Proceedings of the National Academy of Sciences of the United States of America, Jan 11, 2006
In cardiac cells, the coupling between the voltage across the cell membrane (V(m)) and the releas... more In cardiac cells, the coupling between the voltage across the cell membrane (V(m)) and the release of calcium (Ca) from intracellular stores is a crucial ingredient of heart function. Under abnormal conditions and/or rapid pacing, both the action potential duration and the peak Ca concentration in the cell can exhibit well known period-doubling oscillations referred to as "alternans," which have been linked to sudden cardiac death. Fast diffusion of V(m) keeps action potential duration alternans spatially synchronized over the approximately 150-mum-length scale of a cell, but slow diffusion of Ca ions allows Ca alternans within a cell to become spatially asynchronous, as observed in some experiments. This finding raises the question: When are Ca alternans spatially in-phase or out-of-phase on subcellular length scales? This question is investigated by using a spatially distributed model of Ca cycling coupled to V(m). Our main finding is the existence of a Turing-type symme...
Conductances of ion channels and transporters controlling cardiac excitation may vary 14 in a pop... more Conductances of ion channels and transporters controlling cardiac excitation may vary 14 in a population of subjects with different cardiac gene expression patterns. However, the amount 15 of variability and its origin are not quantitatively known. We propose a new conceptual approach to 16 predict this variability that consists of finding combinations of conductances generating a normal 17 intracellular Ca2+ transient without any constraint on the action potential. Furthermore, we validate 18 experimentally its predictions using the Hybrid Mouse Diversity Panel, a model system of 19 genetically diverse mouse strains that allows us to quantify inter-subject versus intra-subject 20 variability. The method predicts that conductances of inward Ca2+ and outward K+ currents 21 compensate each other to generate a normal Ca2+ transient in good quantitative agreement with 22 current measurements in ventricular myocytes from hearts of different isogenic strains. Our results 23 suggest that a...
Circulation. Arrhythmia and electrophysiology, 2018
Sudden death in long-QT syndrome type 1 (LQT1), an inherited disease caused by loss-of-function m... more Sudden death in long-QT syndrome type 1 (LQT1), an inherited disease caused by loss-of-function mutations in KCNQ1, is triggered by early afterdepolarizations (EADs) that initiate polymorphic ventricular tachycardia (pVT). We investigated ionic mechanisms that underlie pVT in LQT1 using a transgenic rabbit model of LQT1. Optical mapping, cellular patch clamping, and computer modeling were used to elucidate the mechanisms of EADs in transgenic LQT1 rabbits. The results showed that shorter action potential duration in the right ventricle (RV) was associated with focal activity during pVT initiation. RV cardiomyocytes demonstrated higher incidence of EADs under 50 nmol/L isoproterenol. Voltage-clamp studies revealed that the transient outward potassium current (I) magnitude was 28% greater in RV associated with KChiP2 but with no differences in terms of calcium-cycling kinetics and other sarcolemmal currents. Perfusing with the I blocker 4-aminopyridine changed the initial focal sites ...
Annual International Conference of the IEEE Engineering in Medicine and Biology Society, 2000
A simplified quantitative ionic model of cardiac action potential, which reproduces accurate rest... more A simplified quantitative ionic model of cardiac action potential, which reproduces accurate restitution curves, is used in conjunction with global tissue characteristics such as rotational cell anisotropy and periodic boundaries to study the transition from ventricular tachycardia (VT) to ventricular fibrillation (VF). The authors give an explanation for the experimental observation that there is a minimum tissue mass required for
Proceedings of the National Academy of Sciences of the United States of America, Jan 11, 2006
In cardiac cells, the coupling between the voltage across the cell membrane (V(m)) and the releas... more In cardiac cells, the coupling between the voltage across the cell membrane (V(m)) and the release of calcium (Ca) from intracellular stores is a crucial ingredient of heart function. Under abnormal conditions and/or rapid pacing, both the action potential duration and the peak Ca concentration in the cell can exhibit well known period-doubling oscillations referred to as "alternans," which have been linked to sudden cardiac death. Fast diffusion of V(m) keeps action potential duration alternans spatially synchronized over the approximately 150-mum-length scale of a cell, but slow diffusion of Ca ions allows Ca alternans within a cell to become spatially asynchronous, as observed in some experiments. This finding raises the question: When are Ca alternans spatially in-phase or out-of-phase on subcellular length scales? This question is investigated by using a spatially distributed model of Ca cycling coupled to V(m). Our main finding is the existence of a Turing-type symme...
Conductances of ion channels and transporters controlling cardiac excitation may vary 14 in a pop... more Conductances of ion channels and transporters controlling cardiac excitation may vary 14 in a population of subjects with different cardiac gene expression patterns. However, the amount 15 of variability and its origin are not quantitatively known. We propose a new conceptual approach to 16 predict this variability that consists of finding combinations of conductances generating a normal 17 intracellular Ca2+ transient without any constraint on the action potential. Furthermore, we validate 18 experimentally its predictions using the Hybrid Mouse Diversity Panel, a model system of 19 genetically diverse mouse strains that allows us to quantify inter-subject versus intra-subject 20 variability. The method predicts that conductances of inward Ca2+ and outward K+ currents 21 compensate each other to generate a normal Ca2+ transient in good quantitative agreement with 22 current measurements in ventricular myocytes from hearts of different isogenic strains. Our results 23 suggest that a...
Circulation. Arrhythmia and electrophysiology, 2018
Sudden death in long-QT syndrome type 1 (LQT1), an inherited disease caused by loss-of-function m... more Sudden death in long-QT syndrome type 1 (LQT1), an inherited disease caused by loss-of-function mutations in KCNQ1, is triggered by early afterdepolarizations (EADs) that initiate polymorphic ventricular tachycardia (pVT). We investigated ionic mechanisms that underlie pVT in LQT1 using a transgenic rabbit model of LQT1. Optical mapping, cellular patch clamping, and computer modeling were used to elucidate the mechanisms of EADs in transgenic LQT1 rabbits. The results showed that shorter action potential duration in the right ventricle (RV) was associated with focal activity during pVT initiation. RV cardiomyocytes demonstrated higher incidence of EADs under 50 nmol/L isoproterenol. Voltage-clamp studies revealed that the transient outward potassium current (I) magnitude was 28% greater in RV associated with KChiP2 but with no differences in terms of calcium-cycling kinetics and other sarcolemmal currents. Perfusing with the I blocker 4-aminopyridine changed the initial focal sites ...
Annual International Conference of the IEEE Engineering in Medicine and Biology Society, 2000
A simplified quantitative ionic model of cardiac action potential, which reproduces accurate rest... more A simplified quantitative ionic model of cardiac action potential, which reproduces accurate restitution curves, is used in conjunction with global tissue characteristics such as rotational cell anisotropy and periodic boundaries to study the transition from ventricular tachycardia (VT) to ventricular fibrillation (VF). The authors give an explanation for the experimental observation that there is a minimum tissue mass required for
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