Altered Dynamics of Action Potential Restitution and Alternans in Humans With Structural Heart Disease

he mechanisms of ventricular fibrillation (VF) remain unclear. The mother rotor hypothesis 1,2 appeals to clinicians, because ablation or pacing delivered to the dominant domain might prevent VF from initiating or being maintained. However, whether the mother rotor, observed in small animal hearts, 3 exists in larger animals has not yet been elucidated. Ideker et al [4][5][6] have been reporting that the dominant domain of VF in large animal is located where the left ventricular posterior wall (LVPW) joins the septum. We previously reported that the posterior papillary muscle (PPM) is the major anchoring structure of VF reentrant wavelets and the site harboring prominent Purkinje potentials and the dominant domain. 7 We also reported that radiofrequency catheter ablation (RFCA) around the papillary muscle reduces VF inducibility in dog and rabbit hearts. 7,8 However, it is unclear whether the high frequency domain around the PPM is a true mother rotor or an epiphenomenon, so we designed this study to elucidate whether the mechanism of VF maintenance is reentry or Circulation Journal Vol.72, July 2008 focal Purkinje firing. The aims of this study were to test the effect of the left ventricular posteroseptal (LVPS) ablation, including PPM ablation (Purkinje destruction), and the LVPW cut-and-sew operation (CSO; blocking reentry) on VF inducibility, and to compare the transmural distribution of Purkinje cells in the LVPS of dogs and swine. Methods Mapping and Testing of VF InducibilityNon-contact endocardial mapping (EnSite, Endocardial Solutions, St Jude Medical, Inc, St. Paul, MN, USA) was performed in 14 dogs and 7 swine that underwent RFCA as described before. 7 The multi-electrode array catheter was positioned in the left ventricular (LV) and the endocardial geometry was generated. To localize the area of the PPM, we marked its location on the 3D reconstructed endocardial anatomy of the non-contact map using echocardiography (Sonos 1500, Hewlett Packard Inc, Palo Alto, CA, USA) ( Fig 1A).In order to induce VF, burst pacing (right ventricular apex endocardial pacing at a pacing cycle length (CL) of 100 ms with 1:1 capture, 5 mA current, 2 ms pulse width and 3 s duration) was repeatedly administered with 30 s intermissions between each pacing train until VF was successfully induced. We defined induced VF as fast and irregular ventricular rhythm lasting >10 s. Induced VF was terminated by biphasic truncated exponential waveform shocks (0.3 J/kg, However, whether the mechanism of VF maintenance is reentry or focal Purkinje firing is unclear. Methods and ResultsIn the present study the effects of RFCA (endocardial ablation of PPM+LVPS in 7 dogs and 7 swine), left ventricular anterolateral wall ablation (LVAL in 7 dogs), and the cut-and-sew operation (CSO: along the left ventricular posterior wall (LVPW) beside PPM in 7 swine) on VF inducibility were compared.(1) VF inducibility was decreased from 100±0% to 21.9±31.2% (p<0.0001) by PPM+LVPS endocardial ablation, but not by LVAL ablation in dogs. (2) LVPW CSO red...

Section: Clinical Implications and Human Vfmentioning

confidence: 99%

Both Purkinje Cells and Left Ventricular Posteroseptal Reentry Contribute to the Maintenance of Ventricular Fibrillation in Open-Chest Dogs and Swine Effects of Catheter Ablation and the Ventricular Cut-and-Sew Operation

Pak

Kim

Lim

et al. 2008

“…The electrical restitution property of the myocardium has been shown to play an important role in determining the susceptibility of the heart to fibrillation. Evidence from experimental 8- 10 and clinical studies 11,12 indicates that the maximum slope of the ventricular action potential duration (APD) restitution curve, which portrays the relation between the local APD and the preceding diastolic interval, reflects the propensity for VF. If the slope of the restitution function at a short diastolic interval exceeds unity, small changes in the diastolic interval can produce large fluctuations in the APD and refractoriness, 9,13 which may lead to functional gradients in repolarization that may promote conduction block and the wavebreak of re-entrant wavefronts.…”

mentioning

confidence: 99%

Abnormal Action Potential Duration Restitution Property in the Right Ventricular Outflow Tract in Brugada Syndrome

Ashino

Watanabe

Kofune

et al. 2010

Background: Although patients with Brugada syndrome (BS) are at risk of ventricular fibrillation (VF) and ensuing death, the action potential duration (APD) restitution properties of the right ventricular outflow tract (RVOT) in patients with BS remain undetermined. Methods and Results:Endocardial monophasic action potentials (MAPs) were obtained from 16 patients with BS and 17 control patients. MAPs were recorded from the RVOT in all patients. The MAP duration at 90% repolarization (MAPD90), effective refractory period (ERP), and maximum slope of the APD restitution curve were obtained. VF was induced with up to 3 extrastimuli from the RV apex or RVOT. There was no difference in MAPD90 between the 2 groups, but the ERP was significantly shorter in patients with BS than in control patients (210.7±10.5 vs 223.8±13.4 ms, P=0.008). MAPD at the shortest diastolic interval was significantly shorter in patients with BS than in control patients (149.9±19.9 vs 179.8±13.7 ms, P<0.001). The maximum slope of the APD restitution curve was steeper in patients with BS than in control patients (2.90±1.29 vs 1.38±0.41, P<0.001). Conclusions:The shorter ERP, shorter MAPD at the shortest diastolic interval and steeply sloped APD restitution curve in the RVOT appear to be related to the inducibility of VF in patients with BS. (Circ J 2010; 74: 664 - 670)

“…To obtain the maximum slope (Slopemax) of the MAPD90 restitution curve, the data were fitted using overlapping least-squares linear segments; a linear fit was performed in 30-ms DI segments in steps of 10 ms, commencing from the shortest DI range to produce a ventricular response. 25,26 The MAP signals filtered between 0.1 and 100 Hz were recorded and stored digitally on an EP lab system (Bard, Billerica, MA, USA). Any MAP traces exhibiting a marked baseline drift, motion artifact or amplitude of <10 mV were excluded from the analysis.…”

Section: Map Recordingsmentioning

confidence: 99%

“…A dynamic pacing protocol, where the CL of the constant stimulation is shortened progressively, might be more appropriate for characterizing the action potential properties responsible for the transition from ventricular tachycardia to fibrillation. 26,44 Third, the study included only patients with no structural heart disease. Bepridil-induced TdP has been reported to be more prevalent in patients with structural heart disease and in the presence of hypokalemia or marked bradycardia, conditions known to reduce the repolarization reserve and increase the spatial heterogeneity of ventricular repolarization.…”

Section: Study Limitationsmentioning

confidence: 99%

Opposing Effects of Bepridil on Ventricular Repolarization in Humans Inhomogeneous Prolongation of the Action Potential Duration vs Flattening of Its Restitution Kinetics

Osaka

Yokoyama

Kushiyama

et al. 2009

Background: Bepridil is highly effective in the treatment of atrial fibrillation, but its clinical usefulness is limited by a potential risk for the drug-induced Torsades de pointes (TdP) in association with its Class III action. Methods and Results: Monophasic action potentials (MAPs) were recorded from the right ventricular outflow tract (RVOT) and apex (RVA) in 9 patients treated with bepridil (172±26 mg/day) and 10 control patients. Bepridil significantly increased the steady-state MAP durations at 90% repolarization (MAPD90s) in a rate-independent manner at pacing cycle lengths ranging from 330 to 750 ms. The bepridil-induced prolongation of the MAPD90 was greater in RVOT (~13%) than RVA (~8%). Bepridil flattened the MAPD90 restitution slope estimated by an S1-S2 protocol in both the RVOT (0.65±0.22 vs 0.95±0.38) and RVA (0.65±0.14 vs 0.94±0.29). The Tpeak-end interval in the ECG was increased by bepridil for S1 but not S2 at the shortest diastolic interval to produce a ventricular response. Conclusions: Bepridil produces an inhomogeneous prolongation of the MAPDs, but flattens their restitution kinetics in the human ventricle. The former effect would favor the functional reentry predisposing to TdP, whereas the latter one would counteract that by reducing the dynamic instability of the repolarization. (Circ J 2009; 73: 1612 -1618