Arrhythmia prevention: novel anti-arrhythmic pacing protocol

One of the major limitations of the current concept of electrical restitution is the fact that it was developed for periodic stimulation only. In this case, there is a partial dependence of the DI on the immediately preceding APD, i.e. feedback that can lead to subsequent destabilization of normal cardiac rhythms. However, in the heart, the actual rate is never periodic. Instead, the heart rate is modulated by many physiological factors, including the influence of circadian rhythms, temperature regulations, changes in cardiac sympathetic and parasympathetic nerve activities, respiratory rhythms, etc. All of these factors lead to the presence of heart rate variability (HRV), which can lead to significant feedback modulation in the heart, and thus, altering predictions of cardiac arrhythmias based on the current restitution concept.

• K. Kulkarni, R.D. Walton, A.A. Armoundas, E.G. Tolkacheva, “Clinical Potential of Beat-to-Beat Diastolic Interval Control in Suppression of Cardiac Arrhythmias”, J Am Heart Assoc. 2021; 10:e020750. DOI: 10.1161/JAHA.121.020750
• S. Newell, P. Parthiban and E.G. Tolkacheva, Effect of constant DI pacing and Voltage-Calcium coupling on bifurcation in cardiac cell. Chaos, 30, 103122 (2020); doi: 10.1063/5.0022066
• S. Thakare, J. Mathew, S. Zlochiver, X. Zhao, E.G. Tolkacheva. Global versus local control of Cardiac Alternans in a 1D Numerical Model of Human Ventricular Tissue, Chaos, 30, 083123 (2020); DOI: 10.1063/5.0005432
• Kulkarni K., Lee S.W., Kluck R., Tolkacheva E.G., Real-Time Closed Loop Diastolic Interval Control Prevents Cardiac Alternans in Isolated Whole Rabbit Hearts, Annals of BME, 2017. DOI: 10.1007/s10439-018-1981-2.
• Zlochiver S., Johnson C. and Tolkacheva E.G. Constant DI Pacing Suppresses Cardiac Alternans Formation in Numerical Cable Models, accepted, Chaos, 2017
• Kanchan Kulkarni, Elena G. Tolkacheva, Real-time Feedback Based Control of Cardiac Restitution Using Optical Mapping, proceedings of IEEE EMBC 2015.
• S.D. McIntyre, V. Kakade, Y. Mori, E.G. Tolkacheva. Heart rate variability and alternans formation in the heart: the role of feedback in cardiac dynamics. JTB, 7, 350:90-97, 2014.

Complex mechanisms of cardiac arrhythmia

We have developed a comprehensive approach that allows us to detect evolution of cardiac rhythms in the heart and to analyze the mechanisms of their formation. Alternans, a beat-to-beat alternation in the action potential duration, has been implicated as being proarrhythmic. We discovered that alternans is a complex spatio-temporal phenomenon that initially occurs locally and then gradually develops in the heart as pacing rate increases.

First, we developed a novel technique for investigating the dynamics of periodically paced cardiac myocytes and predict the local onset of alternans in the heart. We also established electrophysiological mechanisms and the role of short term memory in action potential duration restitution and the formation of spatially discordant alternans in the heart using nonlinear spatio-temporal analysis of the heart’s dynamics.   ​​

• S. W. Lee*, K. Kulkarni*, E. G. Tolkacheva, “Benchtop optical mapping approaches to study arrhythmias”, in Engineering in Medicine, 1^st edition, Advances and challenges, 2018.
• K. Kulkarni, R. Visweswaran, X. Zhao, E.G. Tolkacheva. Characterizing Spatial Dynamics of Bifurcation to Alternans in Isolated Whole Rabbit Hearts Based on Alternate Pacing, BioMed Research International, 2015:170768. doi: 10.1155/2015/170768.
• V. Kakade, X. Zhao, E.G. Tolkacheva, “Prediction of alternans in the heart: a principal component analysis approach”, Phys. Rev. E, 88 (5) 052716, 2013.
• R. Visweswaran, S.D. McIntyre, K. Ramkrishnan, X. Zhao, E.G. Tolkacheva. Spatio-temporal evolution and prediction of APD and Ca alternans in isolated rabbit hearts, J. Cardiovasc. Electrophysiol, 24 (11) 1287-95, 2013.

We also explored the impact of the complex geometry of myocardial ischemia border zone (BZ) and ephaptic coupling as well as the interaction between the two on action potential propagation across the ischemic region.  

• Ning Wei, Elena G. Tolkacheva Mechanisms of arrhythmia termination during acute myocardial ischemia: role of ephaptic coupling and complex geometry of border zone, PLoS One. 2022 Mar 15;17(3):e0264570. doi: 10.1371/journal.pone.0264570.
• Ning Wei, Elena G. Tolkacheva Interplay between ephaptic coupling and complex geometry of myocardial infarction border zone: effect on arrhythmogeneity. Chaos. 2020 Mar; 30 (3):033111. doi: 10.1063/1.5134447.
• N.Wei, Y. Mori, and E. G. Tolkacheva, The dual effect of ephaptic coupling on cardiac conduction with heterogeneous expression of connexin 43, J Theor Biol. 2016 May 21;397:103-14.