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Rotational and Focal Sources of Atrial Fibrillation: Scientific Rationale and Comparative Clinical Mapping

Acknowledgments This work was supported by grants from the National Institutes of Health (NIH) to Dr. Narayan (HL83359, HL103800, and HL149134) and to Dr. Rappel (HL122384 and HL145500). Dr. Zaman is funded by a Fulbright award and by a fellowship from the British Heart Foundation. Introduction A major unresolved question in atrial fibrillation (AF) is whether mapping and targeting patient-specific mechanisms can improve the current 60%…

Role of the Autonomic Nervous System in Atrial Fibrillation

Cardiac Autonomic Nervous System The autonomic nervous system can be viewed as the interface between the central nervous system and the viscera, glands, and blood vessels. Integration of the neural trafficking among the afferent and efferent autonomic nerves and their associated autonomic neurons, maintains a delicate homeostasis of the function of the entire body. In mammalian hearts, the efferent sympathetic preganglionic neurons are located in the…

Sympathetic Modulation of Cardiac Electrophysiology

Introduction The autonomic nervous system plays a pivotal role in the control of cardiac function. Cardiac autonomic control occurs through sympathetic, parasympathetic, and sensory neurons that densely innervate the heart and provide tropic responses. The parasympathetic system promotes negative chronotropic (heart rate), inotropic (contractility), and dromotropic (conduction) responses primarily through the release of acetylcholine (ACh). Cholinergic nerves are most abundant in the atria and cardiac conducting…

Neural Activity and Atrial Tachyarrhythmias

Acknowledgments This study was supported in part by National Institutes of Health (NIH) grants R01HL139829 and 1OT2OD028190 (Dr. Chen), a Charles Fisch Cardiovascular Research Award endowed by Dr. Suzanne B. Knoebel of the Krannert Institute of Cardiology (Drs. Kusayama and Everett), a Medtronic-Zipes Endowment, and the Indiana University Health-Indiana University School of Medicine Strategic Research Initiative (Dr. Chen). The autonomic nervous system (ANS) plays a central…

Autonomic and Oxidant Regulation of Cardiac Sodium Currents: Mechanisms and Consequences

Introduction Posttranslational modification of ion channels and related proteins is an important determinant of transcription, splicing, functional expression, localization, and macromolecular assembly. Ion channels and their modifications are important in virtually all physiologic processes and in the heart and vasculature in development, metabolism, pharmacology, and response to pathologic insults. This chapter focuses on the role of posttranslational modifications (PTMs) of cardiac Na channels and the effect…

Innervation of the Sinoatrial Node

Acknowledgments The authors thank Audrys G. Pauza, MSc, for his graphical assistance in preparing this chapter. The authors are also exceptionally grateful to Prof. José Jalife for his careful reading of the manuscript and friendly editorial assistance. Funding for this study was partly allocated from Grants MIP-11184 and MIP-13037 provided by the Research Council of Lithuania. The mammalian sinoatrial node (SAN), including the human one, is…

Electromechanic Imaging of the Heart

Cardiac fibrillation is an electromechanical dysfunction of the heart that is driven by complex three-dimensional (3D) electrical excitation waves, resulting in incoherent mechanical contraction, loss of pumping function, and risk of sudden cardiac death. The dynamics of vortex-like rotating waves or rotors plays an essential role in the spatiotemporal organization of fibrillation. However, the detailed rotor dynamics, their interaction with each other and with the 3D…

Modeling the Aging Heart

Acknowledgments This work was supported by the National Institutes of Health (U01-HL141074). Introduction Aging Heart The aging heart is characterized by a number of morphologic and structural changes manifested at the different levels of biologic hierarchy. These changes lead to the functional decline of the aging heart and, particularly, to its diminished ability to meet the increases in demand. The progressive changes in cardiac anatomy and…

Computational Approaches for Accurate Rotor Localization in the Atria

Introduction Experimental and clinical data from a number of laboratories support the hypothesis that both acute and persistent atrial fibrillation (AF) in some animal models and groups of human patients is not random. Studies analyzing the spatiotemporal organization of waves and dominant frequency (DF) in the isolated sheep heart demonstrate that AF maintenance depends on reentrant, or so-called “rotor,” sources localized mainly in the left atrium…

Distinct ECG Phenotypes Identified in Hypertrophic Cardiomyopathy Using Machine Learning Associated With Arrhythmic Risk Markers

Introduction Hypertrophic cardiomyopathy (HCM) is a common yet challenging genetic heart disease with a prevalence of 1 in 500 people. It is characterized by an unexplained thickened heart muscle. It is a major cause of sudden cardiac death (SCD) in young adults, but most patients remain asymptomatic with a normal life expectancy. Because of the heterogeneous clinical course of the disease, the identification of at-risk patients…

Theory of Rotors and Arrhythmias

Acknowledgment We thank Vadim N. Biktashev, Alexander Teplenin, and Enid Van Nieuwenhuyse for help in preparation of the manuscript. The main physiologic function of the heart is to pump blood through the circulatory system. This pumping function is controlled by an electrical wave of excitation that propagates through the heart and initiates cardiac contraction. In normal conditions, the waves are periodically initiated at the natural pacemaker…

Calcium Signaling in Cardiomyocyte Models With Realistic Geometries

The microarchitecture of cellular substructures involved in calcium signaling is highly organized in all forms of mammalian striated muscle, and the cardiac ventricular myocyte (VM) is no exception. The ultrastructural characteristics of the T-tubular system and sarcoplasmic reticulum (SR) play an important role in normal cardiac electrophysiology, and their degradation has dire consequences in a number of pathologic contexts. The following sections discuss several electrophysiologically important…

Global Optimization Approaches to Generate Dynamically Robust Electrophysiologic Models

Introduction The electrical activity underlying the cardiac action potential emerges from a complicated process. It involves a large number of proteins including ionic channels and transporters that often have nonlinear dependencies on components such as the transmembrane potential and the concentration of ionic species. As an additional level of complexity, different components influence one another through feedback loops. Complex systems such as this often exhibit emergent…

Computational Prediction of Drug-Induced Arrhythmias

Acknowledgments Dr. Sobie is supported by the National Institutes of Health (U54 HG008098 and U01 HL136297), the National Science Foundation (MCB 1615677), and the US Food and Drug Administration (75F40119C10021). Torsades de pointes (TdP) is a potentially lethal polymorphic ventricular tachycardia. Other chapters in this text discuss in greater detail the etiology and electrocardiographic characteristics of this arrhythmia. This chapter is primarily focused on TdP caused…

Cell Biology of the Specialized Cardiac Conduction System

Acknowledgments This work was supported by National Institutes of Health grants R01HL105983, R01HL142498, and R01HL146107 to G.I.F. and R01HL132073 to D.S.P. The cardiac conduction system (CCS) consists of the impulse generating but slowly conducting sinoatrial node (SAN) and atrioventricular node (AVN) and the rapidly conducting ventricular conduction system (VCS). The SAN is the dominant pacemaker and is located at the junction between the superior vena cava…

Mechanisms of Normal and Dysfunctional Sinoatrial Nodal Excitability and Propagation

Acknowledgments We sincerely thank Fedorov Lab members Drs. Benjamin Buck and Aleksei Mikhailov, Matthew Fazio, Shane Scott, Megan Subr, and Allison Wilson for valuable input during the preparation of this chapter. The sinoatrial node (SAN) is the primary pacemaker of the heart and is responsible for regular cardiac rhythm. Since its discovery by Keith and Flack over a century ago, many important advances have been made…

Cell-To-Cell Communication and Impulse Propagation

Cardiac Cell-To-Cell Communication By Gap Junctions The existence of low-resistance pathways between cardiac cells was postulated from experimental assessment of electronic interactions (cable analysis) between cardiac Purkinje fibers before the existence of gap junction channels was known. During the subsequent decades ion channels between cardiac cells were identified, formed by two connexon hemichannels, with each hemichannel composed of six connexin molecules. The main connexins (Cx) of…

Mapping of Cardiac Action Potentials in Zebrafish to Assess Genetic Variants

Introduction Sudden cardiac death (SCD) is a leading cause of death, with an annual mortality of approximately 1 in 1000. SCD in the young is predominantly caused by inherited cardiac disorders that predispose the patient to the development of life-threatening arrhythmias. Such disorders include conditions with structural cardiac abnormalities (cardiomyopathies) and primary electrical disorders (PED) with disturbances in the electric currents underlying the cardiac action potential…

Coupled Oscillators and Sinoatrial Pacemaker Activity

Acknowledgments This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. Introduction The heart’s pacemaker cells residing in the sinoatrial node (SAN) normally generate spontaneous rhythmic changes of their membrane potential, producing relatively periodic spontaneous action potentials (APs), that is, normal automaticity. The essence of cardiac pacemaker cell automaticity is diastolic depolarization (DD), that is, a slow…

Feedback Mechanisms for Cardiac-Specific microRNAs and cAMP Signaling in Electrical Remodeling

Overview Of Cardiac microRNAs Introduction Over the past 2 decades, advances in next-generation sequencing have demonstrated that even though most of the human genome is transcribed into RNAs, only 1% to 2% of the genome encodes for proteins. Therefore RNAs can be grouped into two major classes: (1) coding RNAs and (2) noncoding RNAs (ncRNAs), which account for the majority of RNAs in humans. Although ncRNAs…