A governing equation for rotor and wavelet number in human clinical ventricular fibrillation: Implications for sudden cardiac death.

BACKGROUND: Ventricular fibrillation (VF) is characterized by multiple wavelets and rotors. No equation to predict the number of rotors and wavelets observed during fibrillation has been validated in human VF. OBJECTIVE: The purpose of this study was to test the hypothesis that a single equation derived from a Markov M/M/∞ birth-death process could predict the number of rotors and wavelets occurring in human clinical VF. METHODS: Epicardial induced VF (256-electrode) recordings obtained from patients undergoing cardiac surgery were studied (12 patients; 62 epochs). Rate constants for phase singularity (PS) (which occur at the pivot points of rotors) and wavefront (WF) formation and destruction were derived by fitting distributions to PS and WF interformation and lifetimes. These rate constants were combined in an M/M/∞ governing equation to predict the number of PS and WF in VF episodes. Observed distributions were compared to those predicted by the M/M/∞ equation. RESULTS: The M/M/∞ equation accurately predicted average PS and WF number and population distribution, demonstrated in all epochs. Self-terminating episodes of VF were distinguished from VF episodes requiring termination by a trend toward slower PS destruction, slower rates of PS formation, and a slower mixing rate of the VF process, indicated by larger values of the second largest eigenvalue modulus of the M/M/∞ birth-death matrix. The longest-lasting PS (associated with rotors) had shorter interactivation time intervals compared to shorter-lasting PS lasting <150 ms (∼1 PS rotation in human VF). CONCLUSION: The M/M/∞ equation explains the number of wavelets and rotors observed, supporting a paradigm of VF based on statistical fibrillatory dynamics.

Time-Averaged Wavefront Analysis Demonstrates Preferential Pathways of Atrial Fibrillation, Predicting Pulmonary Vein Isolation Acute Response.

Electrical activation during atrial fibrillation (AF) appears chaotic and disorganised, which impedes characterisation of the underlying substrate and treatment planning. While globally chaotic, there may be local preferential activation pathways that represent potential ablation targets. This study aimed to identify preferential activation pathways during AF and predict the acute ablation response when these are targeted by pulmonary vein isolation (PVI). In patients with persistent AF (n = 14), simultaneous biatrial contact mapping with basket catheters was performed pre-ablation and following each ablation strategy (PVI, roof, and mitral lines). Unipolar wavefront activation directions were averaged over 10 s to identify preferential activation pathways. Clinical cases were classified as responders or non-responders to PVI during the procedure. Clinical data were augmented with a virtual cohort of 100 models. In AF pre-ablation, pathways originated from the pulmonary vein (PV) antra in PVI responders (7/7) but not in PVI non-responders (6/6). We proposed a novel index that measured activation waves from the PV antra into the atrial body. This index was significantly higher in PVI responders than non-responders (clinical: 16.3 vs. 3.7%, p = 0.04; simulated: 21.1 vs. 14.1%, p = 0.02). Overall, this novel technique and proof of concept study demonstrated that preferential activation pathways exist during AF. Targeting patient-specific activation pathways that flowed from the PV antra to the left atrial body using PVI resulted in AF termination during the procedure. These PV activation flow pathways may correspond to the presence of drivers in the PV regions.

Direct in vivo assessment of global and regional mechanoelectric feedback in the intact human heart.

BACKGROUND: Inhomogeneity of ventricular contraction is associated with sudden cardiac death, but the underlying mechanisms are unclear. Alterations in cardiac contraction impact electrophysiological parameters through mechanoelectric feedback. This has been shown to promote arrhythmias in experimental studies, but its effect in the in vivo human heart is unclear. OBJECTIVE: The purpose of this study was to quantify the impact of regional myocardial deformation provoked by a sudden increase in ventricular loading (aortic occlusion) on human cardiac electrophysiology. METHODS: In 10 patients undergoing open heart cardiac surgery, left ventricular (LV) afterload was modified by transient aortic occlusion. Simultaneous assessment of whole-heart electrophysiology and LV deformation was performed using an epicardial sock (240 electrodes) and speckle-tracking transesophageal echocardiography. Parameters were matched to 6 American Heart Association LV model segments. The association between changes in regional myocardial segment length and activation-recovery interval (ARI; a conventional surrogate for action potential duration) was studied using mixed-effect models. RESULTS: Increased ventricular loading reduced longitudinal shortening (P = .01) and shortened ARI (P = .02), but changes were heterogeneous between cardiac segments. Increased regional longitudinal shortening was associated with ARI shortening (effect size 0.20 [0.01-0.38] ms/%; P = .04) and increased local ARI dispersion (effect size -0.13 [-0.23 to -0.03] ms/%; P = .04). At the whole organ level, increased mechanical dispersion translated into increased dispersion of repolarization (correlation coefficient r = 0.81; P = .01). CONCLUSION: Mechanoelectric feedback can establish a potentially proarrhythmic substrate in the human heart and should be considered to advance our understanding and prevention of cardiac arrhythmias.

Emerging evidence for a mechanistic link between low-frequency oscillation of ventricular repolarization measured from the electrocardiogram T-wave vector and arrhythmia.

Strong recent clinical evidence links the presence of prominent oscillations of ventricular repolarization in the low-frequency range (0.04-0.15 Hz) to the incidence of ventricular arrhythmia and sudden death in post-MI patients and patients with ischaemic and non-ischaemic cardiomyopathy. It has been proposed that these oscillations reflect oscillations of ventricular action potential duration at the sympathetic nerve frequency. Here we review emerging evidence to support that contention and provide insight into possible underlying mechanisms for this association.

Assessing the ability of substrate mapping techniques to guide ventricular tachycardia ablation using computational modelling.

BACKGROUND: Identification of targets for ablation of post-infarction ventricular tachycardias (VTs) remains challenging, often requiring arrhythmia induction to delineate the reentrant circuit. This carries a risk for the patient and may not be feasible. Substrate mapping has emerged as a safer strategy to uncover arrhythmogenic regions. However, VT recurrence remains common. GOAL: To use computer simulations to assess the ability of different substrate mapping approaches to identify VT exit sites. METHODS: A 3D computational model of the porcine post-infarction heart was constructed to simulate VT and paced rhythm. Electroanatomical maps were constructed based on endocardial electrogram features and the reentry vulnerability index (RVI - a metric combining activation (AT) and repolarization timings to identify tissue susceptibility to reentry). Since scar transmurality in our model was not homogeneous, parameters derived from all signals (including dense scar regions) were used in the analysis. Potential ablation targets obtained from each electroanatomical map during pacing were compared to the exit site detected during VT mapping. RESULTS: Simulation data showed that voltage cut-offs applied to bipolar electrograms could delineate the scar, but not the VT circuit. Electrogram fractionation had the highest correlation with scar transmurality. The RVI identified regions closest to VT exit site but was outperformed by AT gradients combined with voltage cut-offs. The performance of all metrics was affected by pacing location. CONCLUSIONS: Substrate mapping could provide information about the infarct, but the directional dependency on activation should be considered. Activation-repolarization metrics have utility in safely identifying VT targets, even with non-transmural scars.

Evaluation of the reentry vulnerability index to predict ventricular tachycardia circuits using high-density contact mapping.

BACKGROUND: Identifying arrhythmogenic sites to improve ventricular tachycardia (VT) ablation outcomes remains unresolved. The reentry vulnerability index (RVI) combines activation and repolarization timings to identify sites critical for reentrant arrhythmia initiation without inducing VT. OBJECTIVE: The purpose of this study was to provide the first assessment of RVI's capability to identify VT sites of origin using high-density contact mapping and comparison with other activation-repolarization markers of functional substrate. METHODS: Eighteen VT ablation patients (16 male; 72% ischemic) were studied. Unipolar electrograms were recorded during ventricular pacing and analyzed offline. Activation time (AT), activation-recovery interval (ARI), and repolarization time (RT) were measured. Vulnerability to reentry was mapped based on RVI and spatial distribution of AT, ARI, and RT. The distance from sites identified as vulnerable to reentry to the VT site of origin was measured, with distances <10 mm and >20 mm indicating accurate and inaccurate localization, respectively. RESULTS: The origins of 18 VTs (6 entrainment, 12 pace-mapping) were identified. RVI maps included 1012 (408-2098) (median, 1st-3rd quartiles) points per patient. RVI accurately localized 72.2% VT sites of origin, with median distance of 5.1 (3.2-10.1) mm. Inaccurate localization was significantly less frequent for RVI than AT (5.6% vs 33.3%; odds ratio 0.12; P = .035). Compared to RVI, distance to VT sites of origin was significantly larger for sites showing prolonged RT and ARI and were nonsignificantly larger for sites showing highest AT and ARI gradients. CONCLUSION: RVI identifies vulnerable regions closest to VT sites of origin. Activation-repolarization metrics may improve VT substrate delineation and inform novel ablation strategies.

Mechanisms Underlying Interactions Between Low-Frequency Oscillations and Beat-to-Beat Variability of Celullar Ventricular Repolarization in Response to Sympathetic Stimulation: Implications for Arrhythmogenesis.

Background and Objectives: Enhanced beat-to-beat variability of ventricular repolarization (BVR) has been linked to arrhythmias and sudden cardiac death. Recent experimental studies on human left ventricular epicardial electrograms have shown that BVR closely interacts with low-frequency (LF) oscillations of activation recovery interval during sympathetic provocation. In this work human ventricular computational cell models are developed to reproduce the experimentally observed interactions between BVR and its LF oscillations, to assess underlying mechanisms and to establish a relationship with arrhythmic risk. Materials and Methods: A set of human ventricular action potential (AP) models covering a range of experimental electrophysiological characteristics was constructed. These models incorporated stochasticity in major ionic currents as well as descriptions of ß-adrenergic stimulation and mechanical effects to investigate the AP response to enhanced sympathetic activity. Statistical methods based on Automatic Relevance Determination and Canonical Correlation Analysis were developed to unravel individual and common factors contributing to BVR and LF patterning of APD in response to sympathetic provocation. Results: Simulated results reproduced experimental evidences on the interactions between BVR and LF oscillations of AP duration (APD), with replication of the high inter-individual variability observed in both phenomena. ICaL, IKr and IK1 currents were identified as common ionic modulators of the inter-individual differences in BVR and LF oscillatory behavior and were shown to be crucial in determining susceptibility to arrhythmogenic events. Conclusions: The calibrated family of human ventricular cell models proposed in this study allows reproducing experimentally reported interactions between BVR and LF oscillations of APD. Ionic factors involving ICaL, IKr and IK1 currents are found to underlie correlated increments in both phenomena in response to sympathetic provocation. A link to arrhythmogenesis is established for concomitantly elevated levels of BVR and its LF oscillations.

Autonomic modulation of the electrical substrate in mice haploinsufficient for cardiac sodium channels: a model of the Brugada syndrome.

A murine line haploinsufficient in the cardiac sodium channel has been used to model human Brugada syndrome: a disease causing sudden cardiac death due to lethal ventricular arrhythmias. We explored the effects of cholinergic tone on electrophysiological parameters in wild-type and genetically modified, heterozygous, Scn5a+/- knockout mice. Scn5a+/- ventricular slices showed longer refractory periods than wild-type both at baseline and during isoprenaline challenge. Scn5a+/- hearts also showed lower conduction velocities and increased mean increase in delay than did littermate controls at baseline and blunted responses to isoprenaline challenge. Carbachol exerted limited effects but reversed the effects of isoprenaline with coapplication. Scn5a+/- mice showed a reduction in conduction reserve in that isoprenaline no longer increased conduction velocity, and this was not antagonized by muscarinic agonists.

Characterizing the clinical implementation of a novel activation-repolarization metric to identify targets for catheter ablation of ventricular tachycardias using computational models.

Identification of targets for catheter ablation of ventricular tachycardias (VTs) remains a significant challenge. VTs are often driven by re-entrant circuits resulting from a complex interaction between the front (activation) and tail (repolarization) of the electrical wavefront. Most mapping techniques do not take into account the tissue repolarization which may hinder the detection of ablation targets. The re-entry vulnerability index (RVI), a recently proposed mapping procedure, incorporates both activation and repolarization times to uncover VT circuits. The method showed potential in a series of experiments, but it still requires further development to enable its incorporation into a clinical protocol. Here, in-silico experiments were conducted to thoroughly assess RVI maps constructed under clinically-relevant mapping conditions. Within idealized as well as anatomically realistic infarct models, we show that parameters of the algorithm such as the search radius can significantly alter the specificity and sensitivity of the RVI maps. When constructed on sparse grids obtained following various placements of clinical recording catheters, RVI maps can identify vulnerable regions as long as two electrodes were placed on both sides of the line of block. Moreover, maps computed during pacing without inducing VT can reveal areas of abnormal repolarization and slow conduction but not directly vulnerability. In conclusion, the RVI algorithm can detect re-entrant circuits during VT from low resolution mapping grids resembling the clinical setting. Furthermore, RVI maps may provide information about the underlying tissue electrophysiology to guide catheter ablation without the need of inducing potentially harmful VT during the clinical procedure. Finally, the ability of the RVI maps to identify vulnerable regions with specificity in high resolution computer models could potentially improve the prediction of optimal ablation targets of simulation-based strategies.

Simultaneous Comparison of Electrocardiographic Imaging and Epicardial Contact Mapping in Structural Heart Disease.

BACKGROUND: The accuracy of ECG imaging (ECGI) in structural heart disease remains uncertain. This study aimed to provide a detailed comparison of ECGI and contact-mapping system (CARTO) electrograms. METHODS: Simultaneous epicardial mapping using CARTO (Biosense-Webster, CA) and ECGI (CardioInsight) in 8 patients was performed to compare electrogram morphology, activation time (AT), and repolarization time (RT). Agreement between AT and RT from CARTO and ECGI was assessed using Pearson correlation coefficient, ρ AT and ρ RT, root mean square error, E AT and E RT, and Bland-Altman plots. RESULTS: After geometric coregistration, 711 (439-905; median, first-third quartiles) ECGI and CARTO points were paired per patient. AT maps showed ρ AT=0.66 (0.53-0.73) and E AT=24 (21-32) ms, RT maps showed ρ RT=0.55 (0.41-0.71) and E RT=51 (38-70) ms. The median correlation coefficient measuring the morphological similarity between the unipolar electrograms was equal to 0.71 (0.65-0.74) for the entire signal, 0.67 (0.59-0.76) for QRS complexes, and 0.57 (0.35-0.76) for T waves. Local activation map correlation, ρ AT, was lower when default filters were used (0.60 (0.30-0.71), P=0.053). Small misalignment of the ECGI and CARTO geometries (below ±4 mm and ±4°) could introduce variations in the median ρ AT up to ±25%. Minimum distance between epicardial pacing sites and the region of earliest activation in ECGI was 13.2 (0.0-28.3) mm from 25 pacing sites with stimulation to QRS interval <40 ms. CONCLUSIONS: This simultaneous assessment demonstrates that ECGI maps activation and repolarization parameters with moderate accuracy. ECGI and contact electrogram correlation is sensitive to electrode apposition and geometric alignment. Further technological developments may improve spatial resolution.

Pulse Arrival Time and Pulse Interval as Accurate Markers to Detect Mechanical Alternans.

Mechanical alternans (MA) is a powerful predictor of adverse prognosis in patients with heart failure and cardiomyopathy, but its use remains limited due to the need of invasive continuous arterial pressure recordings. This study aims to assess novel cardiovascular correlates of MA in the intact human heart to facilitate affordable and non-invasive detection of MA and advance our understanding of the underlying pathophysiology. Arterial pressure, respiration, and ECG were recorded in 12 subjects with healthy ventricles during voluntarily controlled breathing at different respiratory rate, before and after administration of beta-blockers. MA was induced by ventricular pacing. A total of 67 recordings lasting approximately 90 s each were analyzed. Mechanical alternans (MA) was measured in the systolic blood pressure. We studied cardiovascular correlates of MA, including maximum pressure rise during systole (dPdtmax), pulse arrival time (PAT), pulse wave interval (PI), RR interval (RRI), ECG QRS complexes and T-waves. MA was detected in 30% of the analyzed recordings. Beta-blockade significantly reduced MA prevalence (from 50 to 11%, p < 0.05). Binary classification showed that MA was detected by alternans in dPdtmax (100% sens, 96% spec), PAT (100% sens, 81% spec) and PI (80% sens, 81% spec). Alternans in PAT and in PI also showed high degree of temporal synchronization with MA (80 ± 33 and 73 ± 40%, respectively). These data suggest that cardiac contractility is a primary factor in the establishment of MA. Our findings show that MA was highly correlated with invasive measurements of PAT and PI. Since PAT and PI can be estimated using non-invasive technologies, these markers could potentially enable affordable MA detection for risk-prediction.

Mechanistic insights from targeted molecular profiling of repolarization alternans in the intact human heart.

AIMS: Action potential duration (APD) alternans is an established precursor or arrhythmia and sudden cardiac death. Important differences in fundamental electrophysiological properties relevant to arrhythmia exist between experimental models and the diseased in vivo human heart. To investigate mechanisms of APD alternans using a novel approach combining intact heart and cellular cardiac electrophysiology in human in vivo. METHODS AND RESULTS: We developed a novel approach combining intact heart electrophysiological mapping during cardiac surgery with rapid on-site data analysis to guide myocardial biopsies for laboratory analysis, thereby linking repolarization dynamics observed at the organ level with underlying ion channel expression. Alternans-susceptible and alternans-resistant regions were identified by an incremental pacing protocol. Biopsies from these sites (n = 13) demonstrated greater RNA expression in Calsequestrin (CSQN) and Ryanodine (RyR) and ion channels underlying IK1 and Ito at alternans-susceptible sites. Electrical restitution properties (n = 7) showed no difference between alternans-susceptible and resistant sites, whereas spatial gradients of repolarization were greater in alternans-susceptible than in alternans-resistant sites (P = 0.001). The degree of histological fibrosis between alternans-susceptible and resistant sites was equivalent. Mathematical modelling of these changes indicated that both CSQN and RyR up-regulation are key determinants of APD alternans. CONCLUSION: Combined intact heart and cellular electrophysiology show that regions of myocardium in the in vivo human heart exhibiting APD alternans are associated with greater expression of CSQN and RyR and show no difference in restitution properties compared to non-alternans regions. In silico modelling identifies up-regulation and interaction of CSQN with RyR as a major mechanism underlying APD alternans.

Prolonged action potential duration and dynamic transmural action potential duration heterogeneity underlie vulnerability to ventricular tachycardia in patients undergoing ventricular tachycardia ablation.

AIMS: Differences of action potential duration (APD) in regions of myocardial scar and their borderzones are poorly defined in the intact human heart. Heterogeneities in APD may play an important role in the generation of ventricular tachycardia (VT) by creating regions of functional block. We aimed to investigate the transmural and planar differences of APD in patients admitted for VT ablation. METHODS AND RESULTS: Six patients (median age 53 years, five male); (median ejection fraction 35%), were studied. Endocardial (Endo) and epicardial (Epi) 3D electroanatomic mapping was performed. A bipolar voltage of <0.5 mV was defined as dense scar, 0.5-1.5 mV as scar borderzone, and >1.5 mV as normal. Decapolar catheters were positioned transmurally across the scar borderzone to assess differences of APD and repolarization time (RT) during restitution pacing from Endo and Epi. Epi APD was 173 ms in normal tissue vs. 187 ms at scar borderzone and 210 ms in dense scar (P < 0.001). Endocardial APD was 210 ms in normal tissue vs. 222 ms in the scar borderzone and 238 ms in dense scar (P < 0.01). This resulted in significant transmural RT dispersion (ΔRT 22 ms across dense transmural scar vs. 5 ms in normal transmural tissue, P < 0.001), dependent on the scar characteristics in the Endo and Epi, and the pacing site. CONCLUSION: Areas of myocardial scar have prolonged APD compared with normal tissue. Heterogeneity of regional transmural and planar APD result in localized dispersion of repolarization, which may play an important role in initiating VT.

Left ventricular activation-recovery interval variability predicts spontaneous ventricular tachyarrhythmia in patients with heart failure.

BACKGROUND: Enhanced beat-to-beat variability of repolarization is strongly linked to arrhythmogenesis and is largely due to variation in ventricular action potential duration (APD). Previous studies in humans have relied on QT interval measurements; however, a direct relationship between beat-to-beat variability of APD and arrhythmogenesis in humans has yet to be demonstrated. OBJECTIVE: This study aimed to explore the beat-to-beat repolarization dynamics in patients with heart failure at the level of ventricular APD. METHODS: Forty-three patients with heart failure and implanted cardiac resynchronization therapy - defibrillator devices were studied. Activation-recovery intervals as a surrogate for APD were recorded from the left ventricular epicardial lead while pacing from the right ventricular lead to maintain a constant cycle length. RESULTS: During a mean follow-up of 23.6±13.6 months, 11 patients sustained ventricular fibrillation/ventricular tachycardia (VT/VF) and received appropriate implantable cardioverter-defibrillator therapies (antitachycardia pacing or shock therapy). Activation-recovery interval variability (ARIV) was significantly greater in patients with subsequent VT/VF than in those without VT/VF (3.55±1.3 ms vs 2.77±1.09 ms; P=.047). Receiver operating characteristic curve analysis (area under the curve 0.71; P=.046) suggested high- and low-risk ARIV groups for VT/VF. Kaplan-Meier survival analysis demonstrated that the time until first appropriate therapy for VT/VF was significantly shorter in the high-risk ARIV group (P=.028). ARIV was a predictor for VT/VF in the multivariate Cox model (hazard ratio 1.623; 95% confidence interval 1.1-2.393; P=.015). CONCLUSION: Increased left ventricular ARIV is associated with an increased risk of VT/VF in patients with heart failure.

Differences in the upslope of the precordial body surface ECG T wave reflect right to left dispersion of repolarization in the intact human heart.

BACKGROUND: The relationship between the surface electrocardiogram (ECG) T wave to intracardiac repolarization is poorly understood. OBJECTIVE: The purpose of this study was to examine the association between intracardiac ventricular repolarization and the T wave on the body surface ECG (SECGTW). METHODS: Ten patients with a normal heart (age 35 ± 15 years; 6 men) were studied. Decapolar electrophysiological catheters were placed in the right ventricle (RV) and lateral left ventricle (LV) to record in an apicobasal orientation and in the lateral LV branch of the coronary sinus (CS) for transmural recording. Each catheter (CS, LV, RV) was sequentially paced using an S1-S2 restitution protocol. Intracardiac repolarization time and apicobasal, RV-LV, and transmural repolarization dispersion were correlated with the SECGTW, and a total of 23,946 T waves analyzed. RESULTS: RV endocardial repolarization occurred on the upslope of lead V1, V2, and V3 SECGTW, with sensitivity of 0.89, 0.91, and 0.84 and specificity of 0.67, 0.68, and 0.65, respectively. LV basal endocardial, epicardial, and mid-endocardial repolarization occurred on the upslope of leads V6 and I, with sensitivity of 0.79 and 0.8 and specificity of 0.66 and 0.67, respectively. Differences between the end of the upslope in V1, V2, and V3 vs V6 strongly correlated with right to left dispersion of repolarization (intraclass correlation coefficient 0.81, 0.83, and 0.85, respectively; P <.001). Poor association between the T wave and apicobasal and transmural dispersion of repolarization was seen. CONCLUSION: The precordial SECGTW reflects regional repolarization differences between right and left heart. These findings have important implications for accurately identifying biomarkers of arrhythmogenic risk in disease.

Time Course of Low-Frequency Oscillatory Behavior in Human Ventricular Repolarization Following Enhanced Sympathetic Activity and Relation to Arrhythmogenesis.

Background and Objectives: Recent studies in humans and dogs have shown that ventricular repolarization exhibits a low-frequency (LF) oscillatory pattern following enhanced sympathetic activity, which has been related to arrhythmic risk. The appearance of LF oscillations in ventricular repolarization is, however, not immediate, but it may take up to some minutes. This study seeks to characterize the time course of the action potential (AP) duration (APD) oscillatory behavior in response to sympathetic provocations, unveil its underlying mechanisms and establish a potential link to arrhythmogenesis under disease conditions. Materials and Methods: A representative set of human ventricular computational models coupling cellular electrophysiology, calcium dynamics, ß-adrenergic signaling, and mechanics was built. Sympathetic provocation was modeled via phasic changes in ß-adrenergic stimulation (ß-AS) and mechanical stretch at Mayer wave frequencies within the 0.03-0.15 Hz band. Results: Our results show that there are large inter-individual differences in the time lapse for the development of LF oscillations in APD following sympathetic provocation, with some cells requiring just a few seconds and other cells needing more than 3 min. Whereas, the oscillatory response to phasic mechanical stretch is almost immediate, the response to ß-AS is much more prolonged, in line with experimentally reported evidences, thus being this component the one driving the slow development of APD oscillations following enhanced sympathetic activity. If ß-adrenoceptors are priorly stimulated, the time for APD oscillations to become apparent is remarkably reduced, with the oscillation time lapse being an exponential function of the pre-stimulation level. The major mechanism underlying the delay in APD oscillations appearance is related to the slow I Ks phosphorylation kinetics, with its relevance being modulated by the I Ks conductance of each individual cell. Cells presenting short oscillation time lapses are commonly associated with large APD oscillation magnitudes, which facilitate the occurrence of pro-arrhythmic events under disease conditions involving calcium overload and reduced repolarization reserve. Conclusions: The time course of LF oscillatory behavior of APD in response to increased sympathetic activity presents high inter-individual variability, which is associated with different expression and PKA phosphorylation kinetics of the I Ks current. Short time lapses in the development of APD oscillations are associated with large oscillatory magnitudes and pro-arrhythmic risk under disease conditions.

Complex Interaction Between Low-Frequency APD Oscillations and Beat-to-Beat APD Variability in Humans Is Governed by the Sympathetic Nervous System.

BACKGROUND: Recent clinical, experimental and modeling studies link oscillations of ventricular repolarization in the low frequency (LF) (approx. 0.1 Hz) to arrhythmogenesis. Sympathetic provocation has been shown to enhance both LF oscillations of action potential duration (APD) and beat-to-beat variability (BVR) in humans. We hypothesized that beta-adrenergic blockade would reduce LF oscillations of APD and BVR of APD in humans and that the two processes might be linked. METHODS AND RESULTS: Twelve patients with normal ventricles were studied during routine electrophysiological procedures. Activation-recovery intervals (ARI) as a conventional surrogate for APD were recorded from 10 left and 10 right ventricular endocardial sites before and after acute beta-adrenergic adrenergic blockade. Cycle length was maintained constant with right ventricular pacing. Oscillatory behavior of ARI was quantified by spectral analysis and BVR as the short-term variability. Beta-adrenergic blockade reduced LF ARI oscillations (8.6 ± 4.5 ms2 vs. 5.5 ± 3.5 ms2, p = 0.027). A significant correlation was present between the initial control values and reduction seen following beta-adrenergic blockade in LF ARI (r s = 0.62, p = 0.037) such that when initial values are high the effect is greater. A similar relationship was also seen in the beat-to beat variability of ARI (r s = 0.74, p = 0.008). There was a significant correlation between the beta-adrenergic blockade induced reduction in LF power of ARI and the witnessed reduction of beat-to-beat variability of ARI (r s = 0.74, p = 0.01). These clinical results accord with recent computational modeling studies which provide mechanistic insight into the interactions of LF oscillations and beat-to-beat variability of APD at the cellular level. CONCLUSION: Beta-adrenergic blockade reduces LF oscillatory behavior of APD (ARI) in humans in vivo. Our results support the importance of LF oscillations in modulating the response of BVR to beta-adrenergic blockers, suggesting that LF oscillations may play role in modulating beta-adrenergic mechanisms underlying BVR.