Sleep-related breathing disorders are highly prevalent in patients with established cardiovascular disease. Obstructive sleep apnea (OSA) affects an estimated 15 million adult Americans and is present in a large proportion of patients with hypertension and in those with other cardiovascular disorders, including coronary artery disease, stroke, and atrial fibrillation.1–14 In contrast, central sleep apnea (CSA) occurs mainly in patients with heart failure.15–19 The purpose of this Scientific Statement is to describe the types and prevalence of sleep apnea and its relevance to individuals who either are at risk for or already have established cardiovascular disease. Special emphasis is given to recognizing the patient with cardiovascular disease who has coexisting sleep apnea, to understanding the mechanisms by which sleep apnea may contribute to the progression of the cardiovascular condition, and to identifying strategies for treatment. This document is not intended as a systematic review but rather seeks to highlight concepts and evidence important to understanding the interactions between sleep apnea and cardiovascular disease, with particular attention to more recent advances in patient-oriented research. Implicit in this first American Heart Association/American College of Cardiology Scientific Statement on Sleep Apnea and Cardiovascular Disease is the recognition that, although holding great promise, this general area is in need of a substantially expanded knowledge base. Specific questions include whether sleep apnea is important in initiating the development of cardiac and vascular disease, whether sleep apnea in patients with established cardiovascular disease accelerates disease progression, and whether treatment of sleep apnea results in clinical improvement, fewer cardiovascular events, and reduced mortality.

Experimental approaches directed at addressing these issues are limited by several considerations. First, the close association between obesity and OSA often obscures differentiation between the effects of obesity, the effects of OSA, and the effects of synergies between these conditions. Second, multiple comorbidities, …

Sleep Apnea and Cardiovascular Disease An American Heart Association/American College of Cardiology Foundation Scientific Statement From the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council on Cardiovascular Nursing In Collaboration With the National Heart, Lung, and Blood Institute National Center on Sleep Disorders Research (National Institutes of Health)

The experimental and clinical possibilities for studying cardiac arrhythmias in human ventricular myocardium are very limited. Therefore, the use of alternative methods such as computer simulations is of great importance. In this article we introduce a mathematical model of the action potential of human ventricular cells that, while including a high level of electrophysiological detail, is computationally cost-effective enough to be applied in large-scale spatial simulations for the study of reentrant arrhythmias. The model is based on recent experimental data on most of the major ionic currents: the fast sodium, L-type calcium, transient outward, rapid and slow delayed rectifier, and inward rectifier currents. The model includes a basic calcium dynamics, allowing for the realistic modeling of calcium transients, calcium current inactivation, and the contraction staircase. We are able to reproduce human epicardial, endocardial, and M cell action potentials and show that differences can be explained by differences in the transient outward and slow delayed rectifier currents. Our model reproduces the experimentally observed data on action potential duration restitution, which is an important characteristic for reentrant arrhythmias. The conduction velocity restitution of our model is broader than in other models and agrees better with available data. Finally, we model the dynamics of spiral wave rotation in a two-dimensional sheet of human ventricular tissue and show that the spiral wave follows a complex meandering pattern and has a period of 265 ms. We conclude that the proposed model reproduces a variety of electrophysiological behaviors and provides a basis for studies of reentrant arrhythmias in human ventricular tissue.

/pdf/a-model-for-human-ventricular-tissue-3iwzhwqfm7.pdf

A model for human ventricular tissue

Propagation of excitation in the heart involves action potential (AP) generation by cardiac cells and its propagation in the multicellular tissue. AP conduction is the outcome of complex interactions between cellular electrical activity, electrical cell-to-cell communication, and the cardiac tissue structure. As shown in this review, strong interactions occur among these determinants of electrical impulse propagation. A special form of conduction that underlies many cardiac arrhythmias involves circulating excitation. In this situation, the curvature of the propagating excitation wavefront and the interaction of the wavefront with the repolarization tail of the preceding wave are additional important determinants of impulse propagation. This review attempts to synthesize results from computer simulations and experimental preparations to define mechanisms and biophysical principles that govern normal and abnormal conduction in the heart.

Basic Mechanisms of Cardiac Impulse Propagation and Associated Arrhythmias

Background—This study probes the cellular basis for the T wave under baseline and long-QT (LQT) conditions using an arterially perfused canine left ventricular (LV) wedge preparation, which permits direct temporal correlation of cellular transmembrane and ECG events. Methods and Results—Floating microelectrodes were used to record transmembrane action potentials (APs) simultaneously from epicardial, M-region, and endocardial sites or subendocardial Purkinje fibers. A transmural ECG was recorded concurrently. Under baseline and LQT conditions, repolarization of the epicardial action potential, the earliest to repolarize, coincided with the peak of the T wave; repolarization of the M cells, the last to repolarize, coincided with the end of the T wave. Thus, the action potential duration (APD) of the longest M cells determine the QT interval and the Tpeak–Tend interval serves as an index of transmural dispersion of repolarization. Repolarization of Purkinje fibers outlasted that of the M cell but failed to r...

Cellular Basis for the Normal T Wave and the Electrocardiographic Manifestations of the Long-QT Syndrome

Background—Although T-wave alternans has been closely associated with vulnerability to ventricular arrhythmias, the cellular processes underlying T-wave alternans and their role, if any, in the mechanism of reentry remain unclear. Methods and Results—T-wave alternans on the surface ECG was elicited in 8 Langendorff-perfused guinea pig hearts during fixed-rate pacing while action potentials were recorded simultaneously from 128 epicardial sites with voltage-sensitive dyes. Alternans of the repolarization phase of the action potential was observed above a critical threshold heart rate (HR) (209±46 bpm) that was significantly lower (by 57±36 bpm) than the HR threshold for alternation of action potential depolarization. The magnitude (range, 2.7 to 47.0 mV) and HR threshold (range, 171 to 272 bpm) of repolarization alternans varied substantially between cells across the epicardial surface. T-wave alternans on the surface ECG was explained primarily by beat-to-beat alternation in the time course of cellular re...

Mechanism linking T-wave alternans to the genesis of cardiac fibrillation

This document describes, among other things, systems, devices, and methods for predicting how the status of the patient's congestive heart failure (CHF) condition will progress in the future. In one example, a therapy is provided or adjusted at least in part in response to the prediction.

Cardiac rhythm management systems and methods predicting congestive heart failure status

Unique Properties of Optical Action Potentials. Introduction: Optical mapping with voltage-sensitive dyes has made it possible to record cardiac action potentials with high spatial resolution that is unattainable by conventional techniques. Optically recorded signals possess distinct properties that differ importantly from electrograms recorded with extracellular electrodes or action potentials recorded with microelectrode techniques. Despite the growing application of optical mapping to cardiac electrophysiology, relatively little quantitative information is available regarding the characteristics of optical action potentials recorded from cardiac tissue.



Methods and Results: A high-resolution optical mapping system and microelectrode techniques were used to determine the characteristics of guinea pig ventricular action potentials recorded with the voltage-sensitive dye di-4-ANEPPS. The effects of optical magnification, tissue-light interaction, sampling rate, voltage resolution, spatial resolution, and cardiac motion on action potential signal characteristics were determined. The optical action potential signal represents the relative change in transmembrance potential arising from a volume of cells, where the area of a recording site is determined by optical magnification and detector area, and the depth of recording is determined by system optics and the visible light transmission characteristics of cardiac muscle. Using photographic lenses, the depth of tissue contributing to the signal is < 250 μm. The action potential plateau and final repolarization can be accurately reconstructed from data digitized at modest sampling rates (450 to 750 Hz), since the frequency content of optical action potentials is band-limited to approximately 150 Hz. However, faster sampling rates are needed to depict the subtle details of the action potential upstroke. In addition to temporal resolution, it is essential to achieve sufficient dynamic range and voltage resolution to accurately represent the time course of membrane potential change. Voltage resolution is inversely related to the square of spatial resolution, hence, there exists an inherent trade-off between increased spatial resolution and diminished voltage resolution. Cardiac motion, which can otherwise limit spatial resolution as well as signal fidelity, can be effectively reduced using mechanical stabilization of the heart without distorting action potential characteristics.



Conclusions: Optical mapping with voltage-sensitive dyes provides high-fidelity multisite action potential recording with flexible spatial resolution. When recording cardiac action potentials with voltage-sensitive dyes, the Interdependence of temporal, spatial, and voltage resolutions must be carefully considered.

Unique properties of cardiac action potentials recorded with voltage-sensitive dyes.

Recent evidence suggests that ion channels governing the response of action potential duration (APD) to a premature stimulus (ie, APD restitution) are heterogeneously dispersed throughout the heart. However, because of limitations of conventional electrophysiological recording techniques, the effects of restitution in single cells on ventricular repolarization at the level of the intact heart are poorly understood. Using high-resolution optical mapping with voltage-sensitive dyes, we measured APD restitution kinetics at 128 simultaneous sites on the epicardial surface (1 cm2) of intact guinea pig hearts (n = 15). During steady state baseline pacing, APD gradients that produced a spatial dispersion of repolarization were observed. Mean APD was shortened monotonically from 186 +/- 19 ms during baseline pacing (S1-S1 cycle length, 393 +/- 19 ms) to 120 +/- 4 ms as single premature stimuli were introduced at progressively shorter coupling intervals (shortest S1-S2, 190 +/- 15 ms). In contrast, premature stimuli caused biphasic modulation of APD dispersion (defined as the variance of APD measured throughout the mapping field). Over a broad range of increasingly premature coupling intervals, APD dispersion decreased from 70 +/- 29 ms2 to a minimum of 10 +/- 7 ms2 at a critical S1-S2 interval (216 +/- 18 ms), and then, at shorter premature coupling intervals, APD dispersion increased sharply to 66 +/- 25 ms2. Modulation of APD dispersion by premature stimuli was attributed to coupling interval-dependent changes in the magnitude and direction of ventricular APD gradients, which, in turn, were explained by systematic heterogeneities of APD restitution across the epicardial surface. There was a characteristic pattern in the spatial distribution of cellular restitution such that faster restitution kinetics were closely associated with longer baseline APD. This relationship explained the reversal of APD between single cells, inversion of APD gradients across the heart, and ECG T-wave inversion during closely coupled premature stimulation. Therefore, because of the heterogeneous distribution of cellular restitution kinetics across the epicardial surface, a single premature stimulus profoundly altered the pattern and synchronization of ventricular repolarization in the intact ventricle. This response has important mechanistic implications in the initiation of arrhythmias that are dependent on dispersion of repolarization.

Modulation of Ventricular Repolarization by a Premature Stimulus: Role of Epicardial Dispersion of Repolarization Kinetics Demonstrated by Optical Mapping of the Intact Guinea Pig Heart

Background Although the relationship between cardiac wavelength (λ) and path length importantly determines the stability of reentrant arrhythmias, the physiological determinants of λ are poorly understood. To investigate the cellular mechanisms that control λ during reentry, we developed an experimental system for continuously monitoring λ within a reentrant circuit with the use of voltage-sensitive dyes and a new guinea pig model of ventricular tachycardia (VT). Methods and Results Action potentials were recorded simultaneously from 128 ventricular sites in Langendorff-perfused hearts (n=15) in which propagation was confined to a two-dimensional rim of epicardium by an endocardial cryoablating procedure. The reentrant path was precisely controlled by creating an epicardial obstacle (2×10 mm) with an argon laser. To control for fiber orientation and rate-dependent membrane properties, λ during reentry was compared with λ during plane wave propagation transverse and longitudinal to cardiac fibers at a stim...

Steven D. Girouard

Papers

Mechanism linking T-wave alternans to the genesis of cardiac fibrillation

Cardiac rhythm management systems and methods predicting congestive heart failure status

Unique properties of cardiac action potentials recorded with voltage-sensitive dyes.

Modulation of Ventricular Repolarization by a Premature Stimulus: Role of Epicardial Dispersion of Repolarization Kinetics Demonstrated by Optical Mapping of the Intact Guinea Pig Heart

Optical Mapping in a New Guinea Pig Model of Ventricular Tachycardia Reveals Mechanisms for Multiple Wavelengths in a Single Reentrant Circuit