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Europace 05/2013; · 1.98 Impact Factor
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ABSTRACT: BACKGROUND: IKs channels, made of the pore-forming KCNQ1 and auxiliary KCNE1 subunits, play a key role in determining action potential duration (APD) in cardiac myocytes. The drug-induced KCNQ1 splice alteration remains unknown. OBJECTIVE: We study the modulation of KCNQ1 alternative splicing by amiloride and the consequent changes in IKs currents and action potentials (AP) in ventricular myocytes. METHODS: We study the modulation of KCNQ1 splicing by amiloride and the consequent changes in IKs currents and action potentials (AP) in ventricular myocytes. Canine endocardial, midmyocardial, and epicardial ventricular myocytes were isolated. Levels of KCNQ1a and KCNQ1b as well as a series of splicing factors were quantified by RT-PCR and Western blot. The impact of amiloride-induced alterations in KCNQ1b ratio on AP was measured using whole-cell patch clamp with and without isoproterenol. RESULTS: With 50 μmol/L amiloride for 6 hours, KCNQ1a at transcriptional and translational levels increases in midmyocardial but decreases in endo- and epicardial myocytes. Likewise, changes of splicing factors in midmyocardial were opposite to that in endo- and epicardial myocytes. In midmyocardial myocytes amiloride shortens APD and decreases isoproterenol-induced early afterdepolarizations significantly. The same amiloride-induced effects are demonstrated by using human ventricular model for action potentials simulations under β-adrenergic stimulation. Moreover, amiloride reduces the transmural dispersion of repolarization in pseudo-ECG. CONCLUSIONS: Amiloride regulates IKs currents and action potentials with transmural differences and reduces arrhythmogenecity through modulating KCNQ1 splicing. We suggested that modulation of KCNQ1 splicing may prevent arrhythmia.
Heart rhythm: the official journal of the Heart Rhythm Society 04/2013; · 4.56 Impact Factor
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ABSTRACT: Cardiac memory refers to the observation that altered cardiac electrical activation results in repolarization changes that persist after the restoration of a normal activation pattern. Animal studies, however, have yielded disparate conclusions, both regarding the spatial pattern of repolarization changes in cardiac memory and the underlying mechanisms. The present study was undertaken to produce 3-dimensional images of the repolarization changes underlying long-term cardiac memory in humans.
Nine adult subjects with structurally normal hearts and dual-chamber pacemakers were enrolled in the study. Noninvasive electrocardiographic imaging was used before and after 1 month of ventricular pacing to reconstruct epicardial activation and repolarization patterns. Eight subjects exhibited cardiac memory in response to ventricular pacing. In all subjects, ventricular pacing resulted in a prolongation of the activation recovery interval (a surrogate for action potential duration) in the region close to the site of pacemaker-induced activation from 228.4±7.6 ms during sinus rhythm to 328.3±6.2 ms during cardiac memory. As a consequence, increases are observed in both apical-basal and right-left ventricular gradients of repolarization, resulting in a significant increase in the dispersion of repolarization.
These results demonstrate that electrical remodeling in response to ventricular pacing in human subjects results in action potential prolongation near the site of abnormal activation and a marked dispersion of repolarization. This dispersion of repolarization is potentially arrhythmogenic and, intriguingly, was less evident during continuous right ventricular pacing, suggesting the novel possibility that continuous right ventricular pacing at least partially suppresses pacemaker-induced cardiac memory.
Circulation Arrhythmia and Electrophysiology 07/2012; 5(4):773-81. · 6.46 Impact Factor
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ABSTRACT: Key points Ca(2+) release from intracellular stores affects the cardiac action potential via currents through L-type Ca(2+) channels (I(Ca)) and the sodium/calcium exchanger (I(NCX)). Dynamic interactions between released calcium, I(Ca) and I(NCX) occur in a restricted subcellular compartment, close to Ca(2+) released sites, where calcium concentration (Ca(t)) cannot be measured. We used a computational model and experimental data to define this compartment and to provide a theoretical basis for estimating Ca(t). We estimated Ca(t) from recordings of I(Ca) and I(NCX) and optical recordings of whole-cell calcium concentration (Ca(m)). Estimated peak Ca(t) ranged from 6 μm to 25 μm, depending on calcium load. Time to equilibrium between Ca(t) and Ca(m) was ∼350 ms. The Ca(t) values are in the range of I(Ca) and I(NCX) sensitivity to calcium, implying that there is significant effect of Ca(2+) in this restricted domain on their kinetics and on the action potential during cell excitation.
The Journal of Physiology 04/2012; 590(Pt 18):4423-46. · 4.72 Impact Factor
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Heart rhythm: the official journal of the Heart Rhythm Society 01/2012; · 4.56 Impact Factor
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ABSTRACT: Explanations for arrhythmia mechanisms at the cellular level are usually based on experiments in nonhuman myocytes. However, subtle electrophysiological differences between species may lead to different rhythmic or arrhythmic cellular behaviors and drug response given the nonlinear and highly interactive cellular system. Using detailed and quantitatively accurate mathematical models for human, dog, and guinea pig ventricular action potentials (APs), we simulated and compared cell electrophysiology mechanisms and response to drugs. Under basal conditions (absence of β-adrenergic stimulation), Na(+)/K(+)-ATPase changes secondary to Na(+) accumulation determined AP rate dependence for human and dog but not for guinea pig where slow delayed rectifier current (I(Ks)) was the major rate-dependent current. AP prolongation with reduction of rapid delayed rectifier current (I(Kr)) and I(Ks) (due to mutations or drugs) showed strong species dependence in simulations, as in experiments. For humans, AP prolongation was 80% following I(Kr) block. It was 30% for dog and 20% for guinea pig. Under basal conditions, I(Ks) block was of no consequence for human and dog, but for guinea pig, AP prolongation after I(Ks) block was severe. However, with β-adrenergic stimulation, I(Ks) played an important role in all species, particularly in AP shortening at fast rate. Quantitative comparison of AP repolarization, rate-dependence mechanisms, and drug response in human, dog, and guinea pig revealed major species differences (e.g., susceptibility to arrhythmogenic early afterdepolarizations). Extrapolation from animal to human electrophysiology and drug response requires great caution.
AJP Heart and Circulatory Physiology 12/2011; 302(5):H1023-30. · 3.71 Impact Factor
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ABSTRACT: The aim of this study was to noninvasively image the electrophysiological (EP) substrate of human ventricles after myocardial infarction and define its characteristics.
Ventricular infarct border zone is characterized by abnormal cellular electrophysiology and altered structural architecture and is a key contributor to arrhythmogenesis. The ability to noninvasively image its electrical characteristics could contribute to understanding of mechanisms and to risk-stratification for ventricular arrhythmia.
Electrocardiographic imaging, a noninvasive functional EP imaging modality, was performed during sinus rhythm (SR) in 24 subjects with infarct-related myocardial scar. The abnormal EP substrate on the epicardial aspect of the scar was identified, and its location, size, and morphology were compared with the anatomic scar imaged by other noninvasive modalities.
Electrocardiographic imaging constructs epicardial electrograms that have characteristics of reduced amplitude (low voltage) and fractionation. Electrocardiographic imaging colocalizes the epicardial electrical scar to the anatomic scar with a high degree of accuracy (sensitivity 89%, specificity 85%). In nearly all subjects, SR activation patterns were affected by the presence of myocardial scar. Late potentials could be identified and were almost always within ventricular scar.
Electrocardiographic imaging accurately identifies areas of anatomic scar and complements standard anatomic imaging by providing scar-related EP characteristics of low voltages, altered SR activation, electrogram fragmentation, and presence of late potentials.
Journal of the American College of Cardiology 10/2011; 58(18):1893-902. · 14.16 Impact Factor
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ABSTRACT: In subclinical or silent long QT syndrome, the QT interval is normal under basal conditions. The hypothesis that insults to the repolarization reserve may cause arrhythmias in silent mutation carriers but not in noncarriers has been proposed as a general principle, yet crucial aspects remain descriptive, lacking quantification.
To utilize accurate mathematical models of the human action potential and β-adrenergic stimulation to quantitatively investigate arrhythmia-formation mechanisms peculiar to silent long QT syndrome, using mutation Q357R in KCNQ1 (α subunit of slow-delayed rectifier I(Ks)) as a paradigm.
Markov models were formulated to account for altered I(Ks) kinetics in Q357R compared with wild type and introduced into a detailed model of the human ventricular myocyte action potential.
Dominant negative loss of I(Ks) available reserve accurately represents Q357R. Action potential prolongation with mutant I(Ks) was minimal, reproducing the silent phenotype. Partial block of rapid delayed rectifier current (I(Kr)) was needed in addition to fast pacing and isoproterenol application to cause early afterdepolarizations (EADs) in epicardial cells with mutant I(Ks), but this did not produce EADs in wild type. Reduced channel expression at the membrane, not I(Ks) kinetic differences, caused EADs in the silent mutant. With mutant I(Ks), isoproterenol plus partial I(Kr) block resulted in dramatic QT prolongation in the pseudo-electrocardiogram and EADs formed without I(Kr) block in mid-myocardial cells during simulated exercise onset.
Multiple severe insults are needed to evince an arrhythmic phenotype in silent mutation Q357R. Reduced membrane I(Ks) expression, not kinetic changes, underlies the arrhythmic phenotype.
Heart rhythm: the official journal of the Heart Rhythm Society 09/2011; 9(2):275-82. · 4.56 Impact Factor
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ABSTRACT: The closure of a three-residue loop was studied using a developed kinematic method. It was shown that there are infinite number of three-residue loops (a locus of conformations), which can connect two segments of a polypeptide. This adds to the current understanding of a finite number of conformations for three-residue loop-closure. In the developed method, some of the equations can be solved analytically to reduce the computation cost. Benefiting from the reduced computation time, we determined all the relative positions of two polypeptide segments that can be connected by a three-residue loop.
Journal of Computational Chemistry 09/2011; 32(12):2515-25. · 4.58 Impact Factor
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ABSTRACT: The rapid heartbeat of ventricular tachycardia (VT) can lead to sudden cardiac death and is a major health issue worldwide. Efforts to identify patients at risk, determine mechanisms of VT, and effectively prevent and treat VT through a mechanism-based approach would all be facilitated by continuous, noninvasive imaging of the arrhythmia over the entire heart. Here, we present noninvasive real-time images of human ventricular arrhythmias using electrocardiographic imaging (ECGI). Our results reveal diverse activation patterns, mechanisms, and sites of initiation of human VT. The spatial resolution of ECGI is superior to that of the routinely used 12-lead electrocardiogram, which provides only global information, and ECGI has distinct advantages over the currently used method of mapping with invasive catheter-applied electrodes. The spatial resolution of this method and its ability to image electrical activation sequences over the entire ventricular surfaces in a single heartbeat allowed us to determine VT initiation sites and continuation pathways, as well as VT relationships to ventricular substrates, including anatomical scars and abnormal electrophysiological substrate. Thus, ECGI can map the VT activation sequence and identify the location and depth of VT origin in individual patients, allowing personalized treatment of patients with ventricular arrhythmias.
Science translational medicine 08/2011; 3(98):98ra84. · 7.80 Impact Factor
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ABSTRACT: Purkinje cells (Pcell) are characterized by different electrophysiological properties and Ca(2+) cycling processes than ventricular myocytes (Vcell) and are frequently involved in ventricular arrhythmias. Yet, the mechanistic basis for their arrhythmic vulnerability is not completely understood. The objectives were to: (1) characterize Pcell electrophysiology, Ca(2+) cycling, and their rate dependence; (2) investigate mechanisms underlying Pcell arrhythmogenicity; and compare Pcell and Vcell electrophysiology, Ca(2+) cycling, and arrhythmic properties. We developed a new mathematical model of Pcell. The Ca(2+) subsystem includes spatial organization and receptors distribution unique to Pcell. Results were: (1) in Pcell and Vcell, Na(+) accumulation via its augmentation of repolarizing I(NaK) dominates action potential duration adaptation and, in Pcell, I(NaL) contributes additional action potential duration shortening at short cycle length; (2) steep Pcell restitution is attributable to slow recovery of I(NaL); (3) biphasic Ca(2+) transients of Pcell reflect the delay between Ca(2+) release from junctional sarcoplasmic reticulum and corbular sarcoplasmic reticulum; (4) Pcell Ca(2+) alternans, unlike Vcell, can develop without inducing action potential alternans; (5) Pcell action potential alternans develops at a shorter cycle length than Vcell, with increased subcellular heterogeneity of Ca(2+) cycling attributable to refractoriness of Ca(2+) release from corbular sarcoplasmic reticulum and junctional sarcoplasmic reticulum; (6) greater Pcell vulnerability to delayed afterdepolarizations is attributable to higher sarcoplasmic reticulum Ca(2+) content and ionic currents that reduce excitation threshold and promote triggered activity; and (7) early after depolarizations generation in Pcell is mostly attributable to reactivation of I(NaL2), whereas I(CaL) plays this role in Vcell. Steeper rate dependence of action potential and Ca(2+) transients, central peripheral heterogeneity of Ca(2+) cycling, and distinct ion channel profile underlie greater arrhythmic vulnerability of Pcell compared to Vcell.
Circulation Research 06/2011; 109(1):71-9. · 9.49 Impact Factor
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ABSTRACT: In cardiac ventricular myocytes, calcium (Ca) release occurs at distinct structures (dyads) along t-tubules, where L-type Ca channels (LCCs) appose sarcoplasmic reticulum (SR) Ca release channels (RyR2s). We developed a model of the cardiac ventricular myocyte that simulates local stochastic Ca release processes. At the local Ca release level, the model reproduces Ca spark properties. At the whole-cell level, the model reproduces the action potential, Ca currents, and Ca transients. Changes in microscopic dyadic properties (e.g., during detubulation in heart failure) affect whole-cell behavior in complex ways, which we investigated by simulating changes in the dyadic volume and number of LCCs/RyR2s in the dyad, and effects of calsequestrin (CSQN) as a Ca buffer (CSQN buffer) or a luminal Ca sensor (CSQN regulator). We obtained the following results: 1), Increased dyadic volume and reduced LCCs/RyR2s decrease excitation-contraction coupling gain and cause asynchrony of SR Ca release, and interdyad coupling partially compensates for the reduced synchrony. 2), Impaired CSQN buffer depresses Ca transients without affecting the synchrony of SR Ca release. 3), When CSQN regulator function is impaired, interdyad coupling augments diastolic Ca release activity to form Ca waves and long-lasting Ca release events.
Biophysical Journal 06/2011; 100(12):2904-12. · 3.65 Impact Factor
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ABSTRACT: During Ca²⁺ release from the sarcoplasmic reticulum triggered by Ca²⁺ influx through L-type Ca²⁺ channels (LTCCs), [Ca²⁺] near release sites ([Ca²⁺]nrs) temporarily exceeds global cytosolic [Ca²⁺]. [Ca²⁺]nrs can at present not be measured directly but the Na+/Ca2+ exchanger (NCX) near release sites and LTCCs also experience [Ca²⁺]nrs. We have tested the hypothesis that ICaL and INCX could be calibrated to report [Ca²⁺]nrs and would report different time course and values for local [Ca²⁺]. Experiments were performed in pig ventricular myocytes (whole-cell voltage-clamp, Fluo-3 to monitor global cytosolic [Ca²⁺], 37◦C). [Ca²⁺]nrs-dependent inactivation of ICaL during a step to +10 mV peaked around 10 ms. For INCX we computationally isolateda current fraction activated by [Ca²⁺]nrs; values were maximal at 10 ms into depolarization. The recovery of [Ca²⁺]nrs was comparable with both reporters (>90% within 50 ms). Calibration yielded maximal values for [Ca²⁺]nrs between 10 and 15 μmol l⁻¹ with both methods. When applied to a step to less positive potentials (-30 to -20 mV), the time course of [Ca²⁺]nrs was slower but peak values were not very different. In conclusion, both ICaL inactivation and INCX activation, using a subcomponent analysis, can be used to report dynamic changes of [Ca²⁺]nrs. Absolute values obtained by these different methods are within the same range, suggesting that they are reporting on a similar functional compartment near ryanodine receptors. Comparable [Ca²⁺]nrs at +10 mV and -20 mV suggests that, although the number of activated release sites differs at these potentials, local gradients at release sites can reach similar values.
The Journal of Physiology 05/2011; 589(Pt 10):2569-83. · 4.72 Impact Factor
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ABSTRACT: Cellular electrophysiology experiments, important for understanding cardiac arrhythmia mechanisms, are usually performed with channels expressed in non myocytes, or with non-human myocytes. Differences between cell types and species affect results. Thus, an accurate model for the undiseased human ventricular action potential (AP) which reproduces a broad range of physiological behaviors is needed. Such a model requires extensive experimental data, but essential elements have been unavailable. Here, we develop a human ventricular AP model using new undiseased human ventricular data: Ca(2+) versus voltage dependent inactivation of L-type Ca(2+) current (I(CaL)); kinetics for the transient outward, rapid delayed rectifier (I(Kr)), Na(+)/Ca(2+) exchange (I(NaCa)), and inward rectifier currents; AP recordings at all physiological cycle lengths; and rate dependence and restitution of AP duration (APD) with and without a variety of specific channel blockers. Simulated APs reproduced the experimental AP morphology, APD rate dependence, and restitution. Using undiseased human mRNA and protein data, models for different transmural cell types were developed. Experiments for rate dependence of Ca(2+) (including peak and decay) and intracellular sodium ([Na(+)](i)) in undiseased human myocytes were quantitatively reproduced by the model. Early afterdepolarizations were induced by I(Kr) block during slow pacing, and AP and Ca(2+) alternans appeared at rates >200 bpm, as observed in the nonfailing human ventricle. Ca(2+)/calmodulin-dependent protein kinase II (CaMK) modulated rate dependence of Ca(2+) cycling. I(NaCa) linked Ca(2+) alternation to AP alternans. CaMK suppression or SERCA upregulation eliminated alternans. Steady state APD rate dependence was caused primarily by changes in [Na(+)](i), via its modulation of the electrogenic Na(+)/K(+) ATPase current. At fast pacing rates, late Na(+) current and I(CaL) were also contributors. APD shortening during restitution was primarily dependent on reduced late Na(+) and I(CaL) currents due to inactivation at short diastolic intervals, with additional contribution from elevated I(Kr) due to incomplete deactivation.
PLoS Computational Biology 05/2011; 7(5):e1002061. · 5.22 Impact Factor
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Heart rhythm: the official journal of the Heart Rhythm Society 02/2011; · 4.56 Impact Factor
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Ralph J van Oort,
Alejandro Garbino,
Wei Wang,
Sayali S Dixit,
Andrew P Landstrom,
Namit Gaur,
Angela C De Almeida,
Darlene G Skapura, Yoram Rudy,
Alan R Burns,
Michael J Ackerman,
Xander H T Wehrens
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ABSTRACT: Excitation-contraction coupling in striated muscle requires proper communication of plasmalemmal voltage-activated Ca2+ channels and Ca2+ release channels on sarcoplasmic reticulum within junctional membrane complexes. Although previous studies revealed a loss of junctional membrane complexes and embryonic lethality in germ-line junctophilin-2 (JPH2) knockout mice, it has remained unclear whether JPH2 plays an essential role in junctional membrane complex formation and the Ca(2+)-induced Ca(2+) release process in the heart. Our recent work demonstrated loss-of-function mutations in JPH2 in patients with hypertrophic cardiomyopathy.
To elucidate the role of JPH2 in the heart, we developed a novel approach to conditionally reduce JPH2 protein levels using RNA interference. Cardiac-specific JPH2 knockdown resulted in impaired cardiac contractility, which caused heart failure and increased mortality. JPH2 deficiency resulted in loss of excitation-contraction coupling gain, precipitated by a reduction in the number of junctional membrane complexes and increased variability in the plasmalemma-sarcoplasmic reticulum distance.
Loss of JPH2 had profound effects on Ca2+ release channel inactivation, suggesting a novel functional role for JPH2 in regulating intracellular Ca2+ release channels in cardiac myocytes. Thus, our novel approach of cardiac-specific short hairpin RNA-mediated knockdown of junctophilin-2 has uncovered a critical role for junctophilin in intracellular Ca2+ release in the heart.
Circulation 02/2011; 123(9):979-88. · 14.74 Impact Factor
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ABSTRACT: Local signaling domains and numerous interacting molecular pathways and substrates contribute to the whole-cell response of myocytes during β-adrenergic stimulation (βARS). We aimed to elucidate the quantitative contribution of substrates and their local signaling environments during βARS to the canine epicardial ventricular myocyte electrophysiology and calcium transient (CaT). We present a computational compartmental model of βARS and its electrophysiological effects. Novel aspects of the model include localized signaling domains, incorporation of β1 and β2 receptor isoforms, a detailed population-based approach to integrate the βAR and Ca(2+)/Calmodulin kinase (CaMKII) signaling pathways and their effects on a wide range of substrates that affect whole-cell electrophysiology and CaT. The model identifies major roles for phosphodiesterases, adenylyl cyclases, PKA and restricted diffusion in the control of local cAMP levels and shows that activation of specific cAMP domains by different receptor isoforms allows for specific control of action potential and CaT properties. In addition, the model predicts increased CaMKII activity during βARS due to rate-dependent accumulation and increased Ca(2+) cycling. CaMKII inhibition, reduced compartmentation, and selective blockade of β1AR is predicted to reduce the occurrence of delayed afterdepolarizations during βARS. Finally, the relative contribution of each PKA substrate to whole-cell electrophysiology is quantified by comparing simulations with and without phosphorylation of each target. In conclusion, this model enhances our understanding of localized βAR signaling and its whole-cell effects in ventricular myocytes by incorporating receptor isoforms, multiple pathways and a detailed representation of multiple-target phosphorylation; it provides a basis for further studies of βARS under pathological conditions.
Journal of Molecular and Cellular Cardiology 02/2011; 50(5):863-71. · 5.17 Impact Factor
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ABSTRACT: A modeling framework was developed to simulate large and gradual conformational changes within a macromolecule (protein) when its low amplitude high frequency vibrations are not concerned. Governing equations were derived as alternative to Langevin and Smoluchowski equations and used to simulate gating conformational changes of the Kv7.1 ion-channel over the time scale of its gating process (tens of milliseconds). The alternative equations predict the statistical properties of the motion trajectories with good accuracy and do not require the force field to be constant over the diffusion length, as assumed in Langevin equation. The open probability of the ion-channel was determined considering cooperativity of four subunits and solving their concerted transition to the open state analytically. The simulated open probabilities for a series of voltage clamp tests produced current traces that were similar to experimentally recorded currents.
PLoS ONE 01/2011; 6(5):e20186. · 4.09 Impact Factor
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ABSTRACT: Electrocardiographic imaging (ECGI) is a method for noninvasive epicardial electrophysiologic mapping. ECGI previously has been used to characterize the electrophysiologic substrate and electrical synchrony in a very heterogeneous group of patients with varying degrees of coronary disease and ischemic cardiomyopathy.
The purpose of this study was to characterize the left ventricular electrophysiologic substrate and electrical dyssynchrony using ECGI in a homogeneous group of nonischemic cardiomyopathy patients who were previously implanted with a cardiac resynchronization therapy (CRT) device.
ECGI was performed during different rhythms in 25 patients by programming their devices to biventricular pacing, single-chamber (left ventricular or right ventricular) pacing, and native rhythm. The electrical dyssynchrony index (ED) was computed as the standard deviation of activation times at 500 sites on the LV epicardium.
In all patients, native rhythm activation was characterized by lines of conduction block in a region with steep activation-recovery interval (ARI) gradients between the epicardial aspect of the septum and LV lateral wall. A native QRS duration (QRSd) >130 ms was associated with high ED (≥30 ms), whereas QRSd <130 ms was associated with minimal (25 ms) to large (40 ms) ED. CRT responders had very high dyssynchrony (ED = 35.5 ± 3.9 ms) in native rhythm, which was significantly lowered (ED = 23.2 ± 4.4 ms) during CRT. All four nonresponders in the study did not show significant difference in ED between native and CRT rhythms.
The electrophysiologic substrate in nonischemic cardiomyopathy is consistent among all patients, with steep ARI gradients co-localizing with conduction block lines between the epicardial aspect of the septum and the LV lateral wall. QRSd wider than 130 ms is indicative of substantial LV electrical dyssynchrony; however, among patients with QRSd <130 ms, LV dyssynchrony may vary widely.
Heart rhythm: the official journal of the Heart Rhythm Society 01/2011; 8(5):692-9. · 4.56 Impact Factor
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ABSTRACT: The increased incidence of arrhythmia in the healing phase after infarction has been linked to remodeling in the epicardial border zone (EBZ). Ionic models of normal zone (NZ) and EBZ myocytes were incorporated into one-dimensional models of propagation to gain mechanistic insights into how ion channel remodeling affects action potential (AP) duration (APD) and refractoriness, vulnerability to conduction block, and conduction safety postinfarction. We found that EBZ tissue exhibited abnormal APD restitution. The remodeled Na(+) current (I(Na)) and L-type Ca(2+) current (I(Ca,L)) promoted increased effective refractory period and prolonged APD at a short diastolic interval. While postrepolarization refractoriness due to remodeled EBZ I(Na) was the primary determinant of the vulnerable window for conduction block at the NZ-to-EBZ transition in response to premature S2 stimuli, altered EBZ restitution also promoted APD dispersion and increased the vulnerable window at fast S1 pacing rates. Abnormal EBZ APD restitution and refractoriness also led to abnormal periodic conduction block patterns for a range of fast S1 pacing rates. In addition, we found that I(Na) remodeling decreased conduction safety in the EBZ but that inward rectifier K(+) current remodeling partially offset this decrease. EBZ conduction was characterized by a weakened AP upstroke and short intercellular delays, which prevented I(Ca,L) and transient outward K(+) current remodeling from playing a role in EBZ conduction in uncoupled tissue. Simulations of a skeletal muscle Na(+) channel SkM1-I(Na) injection into the EBZ suggested that this recently proposed antiarrhythmic therapy has several desirable effects, including normalization of EBZ effective refractory period and APD restitution, elimination of vulnerability to conduction block, and normalization of conduction in tissue with reduced intercellular coupling.
AJP Heart and Circulatory Physiology 11/2010; 299(5):H1588-97. · 3.71 Impact Factor
