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Monitoring risk for sudden cardiac death: is there a role for EKG patches?
Journal Pre-proof Monitoring Risk for Sudden Cardiac Death: Is there a Role for EKG Patches? In: Current Opinion in Biomedical Engineering Richard L. Verrier, Ph.D.F.A.C.C., F.H.R.S., Associate Professor of Medicine, Bruce D. Nearing, Ph.D., Trudy D. Pang, M.D., Steven C. Schachter, M.D. PII:
S2468-4511(19)30029-7
DOI:
https://doi.org/10.1016/j.cobme.2019.09.001
Reference:
COBME 162
To appear in:
Current Opinion in Biomedical Engineering
Received Date: 17 June 2019 Revised Date:
25 July 2019
Accepted Date: 8 September 2019
Please cite this article as: R.L. Verrier, B.D. Nearing, T.D. Pang, S.C. Schachter, Monitoring Risk for Sudden Cardiac Death: Is there a Role for EKG Patches? In: Current Opinion in Biomedical Engineering Current Opinion in Biomedical Engineering, https://doi.org/10.1016/j.cobme.2019.09.001. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.
Verrier, Nearing, Pang and Schachter, Invited review for COBME Monitoring Risk for Sudden Cardiac Death: Is there a Role for EKG Patches? In: Current Opinion in Biomedical Engineering
Short title: EKG patch-based monitoring
Richard L. Verrier, Ph.D.,a,b Bruce D. Nearing, Ph.D.,a,b Trudy D. Pang, M.D.,a,b Steven C. Schachter, M.D.a,b From: aBeth Israel Deaconess Medical Center, bHarvard Medical School, Boston MA
Length: 2464 words (not including references), 32 references, 4 figures
Corresponding author: Richard L. Verrier, Ph.D., F.A.C.C., F.H.R.S. Associate Professor of Medicine, Harvard Medical School Beth Israel Deaconess Medical Center, Division of Cardiovascular Medicine 99 Brookline Avenue, RN-301 Boston MA 02215-3908 Phone: 617-667-0733; FAX: 617-975-5270 Email address: [email protected]
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Verrier, Nearing, Pang and Schachter, Invited review for COBME ABSTRACT Improved electrocardiographic (EKG) markers and monitoring platforms for sudden cardiac death risk are urgently needed. Wearable wireless EKG patches offer a patient-friendly novel approach to longterm monitoring, in the range of two weeks, extending traditional Holter monitoring, which is typically limited to 24 to 48 hours. The capacity to transmit recordings via telemetry to healthcare providers offers a further benefit for real-time detection and analysis of cardiac events. Until recently, the primary application of EKG patches has been evaluation of syncope and atrial and ventricular rhythm abnormalities. Used in combination with highly accurate algorithms for monitoring QT intervals and T-wave alternans, a beat-to-beat fluctuation in ST-segment and T-wave morphology linked to sudden cardiac death risk, the applications of EKG monitoring can be significantly expanded.
KEYWORDS: ECG patch monitors, atrial fibrillation, sudden cardiac death, QT interval, Twave alternans
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Verrier, Nearing, Pang and Schachter, Invited review for COBME HIGHLIGHTS •
Sudden cardiac death (SCD) due to life-threatening ventricular arrhythmias is the leading cause of death among adults the industrialized world.
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SCD risk monitoring necessitates the development of new EKG markers.
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EKG patches are lightweight, wearable, disposable, wireless, patient-friendly devices for arrhythmia detection.
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Monitoring for ~2 weeks improves capture of syncope and paroxysmal atrial fibrillation.
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Telemetry permits cardiologists to view symptomatic events in real time.
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EKG patches may be suitable for monitoring QT intervals and T-wave alternans to detect risk for ventricular arrhythmia.
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True precordial multi-lead EKG patch monitoring will enhance screening for SCD risk and antiarrhythmic therapy effectiveness.
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Verrier, Nearing, Pang and Schachter, Invited review for COBME ABBREVIATIONS AECG = ambulatory electrocardiogram EKG = electrocardiogram HRV = heart rate variability IKr = rapid component of the delayed rectifier potassium current LQTS = long QT syndrome MMA = modified moving average TdP = Torsades de Pointes TWA = T-wave alternans
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Verrier, Nearing, Pang and Schachter, Invited review for COBME 1.0 INTRODUCTION Identification of individuals at risk for sudden cardiac death (SCD) persists as a major challenge in cardiology. SCD accounts for 1.5 million deaths annually worldwide, including 556,000 annually in the United States [1]. In 45%–50% of cases, SCD is the first indication of underlying heart disease [2, 3]. Epidemiological data suggest that coronary artery abnormalities are responsible for 80% of lethal arrhythmias [4]. Dilated and hypertrophic cardiomyopathies constitute the second largest group of SCDs from cardiac causes. Other disorders, including valvular or congenital heart diseases, acquired infiltrative disorders, primary electrophysiological disorders, and genetically determined ion channel abnormalities, are responsible for only a minor proportion of SCDs. Two main patterns associated with the occurrence of malignant arrhythmias have been identified in individuals with ischemic heart disease. These are ventricular tachyarrhythmia triggered by acute myocardial ischemia in individuals with or without old myocardial scar and ventricular tachyarrhythmia due to an anatomical substrate without active or clinically identifiable myocardial ischemia. Acute myocardial ischemia is generally considered to be the main factor causing fatal arrhythmias. A number of other conditions have been identified, specifically, systemic metabolic and hemodynamic alterations, neurochemical and neurophysiological triggers, and exogenous toxic or proarrhythmic drugs. These precipitating factors can interact with ischemia or cardiac structural abnormalities to culminate in sudden arrhythmic death (Figure 1 from Huikuri et al NEJM).[4]
While standard cardiovascular risk factors including smoking, hypertension, and hyperlipidemia correlate with cardiovascular disease, these conditions do not forewarn of SCD. The contemporary risk factor is depressed left ventricular ejection fraction (LVEF). Its use in
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Verrier, Nearing, Pang and Schachter, Invited review for COBME guiding use of implantable cardioverter-defibrillators (ICDs) is based on the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II randomized controlled trial, which established the fact that ICDs confer improved survival over conventional pharmacologic therapy in patients with LVEF ≤30% [5]. However, in the general population, LVEF has poor sensitivity and specificity,[6] as most individuals who succumb to SCD have relatively preserved LVEF, and only 1 of 8 individuals who receive ICDs according to MADIT II criteria experience appropriate discharge to terminate ventricular tachycardia/fibrillation (VT/VF) across the lifetime of the device. Data from the sizable Israeli National ICD Registry indicate that the numbers of patients needed to treat in a “real-world setting” may be even less favorable, specifically, 1 of 20.[7]
2.0 REVIEW OBJECTIVES The main goal of this brief review is to evaluate the potential roles of EKG patches as tools for monitoring risk for life-threatening ventricular arrhythmias and SCD. This review will provide a basic description of the underlying technology and intrinsic features that may make these devices suitable for detecting the influences of daily stresses and physical activity on vulnerability to ventricular arrhythmias.
3.0 BASIC FEATURES OF EKG PATCHES EKG patches are usually constructed with embedded electrodes that circumvent the need for cable wires, an important source of motion artifact, and typically can record 1- or 2-lead electrograms from pairs of closely spaced electrodes [8]. The patches are compact, lightweight, and water-resistant and do not disrupt patients’ daily routines including showering and exercise.
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Verrier, Nearing, Pang and Schachter, Invited review for COBME An event button permits patients to mark symptomatic episodes. Manufacturers offer different proprietary algorithms to diagnose abnormal rhythms. Two different types of EKG patch recorders are available [9]. The first type is referred to as “system-on-chip,” which are self-contained monitors including acquisition and storage circuitry and battery (Figure 2, upper panel). The EKG recordings are stored and at the end of the recording period, the EKG patch is mailed in a prepaid envelope to a central monitoring station, where the recordings are analyzed using a cloud-based computing platform. The EKGs processed by the automated algorithms are then read by certified cardiographic technicians to ensure accuracy, and the report is provided to the prescribing physician. The Zio Patch (iRhythm Technologies, San Francisco CA) employs this technology in conjunction with its central monitoring system, “Zio EKG Utilization Service” (ZEUS); DMS Service (Los Angeles CA) provides similar analyses for MyPatch recordings. The second type of EKG patch recorders incorporates the capacity for mobile cardiac telemetry. This system is somewhat more elaborate as it involves not only an EKG patch monitor but also a means for Bluetooth communication to a smartphone with proprietary software. The smartphone then communicates cardiac data to servers to be stored in a secure database. The healthcare provider can access patients’ EKG data over a secure internet connection (Figure 2, lower panel). The clinical database stores all of the medical information in a deidentified coded file. The cardiologist in charge can remotely access the server to view the clinical data and EKG tracings in real time. Preventice (Houston TX), BioTel Heart (Malvern PA), and ScottCare (Cleveland OH), as well as other manufacturers, offer this format.
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Verrier, Nearing, Pang and Schachter, Invited review for COBME It discusses the fundamentals of EKG patch monitoring technology and the relatively recent application of quantitative algorithms for assessment of risk for life-threatening ventricular arrhythmias based in EKG patch recordings.
4.0 EKG PATCH-BASED MONITORING OF QT INTERVAL One of the most widely employed markers of increased risk for arrhythmic events is prolongation of the QT interval. This arrhythmogenic condition may be the result of inherited cardiac disease, i.e., the long QT syndrome (LQTS) [10], or an adverse effect of a medication, referred to as drug-induced LQTS [11, 12]. Proarrhythmia represents a major problem associated with diverse medications ranging from the anti-histaminic drug terfenadine to antibiotics, anti-cancer therapy, and antiarrhythmic drugs. These agents have in common their capacity to block the rapid component of the delayed rectifier potassium (IKr) current. A critical challenge is to identify in advance the subjects who will be at risk for developing the lifethreatening drug-induced IKr-related Torsades de Pointes (TdP) ventricular tachyarrhythmias. Castelletti and coworkers [13] addressed for the first time the possibility that an EKG patch would be capable of providing accurate, automated assessment of QT interval duration. The basic design of the study involved assessment of QT-interval duration simultaneously from both the BodyGuardian EKG patch monitor (Preventice, Houston TX) and a high-resolution, 24hour, 12-lead Holter monitor (Mortara Instruments, Milwaukee WI). Expert manual reading of the Holter recordings was performed by cardiologists blinded to clinical status and to the automated output of the EKG patch monitor and analytical software. LQTS patients (N=20) and controls (N=16) were monitored across 24 h, and 351 separate QT-interval determinations were 8
Verrier, Nearing, Pang and Schachter, Invited review for COBME made. The demonstrated correspondence in measurements was remarkable, as in the total of 36 subjects, the QTc interval was 446±41 and 445±45 ms for manual assessment of the Holter record and EKG patch automated measurement, respectively. The overall conclusion was that this EKG patch monitor and software yielded highly accurate automated measurements of QTinterval duration whether obtained in normal subjects or in those with congenital LQTS. The authors drew the inference that it is likely that this technology would be suitable to track changes in QT intervals associated with adverse drug reactions.
5.0 T-WAVE ALTERNANS ASSESSMENT ON EKG PATCHES T-wave alternans (TWA) [14] is a beat-to-beat fluctuation in ST-segment or T-wave morphology. Experimental studies indicate that TWA reflects arrhythmogenic heterogeneity of repolarization and propensity to uni-directional block and reentry [15]. The capacity of TWA analysis to estimate risk for life-threatening arrhythmias has been confirmed by studies in >7000 patients with diverse clinical conditions including ischemic heart disease, heart failure, and the long QT syndrome [16, 17]. The phenomenon is sensitive to the effects of anti- and proarrhythmic agents [18, 19]. A ladder of risk for SCD has been developed to encompass the major conditions associated with sudden arrhythmic death (Figure 3) [20].
Two methods to measure microvolt levels of TWA are FDA cleared. These include the frequency-domain spectral method, which is no longer commercially available, and the timedomain modified moving average (MMA) technique (Figure 4), which employs the noiserejection principle of recursive averaging [14]. The maximum alternation in morphology of the T waves in an every other beat or ABAB pattern is measured to analyze the microvolt 9
Verrier, Nearing, Pang and Schachter, Invited review for COBME differences between successive T waves for cardiac risk determination. As the MMA method has proved to be suitable for ambulatory EKG monitoring, it is a logical utility for EKG patchbased evaluation. However, specific electronic characteristics must be present to assure accurate signal processing by both Holter recorders and EKG patches.
Studies with ambulatory EKG monitoring have reported the presence of high TWA levels among patients with chronic epilepsy (Figure 3), which is consistent with increased risk for cardiac arrhythmias in patients with this condition [21-24]. The first EKG patch-based study of TWA compared patients with newly diagnosed epilepsy to those with chronic epilepsy [25]. This cohort was selected on the grounds that patients with chronic epilepsy are at >3-fold greater risk for sudden cardiac death than is the general population [24]. Also, as patients with epilepsy undergo seizure activity, which is highly disruptive of EKG signals, this application represents an important opportunity to evaluate the inherent utility of wireless EKG patch monitoring to enhance signal stability in this at-risk population. This study by Pang et al [25] demonstrated a significant increase in TWA indicative of cardiac electrical instability in patients with chronic vs. newly diagnosed epilepsy.
6.0 CONCLUSIONS AND FUTURE DIRECTIONS Collectively, the available literature, although somewhat limited with respect to the specific use of EKG-patch based recorders in monitoring markers of sudden cardiac death risk, is nevertheless encouraging. The unique advantages include the patient-friendly nature of lowprofile EKG patches, which circumvent the use of signal-disrupting wires, provide high-quality signals, and extend the monitoring period without disrupting daily activities. These devices also
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Verrier, Nearing, Pang and Schachter, Invited review for COBME benefit from the application of algorithms for monitoring QT intervals and TWA, which have been shown in standard platforms such as traditional ambulatory EKG monitors and exercise treadmills to quantify risk for sudden cardiac death. Additionally, the EKG patches permit measurement of autonomic tone using HRV [26, 27] and autonomic reflexes using heart rate turbulence [28], which are important modulators of susceptibility to malignant ventricular arrhythmias in diverse clinical conditions [29].
In the future, it will be important to transition from the current approach of using single-channel Patch-based EKG recordings, which are suitable for rhythm analysis and detection of arrhythmias such as atrial fibrillation, to multilead recordings to improve assessment of ventricular electrical activity. It will be important to include true precordial recordings, especially V5, as this site has been shown to be optimum for sudden cardiac death risk assessment with TWA [30]. Also, the electronic recording characteristics should be improved in terms of sampling rate, bandwidth, and resolution to approximate standard Holter recordings for better detection of changes in ventricular repolarization waveforms [31]. With these developments, the “power of the patch” [32] can be fully realized, yielding valuable diagnostic utility and improved capacity to guide life-saving therapy.
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Verrier, Nearing, Pang and Schachter, Invited review for COBME FINANCIAL DISCLOSURE STATEMENT: Drs. Nearing and Verrier are co-inventors of the Modified Moving Average Method of T-wave alternans analysis, with patent assigned to Georgetown University and Beth Israel Deaconess Medical Center and licensed by GE Healthcare. Results of MMA-based TWA analysis were summarized in this chapter. They declare no additional competing interests relevant to the manuscript. Drs. Pang and Schachter declare no competing interests relevant to the manuscript.
FUNDING SOURCES: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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Verrier, Nearing, Pang and Schachter, Invited review for COBME LEGENDS: Figure 1: Pathophysiology and epidemiology of sudden death from cardiac causes. Reprinted from Huikuri et al [4] by permission of Massachusetts Medical Society.
Figure 2 (Top): Disposable, wireless ZIO EKG Patch assembly for ≤14-day EKG monitoring and Company-recommended placement on the body.
Figure 2 (Bottom): Illustration of the functioning of BodyGuardian Remote Monitoring System. Left: The EKG patch communicates with the smartphone using proprietary software. Middle: BodyGuardian Connect sends cardiac data to servers to be stored in a secure database. Right: Healthcare professionals access patient’s cardiac data over secure internet connection. Reprinted with permission from Castelletti et al [13].
Figure 3: TWA magnitude in ambulatory ECGs showing “ladder” of risk. Mean values of peak TWA are from patients with stable coronary artery disease (CAD), with cardiomyopathy, acute post-myocardial (MI) patients with and without sudden cardiac death (SCD), ST-elevation MI (STEMI) patients with and without ventricular tachycardia (VT), and patients with chronic epilepsy [22]. Modified from Verrier and Ikeda [20]. Figure 4: Modified moving average technique for detection of T-wave alternans (TWA). Alternate beats are dichotomized into bins of “A” beats (blue) and “B” beats (red) and the Twave morphologies in each bin are averaged. The averaged beats are then superimposed and the difference in the magnitude of the T waves of the A and B averaged beats is quantified in microvolts. This difference is the TWA level. Modified from Verrier and Ikeda [20]. 13
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S2468-4511(19)30029-7
DOI:
https://doi.org/10.1016/j.cobme.2019.09.001
Reference:
COBME 162
To appear in:
Current Opinion in Biomedical Engineering
Received Date: 17 June 2019 Revised Date:
25 July 2019
Accepted Date: 8 September 2019
Please cite this article as: R.L. Verrier, B.D. Nearing, T.D. Pang, S.C. Schachter, Monitoring Risk for Sudden Cardiac Death: Is there a Role for EKG Patches? In: Current Opinion in Biomedical Engineering Current Opinion in Biomedical Engineering, https://doi.org/10.1016/j.cobme.2019.09.001. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.
Verrier, Nearing, Pang and Schachter, Invited review for COBME Monitoring Risk for Sudden Cardiac Death: Is there a Role for EKG Patches? In: Current Opinion in Biomedical Engineering
Short title: EKG patch-based monitoring
Richard L. Verrier, Ph.D.,a,b Bruce D. Nearing, Ph.D.,a,b Trudy D. Pang, M.D.,a,b Steven C. Schachter, M.D.a,b From: aBeth Israel Deaconess Medical Center, bHarvard Medical School, Boston MA
Length: 2464 words (not including references), 32 references, 4 figures
Corresponding author: Richard L. Verrier, Ph.D., F.A.C.C., F.H.R.S. Associate Professor of Medicine, Harvard Medical School Beth Israel Deaconess Medical Center, Division of Cardiovascular Medicine 99 Brookline Avenue, RN-301 Boston MA 02215-3908 Phone: 617-667-0733; FAX: 617-975-5270 Email address: [email protected]
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Verrier, Nearing, Pang and Schachter, Invited review for COBME ABSTRACT Improved electrocardiographic (EKG) markers and monitoring platforms for sudden cardiac death risk are urgently needed. Wearable wireless EKG patches offer a patient-friendly novel approach to longterm monitoring, in the range of two weeks, extending traditional Holter monitoring, which is typically limited to 24 to 48 hours. The capacity to transmit recordings via telemetry to healthcare providers offers a further benefit for real-time detection and analysis of cardiac events. Until recently, the primary application of EKG patches has been evaluation of syncope and atrial and ventricular rhythm abnormalities. Used in combination with highly accurate algorithms for monitoring QT intervals and T-wave alternans, a beat-to-beat fluctuation in ST-segment and T-wave morphology linked to sudden cardiac death risk, the applications of EKG monitoring can be significantly expanded.
KEYWORDS: ECG patch monitors, atrial fibrillation, sudden cardiac death, QT interval, Twave alternans
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Verrier, Nearing, Pang and Schachter, Invited review for COBME HIGHLIGHTS •
Sudden cardiac death (SCD) due to life-threatening ventricular arrhythmias is the leading cause of death among adults the industrialized world.
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SCD risk monitoring necessitates the development of new EKG markers.
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EKG patches are lightweight, wearable, disposable, wireless, patient-friendly devices for arrhythmia detection.
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Monitoring for ~2 weeks improves capture of syncope and paroxysmal atrial fibrillation.
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Telemetry permits cardiologists to view symptomatic events in real time.
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EKG patches may be suitable for monitoring QT intervals and T-wave alternans to detect risk for ventricular arrhythmia.
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True precordial multi-lead EKG patch monitoring will enhance screening for SCD risk and antiarrhythmic therapy effectiveness.
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Verrier, Nearing, Pang and Schachter, Invited review for COBME ABBREVIATIONS AECG = ambulatory electrocardiogram EKG = electrocardiogram HRV = heart rate variability IKr = rapid component of the delayed rectifier potassium current LQTS = long QT syndrome MMA = modified moving average TdP = Torsades de Pointes TWA = T-wave alternans
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Verrier, Nearing, Pang and Schachter, Invited review for COBME 1.0 INTRODUCTION Identification of individuals at risk for sudden cardiac death (SCD) persists as a major challenge in cardiology. SCD accounts for 1.5 million deaths annually worldwide, including 556,000 annually in the United States [1]. In 45%–50% of cases, SCD is the first indication of underlying heart disease [2, 3]. Epidemiological data suggest that coronary artery abnormalities are responsible for 80% of lethal arrhythmias [4]. Dilated and hypertrophic cardiomyopathies constitute the second largest group of SCDs from cardiac causes. Other disorders, including valvular or congenital heart diseases, acquired infiltrative disorders, primary electrophysiological disorders, and genetically determined ion channel abnormalities, are responsible for only a minor proportion of SCDs. Two main patterns associated with the occurrence of malignant arrhythmias have been identified in individuals with ischemic heart disease. These are ventricular tachyarrhythmia triggered by acute myocardial ischemia in individuals with or without old myocardial scar and ventricular tachyarrhythmia due to an anatomical substrate without active or clinically identifiable myocardial ischemia. Acute myocardial ischemia is generally considered to be the main factor causing fatal arrhythmias. A number of other conditions have been identified, specifically, systemic metabolic and hemodynamic alterations, neurochemical and neurophysiological triggers, and exogenous toxic or proarrhythmic drugs. These precipitating factors can interact with ischemia or cardiac structural abnormalities to culminate in sudden arrhythmic death (Figure 1 from Huikuri et al NEJM).[4]
While standard cardiovascular risk factors including smoking, hypertension, and hyperlipidemia correlate with cardiovascular disease, these conditions do not forewarn of SCD. The contemporary risk factor is depressed left ventricular ejection fraction (LVEF). Its use in
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Verrier, Nearing, Pang and Schachter, Invited review for COBME guiding use of implantable cardioverter-defibrillators (ICDs) is based on the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II randomized controlled trial, which established the fact that ICDs confer improved survival over conventional pharmacologic therapy in patients with LVEF ≤30% [5]. However, in the general population, LVEF has poor sensitivity and specificity,[6] as most individuals who succumb to SCD have relatively preserved LVEF, and only 1 of 8 individuals who receive ICDs according to MADIT II criteria experience appropriate discharge to terminate ventricular tachycardia/fibrillation (VT/VF) across the lifetime of the device. Data from the sizable Israeli National ICD Registry indicate that the numbers of patients needed to treat in a “real-world setting” may be even less favorable, specifically, 1 of 20.[7]
2.0 REVIEW OBJECTIVES The main goal of this brief review is to evaluate the potential roles of EKG patches as tools for monitoring risk for life-threatening ventricular arrhythmias and SCD. This review will provide a basic description of the underlying technology and intrinsic features that may make these devices suitable for detecting the influences of daily stresses and physical activity on vulnerability to ventricular arrhythmias.
3.0 BASIC FEATURES OF EKG PATCHES EKG patches are usually constructed with embedded electrodes that circumvent the need for cable wires, an important source of motion artifact, and typically can record 1- or 2-lead electrograms from pairs of closely spaced electrodes [8]. The patches are compact, lightweight, and water-resistant and do not disrupt patients’ daily routines including showering and exercise.
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Verrier, Nearing, Pang and Schachter, Invited review for COBME An event button permits patients to mark symptomatic episodes. Manufacturers offer different proprietary algorithms to diagnose abnormal rhythms. Two different types of EKG patch recorders are available [9]. The first type is referred to as “system-on-chip,” which are self-contained monitors including acquisition and storage circuitry and battery (Figure 2, upper panel). The EKG recordings are stored and at the end of the recording period, the EKG patch is mailed in a prepaid envelope to a central monitoring station, where the recordings are analyzed using a cloud-based computing platform. The EKGs processed by the automated algorithms are then read by certified cardiographic technicians to ensure accuracy, and the report is provided to the prescribing physician. The Zio Patch (iRhythm Technologies, San Francisco CA) employs this technology in conjunction with its central monitoring system, “Zio EKG Utilization Service” (ZEUS); DMS Service (Los Angeles CA) provides similar analyses for MyPatch recordings. The second type of EKG patch recorders incorporates the capacity for mobile cardiac telemetry. This system is somewhat more elaborate as it involves not only an EKG patch monitor but also a means for Bluetooth communication to a smartphone with proprietary software. The smartphone then communicates cardiac data to servers to be stored in a secure database. The healthcare provider can access patients’ EKG data over a secure internet connection (Figure 2, lower panel). The clinical database stores all of the medical information in a deidentified coded file. The cardiologist in charge can remotely access the server to view the clinical data and EKG tracings in real time. Preventice (Houston TX), BioTel Heart (Malvern PA), and ScottCare (Cleveland OH), as well as other manufacturers, offer this format.
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Verrier, Nearing, Pang and Schachter, Invited review for COBME It discusses the fundamentals of EKG patch monitoring technology and the relatively recent application of quantitative algorithms for assessment of risk for life-threatening ventricular arrhythmias based in EKG patch recordings.
4.0 EKG PATCH-BASED MONITORING OF QT INTERVAL One of the most widely employed markers of increased risk for arrhythmic events is prolongation of the QT interval. This arrhythmogenic condition may be the result of inherited cardiac disease, i.e., the long QT syndrome (LQTS) [10], or an adverse effect of a medication, referred to as drug-induced LQTS [11, 12]. Proarrhythmia represents a major problem associated with diverse medications ranging from the anti-histaminic drug terfenadine to antibiotics, anti-cancer therapy, and antiarrhythmic drugs. These agents have in common their capacity to block the rapid component of the delayed rectifier potassium (IKr) current. A critical challenge is to identify in advance the subjects who will be at risk for developing the lifethreatening drug-induced IKr-related Torsades de Pointes (TdP) ventricular tachyarrhythmias. Castelletti and coworkers [13] addressed for the first time the possibility that an EKG patch would be capable of providing accurate, automated assessment of QT interval duration. The basic design of the study involved assessment of QT-interval duration simultaneously from both the BodyGuardian EKG patch monitor (Preventice, Houston TX) and a high-resolution, 24hour, 12-lead Holter monitor (Mortara Instruments, Milwaukee WI). Expert manual reading of the Holter recordings was performed by cardiologists blinded to clinical status and to the automated output of the EKG patch monitor and analytical software. LQTS patients (N=20) and controls (N=16) were monitored across 24 h, and 351 separate QT-interval determinations were 8
Verrier, Nearing, Pang and Schachter, Invited review for COBME made. The demonstrated correspondence in measurements was remarkable, as in the total of 36 subjects, the QTc interval was 446±41 and 445±45 ms for manual assessment of the Holter record and EKG patch automated measurement, respectively. The overall conclusion was that this EKG patch monitor and software yielded highly accurate automated measurements of QTinterval duration whether obtained in normal subjects or in those with congenital LQTS. The authors drew the inference that it is likely that this technology would be suitable to track changes in QT intervals associated with adverse drug reactions.
5.0 T-WAVE ALTERNANS ASSESSMENT ON EKG PATCHES T-wave alternans (TWA) [14] is a beat-to-beat fluctuation in ST-segment or T-wave morphology. Experimental studies indicate that TWA reflects arrhythmogenic heterogeneity of repolarization and propensity to uni-directional block and reentry [15]. The capacity of TWA analysis to estimate risk for life-threatening arrhythmias has been confirmed by studies in >7000 patients with diverse clinical conditions including ischemic heart disease, heart failure, and the long QT syndrome [16, 17]. The phenomenon is sensitive to the effects of anti- and proarrhythmic agents [18, 19]. A ladder of risk for SCD has been developed to encompass the major conditions associated with sudden arrhythmic death (Figure 3) [20].
Two methods to measure microvolt levels of TWA are FDA cleared. These include the frequency-domain spectral method, which is no longer commercially available, and the timedomain modified moving average (MMA) technique (Figure 4), which employs the noiserejection principle of recursive averaging [14]. The maximum alternation in morphology of the T waves in an every other beat or ABAB pattern is measured to analyze the microvolt 9
Verrier, Nearing, Pang and Schachter, Invited review for COBME differences between successive T waves for cardiac risk determination. As the MMA method has proved to be suitable for ambulatory EKG monitoring, it is a logical utility for EKG patchbased evaluation. However, specific electronic characteristics must be present to assure accurate signal processing by both Holter recorders and EKG patches.
Studies with ambulatory EKG monitoring have reported the presence of high TWA levels among patients with chronic epilepsy (Figure 3), which is consistent with increased risk for cardiac arrhythmias in patients with this condition [21-24]. The first EKG patch-based study of TWA compared patients with newly diagnosed epilepsy to those with chronic epilepsy [25]. This cohort was selected on the grounds that patients with chronic epilepsy are at >3-fold greater risk for sudden cardiac death than is the general population [24]. Also, as patients with epilepsy undergo seizure activity, which is highly disruptive of EKG signals, this application represents an important opportunity to evaluate the inherent utility of wireless EKG patch monitoring to enhance signal stability in this at-risk population. This study by Pang et al [25] demonstrated a significant increase in TWA indicative of cardiac electrical instability in patients with chronic vs. newly diagnosed epilepsy.
6.0 CONCLUSIONS AND FUTURE DIRECTIONS Collectively, the available literature, although somewhat limited with respect to the specific use of EKG-patch based recorders in monitoring markers of sudden cardiac death risk, is nevertheless encouraging. The unique advantages include the patient-friendly nature of lowprofile EKG patches, which circumvent the use of signal-disrupting wires, provide high-quality signals, and extend the monitoring period without disrupting daily activities. These devices also
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Verrier, Nearing, Pang and Schachter, Invited review for COBME benefit from the application of algorithms for monitoring QT intervals and TWA, which have been shown in standard platforms such as traditional ambulatory EKG monitors and exercise treadmills to quantify risk for sudden cardiac death. Additionally, the EKG patches permit measurement of autonomic tone using HRV [26, 27] and autonomic reflexes using heart rate turbulence [28], which are important modulators of susceptibility to malignant ventricular arrhythmias in diverse clinical conditions [29].
In the future, it will be important to transition from the current approach of using single-channel Patch-based EKG recordings, which are suitable for rhythm analysis and detection of arrhythmias such as atrial fibrillation, to multilead recordings to improve assessment of ventricular electrical activity. It will be important to include true precordial recordings, especially V5, as this site has been shown to be optimum for sudden cardiac death risk assessment with TWA [30]. Also, the electronic recording characteristics should be improved in terms of sampling rate, bandwidth, and resolution to approximate standard Holter recordings for better detection of changes in ventricular repolarization waveforms [31]. With these developments, the “power of the patch” [32] can be fully realized, yielding valuable diagnostic utility and improved capacity to guide life-saving therapy.
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Verrier, Nearing, Pang and Schachter, Invited review for COBME FINANCIAL DISCLOSURE STATEMENT: Drs. Nearing and Verrier are co-inventors of the Modified Moving Average Method of T-wave alternans analysis, with patent assigned to Georgetown University and Beth Israel Deaconess Medical Center and licensed by GE Healthcare. Results of MMA-based TWA analysis were summarized in this chapter. They declare no additional competing interests relevant to the manuscript. Drs. Pang and Schachter declare no competing interests relevant to the manuscript.
FUNDING SOURCES: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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Verrier, Nearing, Pang and Schachter, Invited review for COBME LEGENDS: Figure 1: Pathophysiology and epidemiology of sudden death from cardiac causes. Reprinted from Huikuri et al [4] by permission of Massachusetts Medical Society.
Figure 2 (Top): Disposable, wireless ZIO EKG Patch assembly for ≤14-day EKG monitoring and Company-recommended placement on the body.
Figure 2 (Bottom): Illustration of the functioning of BodyGuardian Remote Monitoring System. Left: The EKG patch communicates with the smartphone using proprietary software. Middle: BodyGuardian Connect sends cardiac data to servers to be stored in a secure database. Right: Healthcare professionals access patient’s cardiac data over secure internet connection. Reprinted with permission from Castelletti et al [13].
Figure 3: TWA magnitude in ambulatory ECGs showing “ladder” of risk. Mean values of peak TWA are from patients with stable coronary artery disease (CAD), with cardiomyopathy, acute post-myocardial (MI) patients with and without sudden cardiac death (SCD), ST-elevation MI (STEMI) patients with and without ventricular tachycardia (VT), and patients with chronic epilepsy [22]. Modified from Verrier and Ikeda [20]. Figure 4: Modified moving average technique for detection of T-wave alternans (TWA). Alternate beats are dichotomized into bins of “A” beats (blue) and “B” beats (red) and the Twave morphologies in each bin are averaged. The averaged beats are then superimposed and the difference in the magnitude of the T waves of the A and B averaged beats is quantified in microvolts. This difference is the TWA level. Modified from Verrier and Ikeda [20]. 13
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