RawECGNet: Deep Learning Generalization for Atrial Fibrillation Detection From the Raw ECG.

INTRODUCTION: Deep learning models for detecting episodes of atrial fibrillation (AF) using rhythm information in long-term ambulatory ECG recordings have shown high performance. However, the rhythm-based approach does not take advantage of the morphological information conveyed by the different ECG waveforms, particularly the f-waves. As a result, the performance of such models may be inherently limited. METHODS: To address this limitation, we have developed a deep learning model, named RawECGNet, to detect episodes of AF and atrial flutter (AFl) using the raw, single-lead ECG. We compare the generalization performance of RawECGNet on two external data sets that account for distribution shifts in geography, ethnicity, and lead position. RawECGNet is further benchmarked against a state-of-the-art deep learning model, named ArNet2, which utilizes rhythm information as input. RESULTS: Using RawECGNet, the results for the different leads in the external test sets in terms of the F1 score were 0.91-0.94 in RBDB and 0.93 in SHDB, compared to 0.89-0.91 in RBDB and 0.91 in SHDB for ArNet2. The results highlight RawECGNet as a high-performance, generalizable algorithm for detection of AF and AFl episodes, exploiting information on both rhythm and morphology.

Postoperative intravenous patient-controlled analgesia improves pain management after subcutaneous implantable defibrillator implantation.

Objective: Postoperative pain is a major issue with subcutaneous implantable cardioverter defibrillators (S-ICD). In 2020, we introduced intravenous patient-controlled analgesia (IV-PCA) in addition to the conventional, request-based analgesia for postoperative pain control in S-ICD. To determine the effect and safety, we quantitatively assessed the effect of IV-PCA after S-ICD surgery over conventional methods. Methods: During the study period, a total of 113 consecutive patients (age, 50.1 ± 15.5 years: males, 101) underwent a de novo S-ICD implantation under general anesthesia. While the postoperative pain was addressed with either request-based analgesia (by nonsteroid anti-inflammatory drugs, N = 68, dubbed as "PCA absent") or fentanyl-based IV-PCA in addition to the standard care (N = 45, dubbed as "PCA present"). The degree of postoperative pain from immediately after surgery to 1 week were retrospectively investigated by the numerical rating scale (NRS) divided into four groups at rest and during activity (0: no pain, 1-3: mild pain, 4-6: moderate pain, 7-10: severe pain). Results: Although IV-PCA was removed on Day 1, it was associated with continued better pain control compared to PCA absent group. At rest, the proportion of patients expressing pain (mild or more) was significantly lower in the PCA present group from Day 0 to Day 4. In contrast to at rest, a better pain control continued through the entire study period of 7 days. No serious adverse events were observed. A few patients experienced nausea in both groups and the inter-group difference was not found significant. Conclusion: IV-PCA suppresses postoperative pain in S-ICD without major safety concerns.

Synergistic Effect of Motivation for the Elderly and Support for Going Out II: Measures to Induce Elderly Men to Go Out.

BACKGROUND: The second demonstration experiment of supporting elderly people going out with the Choisoko system was conducted. The first study showed that for women, friends, shopping, convenience, and events are factors that have the potential to be effective motivational factors for encouraging these women to go out. On the other hand, these factors did not lead to any behavioral change in men. Since there are approximately 15 million men over the age of 65 in Japan, behavioral changes in the entire elderly population will not occur without guidance for elderly men to go out. METHODS: Sixteen elderly men and forty-seven elderly women participated. Interestingly, men are far more passionate about games than women. Therefore, we hypothesized that a preference for games could be a hint as to how we might encourage older men to go out. Then, a second demonstration experiment was conducted, and we analyzed the relationship between six game preferences and the frequency of going out. RESULTS: Among gaming preferences, men with gaming preferences such as Philanthropists, Achievers, and Free Spirits showed a tendency to go out. CONCLUSIONS: These stimuli may have the potential to be factors that may encourage elderly men to go out.

Does the same lesion index mean the same efficacy and safety profile: influence of the differential power, time, and contact force on the lesion size and steam pops under the same lesion index.

BACKGROUND: The lesion index (LSI) helps predict the lesion size and is widely used in ablation of various types of arrhythmias. However, the influence of the ablation settings on the lesion formation and incidence of steam pops under the same LSI value remains unclear. METHODS: Using a contact force (CF) sensing catheter (TactiCath™) in an ex vivo swine left ventricle model, RF lesions were created with a combination of various power steps (30 W, 40 W, 50 W) and CFs (10 g, 20 g, 30 g, 40 g, 50 g) under the same LSI values (5.2 and 7.0). The correlation between the lesion formation and ablation parameters was evaluated. RESULTS: Ninety RF lesions were created under a target LSI value of 5.2, and eighty-four were developed under a target LSI value of 7.0. In the LSI 5.2 group, the resultant lesion size widely varied according to the ablation power, and a multiple regression analysis indicated that the ablation energy delivered was the best predictor of the lesion formation. To create a lesion depth > 4 mm, an ablation energy of 393 J is the best cutoff value, suggesting a possibility that ablation energy may be used as a supplemental marker that better monitors the progress of the lesion formation in an LSI 5.2 ablation. In contrast, such inconsistency was not obvious in the LSI 7.0 group. Compared with 30 W, the 50-W ablation exhibited a higher incidence of steam pops in both the LSI 5.2 and 7.0 groups. CONCLUSIONS: The LSI-lesion size relationship was not necessarily consistent, especially for an LSI of 5.2. To avoid any unintentional, weak ablation, the ablation energy may be a useful supportive parameter (393 J as a cutoff value for a 4-mm depth) during ablation with an LSI around 5.2. Thanks to a prolonged ablation time, the LSI-lesion size relationship is consistent for an LSI of 7.0. However, it is accompanied by a high incidence of steam pops. Care should be given to the ablation settings even when the same LSI value is used.

Influence of the irrigation flow pattern and catheter tip design on the lesion formation: an ex vivo experimental model.

BACKGROUND: Lesion formation during catheter ablation is influenced by the power, contact force (CF), time, and catheter stability. However, the influence of the irrigation effects on lesion formation remains unknown. METHODS: An ex vivo experiment using conductive gel was performed. Using three different catheter designs (TactiFlex ™ SE [TF], IntellaNav MiFi ™ OI [MiFi], QDOT MICRO™ [QDOT]), a cross-sectional analysis of the lesion size and surface lesion type of 10g/40W lesions with a combination of various ablation times was performed in protocol 1. A longitudinal analysis (combination of various powers [30, 40, and 50W] and various ablation times with a 10g setting) was performed to investigate the influence of the auto-regulated irrigation system (QDOT) on lesion formation in protocol 2. RESULTS: The lesion formation with the QDOT catheter tended to create larger ablation lesions, while that with the TF catheter created smaller lesions than the other catheters. The lesion surface characteristics were divided into two patterns: ring (MiFi catheter and QDOT) and crescent (TF) patterns. The auto-regulated irrigation system did not influence the lesion formation, and the relationship between the lesion formation and RF energy exhibited similar changes regardless of the ablation power setting. CONCLUSION: The lesion formation and lesion surface characteristics differed among the different irrigation tip designs. An auto-regulated irrigation system did not affect the lesion creation or surface lesion characteristics. Care should be given to the inter-product differences in the lesion characteristics during RF catheter ablation, partly due to the irrigation flow control and tip design.

Age-dependent contribution of intrinsic mechanisms to sinoatrial node function in humans.

Average beat interval (BI) and beat interval variability (BIV) are primarily determined by mutual entrainment between the autonomic-nervous system (ANS) and intrinsic mechanisms that govern sinoatrial node (SAN) cell function. While basal heart rate is not affected by age in humans, age-dependent reductions in intrinsic heart rate have been documented even in so-called healthy individuals. The relative contributions of the ANS and intrinsic mechanisms to age-dependent deterioration of SAN function in humans are not clear. We recorded ECG on patients (n = 16 < 21 years and n = 23 41-78 years) in the basal state and after ANS blockade (propranolol and atropine) in the presence of propofol and dexmedetomidine anesthesia. Average BI and BIV were analyzed. A set of BIV features were tested to designated the "signatures" of the ANS and intrinsic mechanisms and also the anesthesia "signature". In young patients, the intrinsic mechanisms and ANS mainly contributed to long- and short-term BIV, respectively. In adults, both ANS and intrinsic mechanisms contributed to short-term BIV, while the latter also contributed to long-term BIV. Furthermore, anesthesia affected ANS function in young patients and both mechanisms in adult. The work also showed that intrinsic mechanism features can be calculated from BIs, without intervention.

Venous thoracic outlet syndrome, as a pitfall for cardiac implantable electronic device implantations.

The subclavian vein is typically used in cardiovascular implantable electronic device (CIED) implantations. External stress on the subclavian vein can lead to lead-related complications. There are several causes of this stress, such as frequent upper extremity movements or external injury. Venous thoracic outlet syndrome (TOS) can also become the cause of external lead stress. However, the diagnosis of venous TOS can be challenging because subclavian venography can appear normal at first glance. We present a unique case of a device infection in a patient with venous TOS. A careful observation of the imaging studies is vital for diagnosing venous TOS and a leadless pacemaker implantation could be an alternative therapeutic option.

cAMP signaling affects age-associated deterioration of pacemaker beating interval dynamics.

Sinoatrial node (SAN) beating interval variability (BIV) and the average beating interval (BI) are regulated by a coupled-clock system, driven by Ca2+-calmodulin activated adenylyl cyclase, cAMP, and downstream PKA signaling. Reduced responsiveness of the BI and BIV to submaximal, [X]50, ß-adrenergic receptor (ß-AR) stimulation, and phosphodiesterase inhibition (PDEI) have been documented in aged SAN tissue, whereas the maximal responses, [X]max, do not differ by age. To determine whether age-associated dysfunction in cAMP signaling leads to altered responsiveness of BI and BIV, we measured cAMP levels and BI in adult (2-4 months n = 27) and aged (22-26 months n = 25) C57/BL6 mouse SAN tissue in control and in response to ß-AR or PDEI at X50 and [X]max. Both cAMP and average BI in adult SAN were reduced at X50, whereas cAMP and BI at Xmax did not differ by age. cAMP levels and average BI were correlated both within and between adult and aged SAN. BIV parameters in long- and short-range terms were correlated with cAMP levels for adult SAN. However, due to reduced cAMP within aged tissues at [X]50, these correlations were diminished in advanced age. Thus, cAMP level generated by the coupled clock mechanisms is tightly linked to average BI. Reduced cAMP level at X50 in aged SAN explains the reduced responsiveness of the BI and BIV to ß-AR stimulation and PDEI.

Detailed investigation of the lesion formation with a novel contact force sensing catheter with a mesh-shaped irrigation tip.

Background: Recently, a novel contact force (CF) sensing catheter with mesh-shaped irrigation tip (TactiFlex SE, Abbott) was invented and is expected to be useful for safe and effective radiofrequency ablation. However, this catheter's detailed characteristics of the lesion formation are unknown. Methods: With an in vitro model, TactiFlex SE and its predecessor, FlexAbility SE, were used. A cross-sectional analysis of 60 s lesions (combination of various energy power settings [30, 40, and 50 W], and CFs [10, 30, and 50 g]) and longitudinal analysis (combination of various powers [40 or 50 W], CFs [10, 30, and 50 g] and ablation times [10, 20, 30, 40, 50, and 60 s]) of both catheters were analyzed and compared. Results: One hundred eighty RF lesions were created in protocol 1 and 300 in protocol 2. The lesion formation, impedance changes, and steam pops characteristics were similar between the two catheters. Higher CFs were related to higher incidences of steam pops. A nonlinear, time-dependent increase in the lesion depth and diameter was observed for all power and CF settings, and linear, positive correlations between the RF delivery time and lesion volume were observed for all power settings. Compared with 40 W, a 50 W ablation created greater lesions. Longer durations with higher CF settings had a higher steam pop incidence. Conclusions: The lesion formation and incidence of steam pops with TactiFlex SE and FlexAbility SE were similar. A 40 or 50 W ablation with careful CF control not to exceed 30 g in addition to monitoring impedance drops was required to safely create transmural lesions.

Detailed analysis of the lesion formation using a diamond tip catheter in an ex vivo experimental model.

BACKGROUND: A novel Diamond Temp™ (DT; Medtronic, Minneapolis, MN, USA) catheter has enabled performing a surface temperature-controlled ablation. The chemical vapor deposition diamond of the ablation catheter acts as a thermal radiator and is useful for effective cooling of the ablation catheter tip. However, a detailed analysis of the lesion formation with this catheter remains unknown. METHODS: DT catheters were used in an excised swine heart experimental model. A cross-sectional analysis of 60-s lesions [a combination of various energy power settings (30, 40, and 50 W), and various contact forces (CF) (10, 30, and 50 g)] and a longitudinal analysis [a combination of various powers (40 W or 50 W), various CFs (10, 30, and 50 g), and various ablation times (5 s, 10 s, 15 s, 20 s, 25 s, 30 s, and 60 s)] of the DT catheter were analyzed. RESULTS: The maximum lesion depth, maximum diameter, and lesion volume with a 10 g ablation were significantly lower than those with a 30 g or 50 g ablation. There were no significant differences in the lesion formation between the 30 g ablation and 50 g ablation under each radiofrequency (RF) power setting. The impedance drops with steam pops were significantly greater than those without steam pops (pop (+) vs. pop (-), 26.2 ±â€¯6.6 Ohm vs. 18.4 ±â€¯7.1 Ohm, p = 0.0001). A non-linear, time-dependent increase in the lesion depth and diameter was observed for all power and CF settings. Comparing the lesion depth and diameter between 40 W and 50 W under the same CF setting and same ablation time, most of the settings had no significant difference. CONCLUSION: Ablation lesions created with the DT catheter were similar to other catheters. Similar ablation lesions were created with the 40 W or 50 W ablation under the same CF setting and same ablation time. Regardless of the ablation power, monitoring the general impedance during the RF application was indispensable for a safe procedure.

Generalizable and robust deep learning algorithm for atrial fibrillation diagnosis across geography, ages and sexes.

To drive health innovation that meets the needs of all and democratize healthcare, there is a need to assess the generalization performance of deep learning (DL) algorithms across various distribution shifts to ensure that these algorithms are robust. This retrospective study is, to the best of our knowledge, an original attempt to develop and assess the generalization performance of a DL model for AF events detection from long term beat-to-beat intervals across geography, ages and sexes. The new recurrent DL model, denoted ArNet2, is developed on a large retrospective dataset of 2,147 patients totaling 51,386 h obtained from continuous electrocardiogram (ECG). The model's generalization is evaluated on manually annotated test sets from four centers (USA, Israel, Japan and China) totaling 402 patients. The model is further validated on a retrospective dataset of 1,825 consecutives Holter recordings from Israel. The model outperforms benchmark state-of-the-art models and generalized well across geography, ages and sexes. For the task of event detection ArNet2 performance was higher for female than male, higher for young adults (less than 61 years old) than other age groups and across geography. Finally, ArNet2 shows better performance for the test sets from the USA and China. The main finding explaining these variations is an impairment in performance in groups with a higher prevalence of atrial flutter (AFL). Our findings on the relative performance of ArNet2 across groups may have clinical implications on the choice of the preferred AF examination method to use relative to the group of interest.

Optimal local impedance parameters for successful pulmonary vein isolation in patients with atrial fibrillation.

INTRODUCTION: Local impedance (LI) parameters of IntellaNav STABLEPOINT for successful pulmonary vein isolation (PVI) of atrial fibrillation (AF) remain unclear. The purpose of this study was to seek LI data achieving successful PVI. METHODS: Consecutive AF patients who underwent catheter ablation with STABLEPOINT were prospectively enrolled in two centers. PVI was performed under a constant 35-or 40-watt power, 20-s duration, and >5-g contact force. The operators were blinded to the LI data. The characteristics of all ablation points with/without conduction gaps (Unsuccess or Success tags) after the first-attempt PVI were evaluated for the right/left PVs and anterior/posterior wall (RPV/LPV and AW/PW, respectively), and cutoff values of LI data were calculated for successful lesion formation. RESULTS: A total of 5257 ablation points in 102 patients (65 [58-72] years old, 65.7% male) were evaluated. The LI drop values were higher in the Success tags than Unsuccess tags on the LPV-AW and RPV-AW/PW (p < .001), except for the LPV-PW (p = .105). The %LI drop values (LI drop/initial LI) were higher for the Success tags in all areas (15.8 [12.2%-19.6%] vs. 11.6 [9.7%-15.6%] in LPV-AW: p < .001, 15.0 [11.5%-19.3%] vs. 11.4 [8.7%-17.3%] in LPV-PW: p = .035, 15.3 [11.5%-19.4%] vs. 9.9 [8.1%-13.7%] in RPV-AW: p < .001, and 13.3 [10.1%-17.4%] vs. 8.1 [6.3%-9.5%] in RPV-PW, p < .001). The LI drop and %LI drop cutoff values were 20.0 ohms and 11.6%, respectively. CONCLUSIONS: An insufficient LI drop with STABLEPOINT was associated with a gap formation during PVI, and the best cutoff values for the LI drop and %LI drop were 20.0 ohms and 11.6%, respectively.

Changes in cAMP signaling are associated with age-related downregulation of spontaneously beating atrial tissue energetic indices.

The prevalence of atria-related diseases increases exponentially with age and is associated with ATP supply-to-demand imbalances. Because evidence suggests that cAMP regulates ATP supply-to-demand, we explored aged-associated alterations in atrial ATP supply-to-demand balance and its correlation with cAMP levels. Right atrial tissues driven by spontaneous sinoatrial node impulses were isolated from aged (22-26 months) and adult (3-4 months) C57/BL6 mice. ATP demand increased by addition of isoproterenol or 3-Isobutyl-1-methylxanthine (IBMX) and decreased by application of carbachol. Each drug was administrated at the dose that led to a maximal change in beating rate (Xmax) and to 50% of that maximal change in adult tissue (X50). cAMP, NADH, NAD + NADH, and ATP levels were measured in the same tissue. The tight correlation between cAMP levels and the beating rate (i.e., the ATP demand) demonstrated in adult atria was altered in aged atria. cAMP levels were lower in aged compared to adult atrial tissue exposed to X50 of ISO or IBMX, but this difference narrowed at Xmax. Neither ATP nor NADH levels correlated with ATP demand in either adult or aged atria. Baseline NADH levels were lower in aged as compared to adult atria, but were restored by drug perturbations that increased cAMP levels. Reduction in Ca2+-activated adenylyl cyclase-induced decreased cAMP and prolongation of the spontaneous beat interval of adult atrial tissue to their baseline levels in aged tissue, brought energetics indices to baseline levels in aged tissue. Thus, cAMP regulates right atrial ATP supply-to-demand matching and can restore age-associated ATP supply-to-demand imbalance.

Impact of long-term optimizing atrioventricular delay using device-based algorithms on cardiac resynchronization therapy.

Sub-optimal atrioventricular delay (AVD) is one of the main causes of non-responder for cardiac resynchronization therapy (CRT). Recently, device-based algorithms (DBAs) that provide optimal AVD based on intracardiac electrograms, have been developed. However, their long-term effectiveness is still unknown. This study aims to investigate the effect of optimizing AVD using DBAs over a long period, on the prognosis of patients undergoing CRT. A total of 118 patients who underwent CRT at our hospital between April 2008 and March 2018, were retrospectively reviewed; 61 of them with optimizing AVD using DBAs were classified into the treated group (group 1), and the remaining 57 were classified into the control group (group 2). The median follow-up period was 46.0 months. The responder and survival rate in group 1 were significantly better than those in group 2 (group 1 vs. group 2: responder rate = 64% vs. 46%, p = 0.046; survival rate: 85.2% vs. 64.9%, p = 0.02). Moreover, investigating only the non-responder population showed that group 1 had an improved survival rate compared to group 2 (group 1 vs. group 2 = 72.7% vs. 45.1%, p = 0.02). Optimizing AVD using DBAs was a significant contributor to the improved survival rate in CRT non-responders in multivariate analysis (HR 3.6, p = 0.01). In conclusion, the long-term optimizing AVD using DBAs improved the survival rate in CRT and the prognosis of CRT non-responders, as well.

Efficacy of SubcutAneous implantable cardioVErter-defibrillators in ≤18 year-old CHILDREN: SAVE-CHILDREN registry.

BACKGROUND: In adult patients, subcutaneous implantable cardioverter defibrillators (S-ICDs) have been reported to be non-inferior to transvenous ICDs with respect to the incidence of device-related complications and inappropriate shocks. Only a few reports have investigated the efficacy of S-ICDs in the pediatric field. This study aimed to investigate the utility and safety of S-ICDs in patients ≤18 years old. METHODS: This study was a multicenter, observational, retrospective study on S-ICD implantations. Patients <18 years old who underwent S-ICD implantations were enrolled. The detailed data on the device implantations and eligibility tests, incidence of appropriate- and inappropriate shocks, and follow-up data were assessed. RESULTS: A total of 62 patients were enrolled from 30 centers. The patients ranged in age from 3 to 18 (median 14 years old [IQR 11.0-16.0 years]). During a median follow up of 27 months (13.3-35.8), a total of 16 patients (26.2%) received appropriate shocks and 13 (21.3%) received inappropriate shocks. The common causes of the inappropriate shocks were sinus tachycardia (n = 4, 30.8%) and T-wave oversensing (n = 4, 30.8%). In spite of the physical growth, the number of suitable sensing vectors did not change during the follow up. No one had any lead fractures or device infections in the chronic phase. CONCLUSIONS: Our study suggested that S-ICDs can prevent sudden cardiac death in the pediatric population with a low incidence of lead complications or device infections. The number of suitable sensing vectors did not change during the patients' growth.

Time dependency in the radiofrequency lesion formation for a local impedance guided catheter in an ex vivo experimental model.

Background: The local impedance (LI) is an emerging technology that monitors tissue-catheter coupling during radiofrequency (RF) ablation. The relationships between the LI, RF delivery time, and lesion formation remain unclear. Methods: Using an LI-enabled RF catheter in an ex vivo experimental model, RF lesions were created combined with various steps in the power (40 and 50 W), CF (10 g, 30 g, and 50 g), and time (10s, 20s, 30s, 40s, 50s, and 60s at 40 W and 5 s, 10s, 20s, 30s, 40s, 50s, and 60s at 50 W). The correlations between the LI drop, lesion size, and RF delivery time were evaluated. The rate of change in the time-dependent gain in the LI, depth, and diameter and the time to reach 90% decay of the peak dY/dT (time to 90% decay) were assessed. Results: The correlation between the LI drop and ablation time revealed non-linear changes. The time to a 90% decay in the LI drop differed depending on the RF ablation setting and was always shorter with the 50 W setting than 40 W setting. The LI drop always correlated with the lesion formation under all ablation power settings. Deeper or wider lesions were predominantly created within the time to 90% decay of the LI drop. Conclusion: The LI drop was useful for predicting lesion sizes. Deeper or wider lesions cannot be obtained with a longer ablation than the 90% decay time of the LI drop. A shorter ablation than the 90% decay time of the LI drop would be preferable for an effective ablation.

Adenosine reduces sinoatrial node cell action potential firing rate by uncoupling its membrane and calcium clocks.

The spontaneous action potential (AP) firing rate of sinoatrial nodal cells (SANC) is regulated by a system of intracellular Ca2+ and membrane ion current clocks driven by Ca2+-calmodulin-activated adenylyl cyclase-protein kinase-A signaling. The mean AP-cycle length (APCL) and APCL variability inform on the effectiveness of clock coupling. Endogenous ATP metabolite adenosine binds to adenosine receptors (A1, A3) that couple to Gi protein-coupled receptors, reducing spontaneous AP firing rate via Gßγ signaling that activates IKAch,Ado. Adenosine also inhibits adenylyl cyclase activity via Gαi signaling, impacting cAMP-mediated protein kinase-A-dependent protein phosphorylation. We hypothesize that in addition to IKAch,Ado activation, adenosine impacts also Ca2+ via Gαi signaling and that both effects reduce AP firing rate by reducing the effectiveness of the Ca2+ and membrane clock coupling. To this end, we measured Ca2+ and membrane potential characteristics in enzymatically isolated single rabbit SANC. 10 µM adenosine substantially increased both the mean APCL (on average by 43%, n = 10) and AP beat-to-beat variability from 5.1 ± 1.7% to 7.2 ± 2.0% (n = 10) measured via membrane potential and 5.0 ± 2.2% to 10.6 ± 5.9% (n = 40) measured via Ca2+ (assessed as the coefficient of variability = SD/mean). These effects were mediated by hyperpolarization of the maximum diastolic membrane potential (membrane clock effect) and suppression of diastolic local Ca2+releases (LCRs) (Ca2+-clock effect): as LCR size distributions shifted to smaller values, the time of LCR occurrence during diastolic depolarization (LCR period) became prolonged, and the ensemble LCR signal became reduced. The tight linear relationship of coupling between LCR period to the APCL in the presence of adenosine "drifted" upward and leftward, i.e. for a given LCR period, APCL was prolonged, becoming non-linear indicating clock uncoupling. An extreme case of uncoupling occurred at higher adenosine concentrations (>100 µM): small stochastic LCRs failed to self-organize and synchronize to the membrane clock, thus creating a failed attempt to generate an AP resulting in arrhythmia and cessation of AP firing. Thus, the effects of adenosine to activate Gßγ and IKACh,Ado and to activate Gαi, suppressing adenylyl cyclase activity, both contribute to the adenosine-induced increase in the mean APCL and APCL variability by reducing the fidelity of clock coupling and AP firing rate.