Monopolar biphasic focal pulsed field ablation directly at the atrioventricular junction and from within the noncoronary cusp: The PFA-CONDUCT study.

Selective cardioneuroablation of the posteromedial left ganglionated plexus for drug-resistant swallow syncope with functional atrioventricular block

Atrioventricular nodal reentrant tachycardia in patients with complex congenital heart disease and twin atrioventricular nodes

POSTER PRESENTATIONS

Atrioventricular nodal reentrant tachycardia (AVNRT) represents the most common regular supraventricular arrhythmia in humans.1 The precise anatomic site and nature of the pathways involved have not yet been established, and several attempts to provide a reasonable hypothesis based on anatomic or anisotropic models have been made.2 There has been considerable evidence that the right and left inferior extensions of the human atrioventricular (AV) node and the atrionodal inputs they facilitate may provide the anatomic substrate of the slow pathway, and a comprehensive model of the tachycardia circuit for all forms of AVNRT based on the concept of atrionodal inputs has been proposed.2 Still, however, the circuit of AVNRT remains elusive. Recently, time-honored conventional schemes for the diagnosis and classification of the various forms of the arrhythmia have been refuted in part by evolving evidence. Recognition of the various types of AVNRT is important, however, to expedite diagnosis and allow implementation of appropriate ablation therapy without complications. We present an update on AVNRT with a particular emphasis on electrophysiological criteria used for the differential diagnosis of regular, supraventricular tachycardias. Typically, AVNRT is a narrow-complex tachycardia, ie, QRS duration <120 ms, unless aberrant conduction, which is usually of the right bundle-branch type, or a previous conduction defect exists. Tachycardia-related ST depression and RR-interval variation may be seen. RR alternans in AVNRT has been attributed to the proposed model of a figure of 8 reentry with continuous crossing over of antegrade activation through an inferior input to the contralateral superior input via the node.2 In the typical form of AVNRT (slow-fast), abnormal (retrograde) P′ waves are constantly related to the QRS and in the majority of cases are indiscernible or very close to the QRS complex (RP′/RR <0.5). Thus, P′ waves are either masked by the QRS complex or …

The concept of cooling to treat medical disorders dates back to the ancient Egyptian Edwin Smith Papyrus on surgical trauma, written between 3000 and 2500 B.C. Hypothermic therapy was recommended for abscesses that were "oily, like fluid under thy hand, [which] produce some clamminess of the surface."1 Modern forms of cryothermal tissue ablation have been used surgically for decades in numerous organ systems and for various pathologies. Unlike heat that destroys cells by coagulation and tissue necrosis with potential for thrombus formation and aneurysmal dilatation, cryoablation involves a distinct pathophysiological process. As such, it carries a unique safety and efficacy profile. While not novel as an energy modality, harnessing cryoenergy into a steerable transcatheter format represents a more recent landmark in the history of arrhythmia therapy. In Part I of this two-part series, we will focus on the body of knowledge underlying the development of a transcatheter cryoablation system. Pertinent features related to biophysics and mechanisms of cryothermal tissue injury will be highlighted, key historical developments considered, and experience gained from cryosurgery with hand-held probes summarized. Preclinical studies with transcatheter cryoablation will be detailed, setting the framework for human applications. Part II of this series will review the current state of knowledge regarding clinical experience with transcatheter cryoablation. The objective of cryoablation is to freeze tissue in a discrete and focused fashion to destroy cells in a targeted area. Simplifying complex mechanisms of cellular injury, tissue damage involves freezing and thawing, hemorrhage and inflammation, replacement fibrosis, and apoptosis.2 Hypothermia causes cardiomyocytes to become less fluid as metabolism slows, ion pumps lose transport capabilities, and intracellular pH becomes more acidic.3 These effects are entirely transient, provided that the duration of nonfreezing cooling temperatures does not exceed a few minutes. Indeed, the briefer the exposure to a hypothermic insult, the more rapidly cells recover. As a clinical correlate, this characteristic of cryoenergy permits functional assessment of putative ablation sites (i.e., cryomapping) without cellular destruction. In contrast, the hallmark of permanent tissue injury is ice formation. As cells are rapidly cooled to freezing temperatures, ice crystals form within the extracellular matrix and then intracellularly as well.4 The size of ice crystals and their density is dependent on proximity to the cryoenergy source, the local tissue temperature achieved, and the rate of freezing. While the crystals do not characteristically destroy cell membranes, they compress and deform nuclei and cytoplasmic components.5, 6 Mitochondria are particularly sensitive to ice crystals and are the first structures to suffer irreversible damage.7-9 Upon completion of freezing, the tissue passively returns to body temperature, resulting in a "thawing effect." This is an important component of cryoablation, as rewarming causes intracellular crystals to enlarge and fuse into larger masses that extend cellular destruction.3, 4, 10, 11 Hemorrhage12 and inflammation6 characterize the second later phase of cryoablation.2 In what has been termed a "solution effect," water migrates out of myocardial cells to reestablish the osmotic equilibrium that was disturbed by ice crystals. In effect, this increases the intracellular solute concentration to a hyperosmotic state that may damage cell membranes.10 As the microcirculation is restored to previously frozen tissue, edema ensues. The fluid traverses damaged microvascular endothelial cells, resulting in ischemic necrosis. In the final phase of cryoinjury, replacement fibrosis and apoptosis of cells near the periphery of frozen tissue give rise to a mature lesion within weeks.13 Typically, these lesions are well circumscribed, with distinct borders, dense areas of fibrotic tissue, contraction band necrosis, and a conserved tissue matrix, including endothelial cell layers.14 Cryosurgical devices cooled by liquid nitrogen were introduced in the early 1960s.15 This technology was extended to treat a wide spectrum of pathologies including dermatologic, prostatic, hepatic, gynecologic, ophthalmologic, neurosurgical, and oncologic disorders.3, 16-18 Preceding these widespread applications, Hass19 and Taylor et al.20 first described predictable controlled myocardial lesions with cryoenergy using carbon dioxide as a refrigerant. Initial descriptions of tissue characteristics remain valid today. Notably, lesions were described as homogeneous and sharply demarcated with preserved ultrastructural integrity. These attributes, with absence of aneurysmal dilation or rupture, were attributed to the remarkable resilience of collagen and fibroblasts to hypothermal injury.21 Table I summarizes key historical landmarks in the development of a transvenous cryoablation system for cardiac arrhythmias.15, 19, 21-25 It was in 1964 that Lister et al.22 first described the application of cryoenergy to the cardiac conduction tissue by suturing a 4-mm "U"-shaped silver tube near the bundle of His. This may be considered the origin of "cryomapping" as well. Sinus node function was inhibited by cooling with an alcohol and carbon dioxide mixture at −10°C to −20°C. At the atrioventricular (AV) node, PR interval prolongation occurred at −45°C and progressed to high-grade AV block. Normal AV conduction resumed almost instantaneously upon discontinuation of cooling. In 1977, Harrison et al.21 introduced cryosurgery with hand-held bipolar electrode probes, first in 20 dogs with AV nodal ablation followed by three patients with refractory supraventricular tachycardia. Under cardiopulmonary bypass, complete but reversible AV block was achieved in all patients when the temperature of the nitrous oxide probe was lowered to 0°C at the His bundle site. Permanent complete AV block resulted when the temperature was further lowered to −60°C for 90 to 120 seconds and at least two consecutive freeze/thaw cycles were delivered. Longer-term follow-up on a larger series was later reported, with AV block achieved successfully in 17 of 22 patients.26 Additional studies reported similar results.27-29 Approaches not requiring extracorporeal bypass were later devised.28, 30, 31 Bredikis28 described a technique consisting of two atriotomy incisions; one for digital palpation and the second for the cryoprobe. Positioning of the cryoprobe was guided by recording electrodes, cryomapping, and/or pressure-induced AV block. Using this method, complete AV block was achieved in 85% of 34 patients28 and 92% of 72 patients.30 Louagie et al.31 proposed an alternative epicardial approach via the right coronary fossa. Gallagher and coworkers32 reported the first two cases of successful cryosurgical accessory pathway ablation in 1977. One pathway was concealed and paraseptal and the second manifest and left-sided. Several case series followed,33-38 with the largest reporting an epicardial approach in 105 consecutive patients with Wolff-Parkinson-White syndrome (74 left lateral, 23 paraseptal, and 11 right ventricular free wall).36 The AV fat pat was mobilized and dissected and the accessory pathway exposed and cryoablated. All but one patient had acutely successful ablation. However, four required repeat interventions for what the authors believed were subendocardial pathways protected by warming effects of circulating blood. A different approach to ablation was described in a series of 21 patients.34 Left-sided pathways were targeted by cryoprobes designed to enter the coronary sinus, obviating the need for extracorporeal bypass. Overall, 19 of 21 patients were successfully treated. Acute rupture of the coronary sinus occurred in two instances and required surgical ligation. In 1978, Gallagher et al.39 cryosurgically ablated a pharmacologically resistant ventricular tachycardia focus in the anterior right ventricular free wall with three 90-second applications at −60°C. A second case was reported the following year.40 Cryosurgery has since become a recognized treatment for selected patients with refractory ventricular arrhythmias,16, 27, 41-44 often as an adjunct to more extensive surgery including aneurysmectomy, subendocardial resection, encircling endocardial ventriculotomy, coronary artery bypass grafting, and valvar replacement.2 To date, no prospective studies have compared cryosurgical efficacy and safety to other treatment modalities. With cryosurgery alone, Caceres et al.45 and others46 reported 93% event-free follow-up in patients with refractory ventricular tachycardia. These results compare favorably to historical cohorts that used other surgical modalities for ventricular tachycardia.46-48 Surgical cryoablation has also been described for less common arrhythmias including nodoventricular tachycardia,49 sinoatrial reentrant tachycardia,50 ventricular disabling bigeminy,51 bidirectional bundle branch reentry tachycardia,52 and fetal malignant tachyarrhythmias.53 It has also been used in AV nodal reentrant tachycardia and other arrhythmias with rapid AV conduction with the shared objective of slowing but preserving nodal conduction.54-56 Holman et al.57 successfully eliminated dual AV nodal physiology in three dogs. Cox et al.58 later applied hand-held cryoprobes to eight patients with drug-refractory AV nodal reentry tachycardia. All patients were successfully treated without requiring permanent pacing, although right bundle-branch block was induced in three cases. Animal studies of cryosurgical ablation have characterized lesions and demonstrated that dimensions relate to temperature of the cryoprobe and myocardium, probe diameter in contact with cardiac tissue, exposure time, and number of freeze/thaw cycles.12, 59-61 Longer duration of freezing and lower temperatures produce larger lesions, although a plateau is reached within five minutes.6, 10 Double freeze/thaw cycles generate larger lesions than single applications of longer duration.62, 63 Such parameters could be varied to produce predictable lesions.11, 61 As illustrated in Figure 1, cardiac cryosurgery is still used today, although less commonly. Insights gained from the cryosurgical experience contributed invaluably to conceptualizing the modern transcatheter cryoablation system. Surgical ablation with a cryoprobe. Gillette et al. reported the first animal study using a transvenous cryocatheter in 1991.23 In five miniature swine, complete AV block was produced with an 11-French cryocatheter cooled by pressurized nitrous oxide. Cryothermia was applied for three minutes and repeated up to three times. Four of the five pigs remained in AV block for one hour, while one recovered partially with 2:1 AV conduction. Histologically, acute lesions were sharply delineated and hemorrhagic. In a chronic study of eight swine, successive three-minute cryoapplications were delivered to the AV junction at −60°C via 8 or 11-French cryocatheters.64 Long-term AV block was maintained in five of eight animals. At six weeks, well-defined dense lesions were noted histologically, free of inflammation or thrombus formation. Although feasibility of transcatheter cryolesion formation was demonstrated, limited success was attributed to lack of steerability and recording electrodes. Cryocatheter placement required using a second catheter to record local signals. Transcatheter cryoablation was revived several years later, ultimately leading to clinical use. We reported the first animal experiment using a steerable cryocatheter with integrated recording and pacing electrodes in 1998.24 Right and left ventricular lesions were created in six dogs using a 9-French catheter with a 4-mm electrode tip and Halocarbon 502 (Freon®) as a refrigerant. Cryomapping (i.e., reversible ice mapping) of the AV node was demonstrated by sequentially applying lower temperatures to the AV nodal junction. When high-degree AV block or >50% PR prolongation was achieved, the cryoapplication was interrupted. In all cases, 1:1 AV conduction resumed within seconds. No lesion was identifiable on gross and microscopic histopathology. In a further study of cryomapping with more detailed electrophysiological measurements, reversible AV nodal effects were achieved in seven of eight dogs at a mean temperature of −40°C.13 Parameters including sinus cycle length, atrial-His (AH) interval, His ventricular (HV) interval, Wenckebach cycle length, and AV node effective refractory periods, measured before, 20 minutes, 60 minutes, and up to 56 days after cryomapping were not significantly different. Chronic cryoablation lesions, created at a mean temperature −55°C, were later characterized in nine mongrel dogs sacrificed three and six weeks after ablation.13 Histologically, well-demarcated ultrastructurally intact lesions devoid of thrombus were observed. Similar results were obtained with 8.5-French cryocatheters in six dogs65 and seven pigs.66 To better define optimal cryoablation parameters, single versus double freeze/thaw cycles were compared at the lowest temperature (−50°C to −55°C) permitted by the system at the time.13 These lesions were applied to sites where cryomapping (>−40°C) had been successful. Permanent chronic AV block was achieved in all six dogs with double freeze/thaw cycles compared to only one of six with single freeze/thaw cycles. Consonant with this observation, intralesion residual strands of viable tissue were noted histologically with single but not double freeze/thaw cycles. Thus, at these temperature and freezing rates, double cycles were more effective than single ones for AV nodal ablation. Larger lesions with more extensive tissue injury have been consistently reported with double freeze/thaw cycles applied to other organs as well.3, 17 However, later iterations of the transcatheter cryoablation system permitted lower attainable temperatures (−80°C) and faster cooling rates when nitrous oxide was used as a refrigerant. Cryobiology experts have since refrained from systematically recommending double freeze/thaw cycles. Preclinical studies contributed importantly to our understanding of the impact of cooling rate and catheter tip-temperature on tissue effects.3, 13, 16, 24, 27 Cooling first occurs at the distal catheter tip in contact with endocardial tissue. Freezing then extends radially into the tissues, establishing a temperature gradient. The lowest temperature and fastest freezing rate is generated at the point of contact, with slower tissue cooling rates more peripherally. Of importance, as distant tissue achieves a temperature in the order of −20°C to −30°C, a "dynamic cryomap" is obtained. Reversible local tissue effects precede cell death. A clinical corollary is that despite an initial reassuring cryomap, vigilance for perinodal substrates is mandated as the iceball continues to expand during cryoablation and the centrifugal temperature gradient further extends into the tissue.12, 13, 24, 60, 61 The first cryosurgical device developed by Cooper in 196315 produced cooling by means of a liquid to gas phase change in nitrogen. Principles such as the Joule-Thompson effect (cooling by expansion of a compressed gas after passage through a needle valve) and Peltier effect (thermoelectric cooling) have been incorporated into the design of cryoprobes.11, 16 A variety of devices were developed using several methods of refrigeration and numerous cryogens including nitrogen, nitrous oxide, solid carbon dioxide, argon, and several fluorinated hydrocarbons.3 We initially described a transvenous cryocatheter system that used Halocarbon 502 (Freon®) as a refrigerant (Cryocath Technologies Inc., Montreal, Canada)24 (Fig. 2). The refrigerant was later changed to Genetron® AZ-2067 and then nitrous oxide,14 used currently. The cryocatheter essentially consists of a hollow shaft with a closed distal end containing a cooling electrode tip and three proximal ring electrodes for recording and pacing. A central console that contains the refrigerant fluid releases the cryogen under pressure. The cooling liquid travels through the inner delivery lumen to the distal electrode that is maintained under vacuum. At the cryocatheter tip, the liquid cryogen boils. This accelerated liquid-to-gas phase change results in rapid cooling of the distal tip. The gas is then conducted away from the catheter tip via a vacuum return lumen and back to the console where it is collected and restored to its liquid state. Temperature is recorded at the distal tip by an integrated thermocouple device. Catheter cryoablation system. Reproduced with permission from Dubuc et al.,24 Please see text for a detailed description of the various components. Several theoretical advantages are noted when cryoablation is compared to radiofrequency (RF) energy, as summarized in Table II. With hypothermia generated at the distal cooling electrode, the catheter adheres to tissue affording greater catheter stability. Metaphorically, this has been likened to the adhesiveness of a wet tongue contacting a frozen pole. Since the catheter is latched on to endocardium, programmed electrical stimulation may be performed during cryoablation without concern for catheter dislodgement. Moreover, "brushing effects" that occur during beat-to-beat rocking heart motions and with respiratory variations are eliminated. This advantage may be particularly profitable if the arrhythmogenic substrate is located at a site where contact is difficult to maintain24, 25 or ablation of nearby tissue is deemed hazardous. It also permits ablation to be performed during tachycardia without the menace of catheter dislodgement upon abrupt arrhythmia termination. In a preclinical study of 22 mongrel dogs,14 RF and cryolesion dimensions created by 4-mm-tip catheters were compared. Overall, RF lesions were of greater surface area (42 vs 20 mm2, P = 0.0018), with nearly significantly larger volumes (95 vs 43 mm3, P = 0.0585). Notably, no difference in lesion depth was observed (5 to 6 mm). Histologically, cryolesions were more homogeneous with clearer and smoother demarcations from underlying normal myocardium, as shown in Figure 3. In contrast, RF lesions had rougher more ragged edges. Thus, more focused lesions were noted with cryoablation. Additionally, sharper borders may theoretically be less arrhythmogenic.13, 65 Border zones with damaged but viable cells are more susceptible to spontaneous depolarization. Histological characteristics one week after cryoablation when magnified 16-fold. Note the homogeneous cryolesion with a smooth border, sharp demarcation from intact myocardium, and absence of thrombus. Indentation of the lesion surface arose from mechanical catheter pressure. Cryolesion dimensions created by 9 versus 7-French catheters were equal in depth but greater in surface area and volume.14 Colder temperatures were associated with deeper lesions. On average, achieving a peak temperature 10°C colder resulted in a lesion 0.4-mm deeper (P = 0.0001). Not unexpectedly, ventricular lesions were deeper than their atrial counterparts and all atrial lesions were transmural. It was therefore demonstrated that larger lesions could be created by reducing the temperature or increasing the surface area of the catheter tip in contact with endocardium.61 A more recent in vitro experiment conducted on porcine ventricular myocardium found that lesion dimensions and tissue temperatures were modulated by convective warming as controlled by superfusate flow, electrode orientation, contact pressure, electrode size, and catheter refrigerant flow rate.68 Catheter size modified the effect of electrode temperature on lesion dimensions. To compare thrombogenesis of RF and cryoenergy ablation, we conducted a randomized preclinical study involving 197 ablation lesions in 22 dogs at right atrial, right ventricular, and left ventricular sites.14 RF energy was five times more thrombogenic than cryoablation by histological morphometric analyses seven days after ablation. Moreover, thrombus volume was significantly greater with RF compared to cryoablation (P < 0.0001). Interestingly, the extent of hyperthermic tissue injury was positively correlated with thrombus bulk. This was unlike cryoenergy, where lesion dimensions were not predictive of thrombus size. It was conjectured that this disparity likely reflected the fact that intact tissue ultrastructure with endothelial cell preservation was maintained with cryoenergy. In the 1990s, the ability to provide continuous real-time imaging of the freezing process was considered a major technological advancement that sparked renewed interest in visceral cryosurgery.3 Indeed, ultrasonographic monitoring of the freeze/thaw cycle and frozen tissue volume contributed to rapid improvements in hepatic and prostatic surgery. The ability to visualize "ice ball" formation by ultrasonic means was similarly demonstrated in preclinical transcatheter cryoablation studies.13 Using a 12.5-MHz rotating transducer mounted on a 6.2-French catheter, intracardiac ultrasound was performed in six dogs who received double freeze/thaw cycles. Endocardial contact was confirmed by echocardiography and serial measurements were made to assess ice ball growth. Intracardiac echocardiography clearly identified ice ball formation as a hypoechogenic density with a bordering and No of was observed during cryoablation. The size of the ice ball was shown to enlarge during the first three minutes of the freezing cycle and remain These the current to the cryoablation to four minutes. Several have been regarding RF ablation near the and within the coronary sinus RF ablation the and may fibrosis and and are potential However, the is coronary artery The and/or right coronary artery may in proximity to the arrhythmia Moreover, the AV nodal artery near the of the coronary ablation may damage this Preclinical studies a lower of coronary artery following cryoablation compared to RF ablation. In an study in to within the and distal coronary sinus, no coronary was observed and coronary artery and were In a et demonstrated that cryoablation in the coronary sinus within of the left artery produced myocardial lesions similar to RF energy but with a of coronary artery Histologically, of the randomized to RF energy had coronary artery damage compared to with cryoablation. The of and clinical experience with surgical cryoablation the for transcatheter cryoablation. potential advantages were demonstrated in preclinical including catheter for thrombus temperature for reversible ultrasonographic and delineated focused lesions. cryoablation systems were as catheter were to the 7-French mechanisms and modified to more rapid cooling and lower a the initial 9-French steerable catheter with cooling and a temperature of was into the modern 7-French with rapid cooling and temperatures In transcatheter cryoablation was first applied to This was in by a in and

Concealed bundle of his extrasystoles simulating nonconducted atrial premature beats

Catheter ablation as a treatment of atrioventricular block

Advantages and pitfalls of selective cardioneuroablation targeting the atrioventricular node

The prevalence of adult congenital heart disease (ACHD) has risen markedly over the past 2 decades, with the number of adults now rivaling the number of children with severe defects.1 This is, perhaps, not surprising given that current care allows nearly 90% of infants born with heart defects to thrive into their adult years.1,2 This remarkable triumph is tempered, however, by the realization that early interventions were reparative and not curative. Numerous complications may surface years after uneventful childhood courses, justifying vigilant clinical follow-up throughout adulthood. The 12-lead ECG remains an invaluable cornerstone in the clinical appraisal of adults with congenital heart disease that, in certain circumstances, provides diagnostic and/or prognostic information. The present review imparts a clinical perspective to ECG interpretation in ACHD, emphasizing practical and pathogenomonic findings in the more frequently encountered congenital defects in adults. Anatomic features of the conduction system relevant to ECG findings in ACHD are summarized, including variations in the location of the sinus node, atrioventricular (AV) node, and His-Purkinje system. Thereafter, pertinent ECG features are highlighted for common subtypes of ACHD (Table). Examples are provided throughout for illustration. View this table: Table. Typical ECG Features in Common Forms of ACHD ### Sinus Node In the morphologically normal heart, a crescent-shaped sinus node is characteristically located epicardially along the lateral aspect of the superior cavoatrial junction. It generates a P-wave axis typically between 15° and 75°. Most patients with ACHD have normally positioned atrial chambers, called atrial situs solitus, with normal sinus node location. The position of the sinus node may, however, vary with the atrial chambers and their appendages. #### Juxtaposition of the Atrial Appendages In juxtaposition of the atrial appendages, both appendages are on the same side of the arterial pedicle rather than each being ipsilateral to its respective atrium. Left juxtaposition, with left-sided atrial appendages, frequently accompanies tricuspid atresia and has …

Radiofrequency (RF) ablation is effective for ablation of atrial arrhythmias. However, RF ablation in the vicinity of the atrioventricular (AV) node is associated with a risk of inadvertent, irreversible high-grade AV block, depending on the type of substrate. Cryoablation is an alternative method. The objective was to investigate the acute and long-term risks of AV block during cryoablation. We studied 1303 consecutive cryoablations of substrates in the vicinity of the AV node in 1201 patients (median age 51 years, range 6-89 years) on acute and long-term impairment to the AV nodal conduction system. The arrhythmias treated were AV nodal reentrant tachycardias (n=1116), paraseptal and superoparaseptal accessory pathways (n=100), and focal atrial tachycardias (n=87). In 158 (12%) procedures, cryomapping (38 cases) or cryoablation (120 cases) were stopped due to transient AV block (first-degree AV block 74 cases, second-degree AV block 67 cases, and third-degree AV block 17 cases) after which another site was tested. Transient AV block occurred within seconds of mapping up to 3 min of ablation. The incidence of AV block was similar for different substrates. In most cases, AV nodal conduction was restored within seconds but in two cases transient AV block lasted 21 and 45 min, respectively. There were no cases of acute permanent AV blocks. No late AV blocks occurred during follow-up (mean 24 months, range 6-96 months). Cryoablation adjacent to the AV node carries a negligible risk of permanent AV block. Transient AV block during ablation is a benign finding.

Closed chest catheter desiccation of the atrioventricular junction using radiofrequency energy—A new method of catheter ablation

Optical mapping of the atrioventricular junction

Third‐Degree Atrioventricular Block in a Horse Secondary to Rattlesnake Envenomation

BackgroundSecond-degree atrioventricular (AV) block at rest is very common in horses. The underlying molecular mechanisms are unexplored, but commonly attributed to high vagal tone.AimTo assess whether AV block in horses is due to altered expression of the effectors of vagal signalling in the AV node, with specific emphasis on the muscarinic acetylcholine receptor (M2) and the G protein-gated inwardly rectifying K+ (GIRK4) channel that mediates the cardiac IK,ACh current.MethodEighteen horses with a low burden of second-degree AV block (median 8 block per 20 h, IQR: 32 per 20 h) were assigned to the control group, while 17 horses with a high burden of second-degree AV block (median: 408 block per 20 h, IQR: 1,436 per 20 h) were assigned to the AV block group. Radiotelemetry ECG recordings were performed to assess PR interval and incidence of second-degree AV block episodes at baseline and on pharmacological blockade of the autonomic nervous system (ANS). Wenckebach cycle length was measured by intracardiac pacing (n = 16). Furthermore, the expression levels of the M2 receptor and the GIRK4 subunit of the IKACh channel were quantified in biopsies from the right atrium, the AV node and right ventricle using immunohistochemistry and machine learning-based automated segmentation analysis (n = 9 + 9).ResultsThe AV block group had a significantly longer PR interval (mean ± SD, 0.40 ± 0.05 s; p < 0.001) and a longer Wenckebach cycle length (mean ± SD, 995 ± 86 ms; p = 0.007) at baseline. After blocking the ANS, all second-degree AV block episodes were abolished, and the difference in PR interval disappered (p = 0.80). The AV block group had significantly higher expression of the M2 receptor (p = 0.02), but not the GIRK4 (p = 0.25) in the AV node compared to the control group. Both M2 and GIRK4 were highly expressed in the AV node and less expressed in the atria and the ventricles.ConclusionHere, we demonstrate the involvement of the m2R-IK,ACh pathway in underlying second-degree AV block in horses. The high expression level of the M2 receptor may be responsible for the high burden of second-degree AV blocks seen in some horses.

Selective experimental chelation of calcium in the AV node and His bundle