Cardiac alternans is characterized by a beat-to-beat alternation in membrane potential that is known to trigger cardiac reentry in experiments and has been correlated with risk for clinical tachyarrhythmias. In recent years progress has been made in illuminating the mechanisms of alternans. However, significant uncertainty remains. Studies have suggested that alternans may result from dynamical instabilities in either or both membrane voltage or calcium cycling. More specifically, the two proposed mechanisms are: (i) sarcolemmal ion current dynamics cause repolarization alternans, which in turn produces calcium alternans, and (ii) sarcoplasmic reticulum calcium uptake and release mismatch causes calcium alternans, which in turn produces repolarization alternans via calcium coupling to sarcolemmal currents. For many years, mechanism (i) was thought to explain the occurrence of alternans. Specifically, the action potential duration (APD) restitution function was used to predict alternans based on the hypothesis that restitution slopes >1 dictate that intrinsic APD variations will be amplified into alternans. However, evidence has mounted that this relationship often does not hold. In contrast, evidence for mechanism (ii) has accumulated, pushing that theory to the forefront. All that being said, in spite of widespread interest in identifying "the" mechanism of alternans, we hypothesize that there is not necessarily one generic mechanism for alternans, but rather that mechanisms (i) and (ii) play varying, but quantifiable, roles for different cardiac cell types. To investigate this hypothesis, we will use synergistic computational and experimental approaches: 1. To quantify the sensitivity of cellular alternans to action-potential morphology. 2. To quantify the cell-type dependence of whole-cell and subcellular alternans mechanisms in vitro. 3. To investigate the tissue-level implications of cellular alternans mechanisms using computational modeling and ex vivo optical mapping experiments. By spanning several spatial scales, from subcellular to tissue-level, the synergistic computational and experimental studies proposed here will help to provide an integrated understanding of alternans dynamics. Furthermore, identification of the mechanisms of alternans will help advance our understanding of alternans arrhythmogenesis, which may have clinical implications.
(Using no more than two or three sentences, describe the relevance of this research to public health.) Alternans, which is a cardiac rhythm occurrence in which cellular behavior alternates on a beat-to-beat basis, has been shown to trigger cardiac arrhythmias in experiments and has been correlated with risk for lethal cardiac arrhythmias. Our central objective is to illuminate the mechanisms of alternans, which remain unclear, through novel quantitative analyses applied to synergistic computational modeling and experimental studies. By doing so, the proposed work may help improve our understanding of how alternans may trigger cardiac arrhythmias.
|Maoz, Anat; Christini, David J; Krogh-Madsen, Trine (2014) Dependence of phase-2 reentry and repolarization dispersion on epicardial and transmural ionic heterogeneity: a simulation study. Europace 16:458-65|
|Groenendaal, Willemijn; Ortega, Francis A; Krogh-Madsen, Trine et al. (2014) Voltage and calcium dynamics both underlie cellular alternans in cardiac myocytes. Biophys J 106:2222-32|
|Krogh-Madsen, Trine; Christini, David J (2012) Nonlinear dynamics in cardiology. Annu Rev Biomed Eng 14:179-203|
|Roberts, Byron N; Christini, David J (2012) The relative influences of phosphometabolites and pH on action potential morphology during myocardial reperfusion: a simulation study. PLoS One 7:e47117|
|Bot, Corina T; Kherlopian, Armen R; Ortega, Francis A et al. (2012) Rapid genetic algorithm optimization of a mouse computational model: benefits for anthropomorphization of neonatal mouse cardiomyocytes. Front Physiol 3:421|
|Iravanian, Shahriar; Kanu, Uche B; Christini, David J (2012) A class of Monte-Carlo-based statistical algorithms for efficient detection of repolarization alternans. IEEE Trans Biomed Eng 59:1882-91|
|Krogh-Madsen, Trine; Abbott, Geoffrey W; Christini, David J (2012) Effects of electrical and structural remodeling on atrial fibrillation maintenance: a simulation study. PLoS Comput Biol 8:e1002390|
|Roberts, Byron N; Christini, David J (2011) NHE inhibition does not improve Na(+) or Ca(2+) overload during reperfusion: using modeling to illuminate the mechanisms underlying a therapeutic failure. PLoS Comput Biol 7:e1002241|
|Kanu, Uche B; Iravanian, Shahriar; Gilmour Jr, Robert F et al. (2011) Control of action potential duration alternans in canine cardiac ventricular tissue. IEEE Trans Biomed Eng 58:894-904|
|Krogh-Madsen, Trine; Karma, Alain; Riccio, Mark L et al. (2010) Off-site control of repolarization alternans in cardiac fibers. Phys Rev E Stat Nonlin Soft Matter Phys 81:011915|
Showing the most recent 10 out of 13 publications