Dataset Information

Role of spatial dispersion of repolarization in reentry around a functional core versus reentry around a fixed anatomical core.

ABSTRACT:

Introduction

Successful initiation of spiral wave reentry in the neonatal rat ventricular myocyte (NRVM) monolayer implicitly assumes the presence of spatial dispersion of repolarization (DR), which is difficult to quantify. We recently introduced a NRVM monolayer that utilizes anthopleurin-A to impart a prolonged plateau to the NRVM action potential. This was associated with a significant degree of spatial DR that lends itself to accurate quantification.

Methods and results

We utilized the monolayer and fluorescence optical mapping of intracellular calcium transients (F_Cai ) to systematically study and compare the contribution of spatial dispersion of the duration of F_Cai (as a surrogate of DR) to induction of spiral wave reentry around a functional core versus reentry around a fixed anatomical obstacle. We show that functional reentry could be initiated by a premature stimulus acting on a substrate of spatial DR resulting in a functional line of propagation block. Subsequent wave fronts circulated around a central core of functional obstacle created by sustained depolarization from the circulating wave front. Both initiation and termination of spiral wave reentry around an anatomical obstacle consistently required participation of a region of functional propagation block. This region was similarly based on spatial DR. Spontaneous termination of spiral wave reentry also resulted from block in the functional component of the circuit obstacle, usually preceded by beat-to-beat slowing of propagation.

Conclusions

The study demonstrates the critical contribution of DR to spiral wave reentry around a purely functional core as well as reentry around a fixed anatomical core.

SUBMITTER: Himel HD

PROVIDER: S-EPMC6931426 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Publications

Role of spatial dispersion of repolarization in reentry around a functional core versus reentry around a fixed anatomical core.

Himel Herman D HD Cupelli Michael M Gantt Martin M Boutjdir Mohamed M El-Sherif Nabil N

Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc 20190321 4

<h4>Introduction</h4>Successful initiation of spiral wave reentry in the neonatal rat ventricular myocyte (NRVM) monolayer implicitly assumes the presence of spatial dispersion of repolarization (DR), which is difficult to quantify. We recently introduced a NRVM monolayer that utilizes anthopleurin-A to impart a prolonged plateau to the NRVM action potential. This was associated with a significant degree of spatial DR that lends itself to accurate quantification.<h4>Methods and results</h4>We ut ...[more]

PMID: 30896072

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Project description:BackgroundMany patients have symptoms suggestive of coronary artery disease (CAD) and are often evaluated with the use of diagnostic testing, although there are limited data from randomized trials to guide care.MethodsWe randomly assigned 10,003 symptomatic patients to a strategy of initial anatomical testing with the use of coronary computed tomographic angiography (CTA) or to functional testing (exercise electrocardiography, nuclear stress testing, or stress echocardiography). The composite primary end point was death, myocardial infarction, hospitalization for unstable angina, or major procedural complication. Secondary end points included invasive cardiac catheterization that did not show obstructive CAD and radiation exposure.ResultsThe mean age of the patients was 60.8±8.3 years, 52.7% were women, and 87.7% had chest pain or dyspnea on exertion. The mean pretest likelihood of obstructive CAD was 53.3±21.4%. Over a median follow-up period of 25 months, a primary end-point event occurred in 164 of 4996 patients in the CTA group (3.3%) and in 151 of 5007 (3.0%) in the functional-testing group (adjusted hazard ratio, 1.04; 95% confidence interval, 0.83 to 1.29; P=0.75). CTA was associated with fewer catheterizations showing no obstructive CAD than was functional testing (3.4% vs. 4.3%, P=0.02), although more patients in the CTA group underwent catheterization within 90 days after randomization (12.2% vs. 8.1%). The median cumulative radiation exposure per patient was lower in the CTA group than in the functional-testing group (10.0 mSv vs. 11.3 mSv), but 32.6% of the patients in the functional-testing group had no exposure, so the overall exposure was higher in the CTA group (mean, 12.0 mSv vs. 10.1 mSv; P<0.001).ConclusionsIn symptomatic patients with suspected CAD who required noninvasive testing, a strategy of initial CTA, as compared with functional testing, did not improve clinical outcomes over a median follow-up of 2 years. (Funded by the National Heart, Lung, and Blood Institute; PROMISE ClinicalTrials.gov number, NCT01174550.).

Project description:Bradycardia prolongs action potential (AP) durations (APD adaptation), enhances dispersion of repolarization (DOR), and promotes tachyarrhythmias. Yet, the mechanisms responsible for enhanced DOR and tachyarrhythmias remain largely unexplored. Ca(2+) transients and APs were measured optically from Langendorff rabbit hearts at high (150 × 150 ?m(2)) or low (1.5 × 1.5 cm(2)) magnification while pacing at a physiological (120 beats/min) or a slow heart rate (SHR = 50 beats/min). Western blots and pharmacological interventions were used to elucidate the regional effects of bradycardia. As a result, bradycardia (SHR 50 beats/min) increased APDs gradually (time constant ?f?s = 48 ± 9.2 s) and caused a secondary Ca(2+) release (SCR) from the sarcoplasmic reticulum during AP plateaus, occurring at the base on average of 184.4 ± 9.7 ms after the Ca(2+) transient upstroke. In subcellular imaging, SCRs were temporally synchronous and spatially homogeneous within myocytes. In diastole, SHR elicited variable asynchronous sarcoplasmic reticulum Ca(2+) release events leading to subcellular Ca(2+) waves, detectable only at high magnification. SCR was regionally heterogeneous, correlated with APD prolongation (P < 0.01, n = 5), enhanced DOR (r = 0.9277 ± 0.03, n = 7), and was gradually reversed by pacing at 120 beats/min along with APD shortening (P < 0.05, n = 5). A stabilizer of leaky ryanodine receptors (RyR2), 3-(4-benzylcyclohexyl)-1-(7-methoxy-2,3-dihydrobenzo[f][1,4]thiazepin-4(5H)-yl)propan-1-one (K201; 1 ?M), suppressed SCR and reduced APD at the base, thereby reducing DOR (P < 0.02, n = 5). Ventricular ectopy induced by bradycardia (n = 5/15) was suppressed by K201. Western blot analysis revealed spatial differences of voltage-gated L-type Ca(2+) channel protein (Cav1.2?), Na(+)-Ca(2+) exchange (NCX1), voltage-gated Na(+) channel (Nav1.5), and rabbit ether-a-go-go-related (rERG) protein [but not RyR2 or sarcoplasmic reticulum Ca(2+) ATPase 2a] that correlate with the SCR distribution and explain the molecular basis for SCR heterogeneities. In conclusion, acute bradycardia elicits synchronized subcellular SCRs of sufficient magnitude to overcome the source-sink mismatch and to promote afterdepolarizations.

Project description:PROMISE (PROspective Multicenter Imaging Study for Evaluation of Chest Pain) found that initial use of at least 64-slice multidetector computed tomography angiography (CTA) versus functional diagnostic testing strategies did not improve clinical outcomes in stable symptomatic patients with suspected coronary artery disease (CAD) requiring noninvasive testing.To conduct an economic analysis for PROMISE (a major secondary aim of the study).Prospective economic study from the U.S. perspective. Comparisons were made according to the intention-to-treat principle, and CIs were calculated using bootstrap methods. (ClinicalTrials.gov: NCT01174550).190 U.S. centers.9649 U.S. patients enrolled in PROMISE between July 2010 and September 2013. Median follow-up was 25 months.Technical costs of the initial (outpatient) testing strategy were estimated from Premier Research Database data. Hospital-based costs were estimated using hospital bills and Medicare cost-charge ratios. Physician fees were taken from the Medicare Physician Fee Schedule. Costs were expressed in 2014 U.S. dollars, discounted at 3% annually, and estimated out to 3 years using inverse probability weighting methods.The mean initial testing costs were $174 for exercise electrocardiography; $404 for CTA; $501 to $514 for pharmacologic and exercise stress echocardiography, respectively; and $946 to $1132 for exercise and pharmacologic stress nuclear testing, respectively. Mean costs at 90 days were $2494 for the CTA strategy versus $2240 for the functional strategy (mean difference, $254 [95% CI, -$634 to $906]). The difference was associated with more revascularizations and catheterizations (4.25 per 100 patients) with CTA use. After 90 days, the mean cost difference between the groups out to 3 years remained small.Cost weights for test strategies were obtained from sources outside PROMISE.Computed tomography angiography and functional diagnostic testing strategies in patients with suspected CAD have similar costs through 3 years of follow-up.National Heart, Lung, and Blood Institute.

Dataset Information

Role of spatial dispersion of repolarization in reentry around a functional core versus reentry around a fixed anatomical core.

Introduction

Methods and results

Conclusions

Publications

Role of spatial dispersion of repolarization in reentry around a functional core versus reentry around a fixed anatomical core.

Similar Datasets

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