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Personal Cardiac Monitoring

Introduction Over the past 30 years, globalization of the Internet and establishment of the smartphone as the dominant computing platform of our time have created enormous cultural shifts. The ability of an individual to instantly access personalized information and services has revolutionized nearly every sector of society including finance, transportation, media, entertainment, travel, and education ( Fig. 63.1 ). U.S. technology companies, now among the leading…

Electrocardiographic Monitoring: Short- and Long-Term Recording

Introduction Ambulatory cardiac monitoring to detect arrhythmias became practical with the development of Holter monitoring and its subsequent derivatives. The clinician is currently armed with an array of tools to provide progressively longer durations of electrocardiogram (ECG) monitoring to obtain a rhythm profile and to establish a symptom rhythm correlation in patients with infrequent symptoms ( Fig. 62.1 ). Clinical trials using traditional skin electrodes, patches,…

Differential Diagnosis of Narrow and Wide Complex Tachycardias

Introduction The differential diagnosis of tachycardias using the electrocardiogram (ECG) remains among the most difficult problems faced by cardiologists in daily practice. Distinguishing supraventricular tachycardias (SVTs) from ventricular tachycardias (VTs) has obvious importance because treatments are very different. This chapter explores the tools available to address the diagnosis; after this has been obtained, further evaluation and treatment strategies generally flow naturally. An important distinguishing feature for…

Assessment of the Patient With a Cardiac Arrhythmia

Introduction Evaluation of the patient suspected to have a cardiac arrhythmia is a frequent reason for referral to a cardiologist. In patients presenting with an acute, ongoing arrhythmia, the role of the cardiologist is to quickly gather and synthesize the necessary data to arrive at a diagnosis and form both a short-term and long-term treatment plan. More commonly, in the otherwise stable patient, sinus rhythm is…

Challenges of Human iPSC-CM Technology: Increasingly Complex Approaches Improve Cell Maturation and Relevance to Modeling Human Cardiac Disease

Acknowledgments We thank Álvaro Macías Martínez, Francisco Miguel Cruz Uréndez, Ana Isabel Moreno Manuel, Lilian Karina Gutiérrez Espinosa de los Monteros, and Isabel Martínez Carrascoso for their helpful discussions and critical review of the manuscript. J.J. has received funding from “la Caixa” Banking Foundation under the project code HR18-00304. Support also came from a Severo Ochoa CNIC Intramural Project (Expediente 12-2016 IGP) to J.J. The CNIC…

Functional Cardiac Fibroblasts Derived From Human Pluripotent Stem Cells via Second Heart Field Progenitors

Introduction The mesenchymal cell populations present in the myocardium are often referred to as cardiac fibroblasts (CFs) and are distinct from fibroblasts present in other organs. CFs play many essential roles in the developing and adult heart by contributing to homeostasis of the organ. In developing hearts, CFs provide key signals to promote the proliferation of cardiomyocytes (CMs) and contribute to endocardial cushion formation and genesis…

High-Throughput Optical Mapping of Two-Dimensional hiPSC-CM Platforms for Drug Discovery and Cardiotoxicity Testing

Current Guidelines for Cardiotoxicity and Proarrhythmia Screening Cardiotoxicity is a major reason for drug attrition and is thus a core subject in preclinical and clinical safety testing of new drugs. Cardiac safety testing of new chemical entities that become lead drug candidates is a critical aspect of the drug discovery and development pipeline. A large number of cardiac side effects of cardiac and noncardiac drugs are…

Cardiac Remodeling and Regeneration

Cardiovascular disease continues to be the global leader when it comes to cause of death, despite a steadily declining mortality rate. In 2016, the global age-adjusted death rate had decreased by 14.5% compared with 2006. Cardiovascular disease often results in irreversible damage to the myocardium that contributes to cardiomyopathies and ultimately results in heart failure (HF). HF is the leading cause of death in the United…

Gene Therapy for Atrial Fibrillation

Introduction Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a frequent cause of stroke. , Despite its clinical importance, AF is a difficult condition to treat, with limited efficacy of current therapeutic strategies including antiarrhythmic drugs and catheter ablation. A major reason for the low efficacy of the current therapies is that they do not target the molecular mechanisms underlying AF. Antiarrhythmic drugs,…

Deep Phenotyping: Adding New Tools to Understand Disease

DefiNing Phenotype The terms genotype and phenotype were introduced by the Danish plant physiologist and geneticist Wilhelm Johannsen in 1909. The genotype refers to parts or all of the genetic material, whereas the phenotype may be made up of any observable characteristic or trait resulting from the genotype in the context of environmental and stochastic variation. Any molecular (including epigenetic marks), biochemical, physiologic, or morphologic property…

Pharmacogenomics of Cardiac Arrhythmias

Introduction Individuals vary widely in their responses to therapy with most drugs. Indeed, response to cardiovascular drug therapy, and antiarrhythmics in particular, is so highly variable that studying the underlying mechanisms has elucidated important lessons for understanding variable responses to drug therapy in general. By disrupting gene product function, single nucleotide changes can produce dramatic changes in physiology; the long QT syndromes and inherited errors of…

Dominant Frequency as a Tool for Personalized Monitoring of Atrial Fibrillation Progression and Upstream Therapy

Acknowledgments I thank Omer Berenfeld, David Filgueiras-Rama, Raphael Martins, Yoshio Takemoto, Rafael Ramirez, Jiang Jiang, and all other members of the Center for Arrhythmia Research of the University of Michigan who participated in the studies that are the focus of this chapter. The successful accomplishment of all the studies would have been impossible without their commitment to the projects on AF progression in the sheep model…

Inheritable Phenotypes Associated With Altered Intracellular Calcium Regulation

Physiologist Sidney Ringer realized in the 19th century that calcium (Ca 2+) is essential for cardiac contraction. Working with isolated frog hearts, he noticed that removal of Ca 2+ from the perfusion buffer stopped contraction, whereas its re-addition restored and maintained contractility. , Ca 2+ is now regarded as the most ubiquitous and versatile intracellular messenger, participating in a variety of processes ranging from heart contraction…

Inheritable Potassium Channel Diseases

Introduction KVLQT1 (now referred to as KCNQ1 ) and human ether-a-go-go related gene ( hERG; now referred to as KCNH2 ), each encoding a major cardiac K + channel, were among the first genes that were linked to an inheritable arrhythmic phenotype (i.e., the long QT syndrome [LQTS]). These discoveries stimulated geneticists around the world to search for mutations in families or single affected subjects with…

Genetic, Ionic, and Cellular Mechanisms Underlying the J Wave Syndromes

Acknowledgment We gratefully acknowledge support from NHLBI (HL47678 and HL138103), the W.W. Smith Chartibale Trust, and the Martha and Wistar Morris Fund. Introduction The J wave syndromes, consisting of Brugada syndrome (BrS) and early repolarization syndromes (ERS), have intrigued the cardiology community since the initial delineation of BrS as a clinical entity in 1992. The clinical impact of ERS was not fully realized until 2008, when…

Mechanisms in Genetic Sodium Channel Diseases

The discovery of the first mutation in the SCN5A gene encoding the human cardiac voltage-gated sodium channel more than 2 decades ago launched a new era in our understanding of the molecular and genetic basis of arrhythmias. Subsequent work has revealed an unexpectedly large number of clinically and pathophysiologically diverse conditions ( Box 48.1 ) associated with an ever-increasing number of mutations in this gene and…

Genetics of Atrial Fibrillation

The pathophysiology of atrial fibrillation (AF) remains incompletely characterized; however, epidemiologic studies demonstrate a heritable basis for the arrhythmia. In recent years, the appreciation of AF heritability has stimulated the search for the genetic underpinnings of the disease. Genetic mapping studies have identified rare mutations and common variants associated with AF. In addition to validating suspected electrophysiologic mechanisms underlying AF, recent genetic discoveries have identified previously…

Mechanisms of Human Ventricular Tachycardia and Human Ventricular Fibrillation

Introduction Ventricular tachycardia (VT) and ventricular fibrillation (VF) represent the most common rhythms documented in patients with sudden cardiac arrest. , Even in specific population subsets, such as patients with preexisting intraventricular conduction disease, ventricular tachyarrhythmias are the most common rhythm at the time of cardiac arrest. In patients with implantable cardioverter defibrillators (ICDs), sustained and nonsustained monomorphic VT episodes are substantially more common than VF…

Mechanistic Approaches for Persistent Atrial Fibrillation Ablation

Introduction Atrial fibrillation (AF) is the most common sustained arrhythmia seen in clinical practice, and its prevalence is progressively increasing in developed countries. The highly successful catheter-based procedure, pioneered by Haissaguerre and colleagues, of ablating ectopic triggers that arise from the pulmonary veins in paroxysmal AF has evolved and progressively been extended to a much more heterogeneous population, in which unfortunately the success rate is significantly…

Noninvasive Frequency-Phase Mapping of Atrial Fibrillation

Acknowledgments This work is supported in part by the Instituto de Salud Carlos III FEDER (Fondo Europeo de Desarrollo Regional; DTS16/00160; PI14/00857, PI16/01123; PI17/01059; PI17/01106); the Agencia Estatal de Investigación RYC2018-024346-I, Generalitat Valenciana grants (APOSTD/2017 and APOSTD/2018) and projects (GVA/2018/267); EITHealth 19600 AFFINE; and CIBERCV, Centro de Investigacion Biomedica en Red de Enfermedades Cardiovasculares. Introduction Translation of knowledge derived from animal experiments using high-resolution optical mapping…