conclusion

Prog Biophys Mol Biol

J Mol Cell Cardiol

JACC Clin Electrophysiol

J Am Coll Cardiol

The form and nature of the muscular connections between the primary divisions of the vertebrate heart

J Anat Physiol

Atrial activation mapping in sinus rhythm in the clinical electrophysiology laboratory

J Cardiovasc Electrophysiol

Electrophysiological and electroanatomic characterization of the atria in sinus node disease

Circulation

Left atrial appendage isolation in addition to pulmonary vein isolation in persistent atrial fibrillation: one-year clinical outcome after cryoballoon-based ablation

Europace

Redundant and diverse intranodal pacemakers and conduction pathways protect the human sinoatrial node from failure

Sci Transl Med

Clinical
Imaging/Mapping
Simultaneous epicardial–endocardial mapping of the sinus node in humans with structural heart disease: Impact of overdrive suppression on sinoatrial exits