Arnold H. Seto, MD, MPA

A mbulatory electrocardiography (ECG) began in 1949 when Norman “Jeff” Holter developed a monitor that could wirelessly transmit electrophysiologic data.¹ His original device used vacuum tubes, weighed 85 pounds, and had to be carried in a backpack. Furthermore, it could send a signal a distance of only 1 block.²

At the time, it was uncertain if this technology would have any clinical utility. However, in 1952, Holter published the first tracing of abnormal cardiac electrical activity in a patient who had suffered a posterior myocardial infarction.³ By the 1960s, Holter monitoring systems were in full production and use.⁴

Since then, advances in technology have led to small, lightweight devices that enable clinicians to evaluate patients for arrhythmias in a real-world context for extended times, often with the ability to respond in real time.

Many ambulatory devices are available, and choosing the optimal one requires an understanding of which features they have and which are the most appropriate for the specific clinical context. This article reviews the features, indications, advantages, and disadvantages of current devices, and their best use in clinical practice.

INDICATIONS FOR AMBULATORY ECG MONITORING

Diagnosis

The most common diagnostic role of monitoring is to correlate unexplained symptoms, including palpitations, presyncope, and syncope, with a transient cardiac arrhythmia. Monitoring can be considered successful if findings on ECG identify risks for serious arrhythmia and either correlate symptoms with those findings or demonstrate no arrhythmia when symptoms occur.

A range of arrhythmias can cause symptoms. Some, such as premature atrial contractions and premature ventricular contractions, may be benign in many clinical contexts. Others, such as atrial fibrillation, are more serious, and some, such as third-degree heart block and ventricular tachycardia, can be lethal.

Arrhythmia symptoms can vary in frequency and cause differing degrees of debility. The patient’s symptoms, family history, and baseline ECG findings can suggest a more serious or a less serious underlying rhythm. These factors are important when determining which device is most appropriate.

Ambulatory ECG can also be useful in looking for a cause of cryptogenic stroke, ie, an ischemic stroke with an unexplained cause, even after a thorough initial workup. Paroxysmal atrial fibrillation is a frequent cause of cryptogenic stroke, and because it is transient, short-term inpatient telemetry may not be sufficient to detect it. Extended cardiac monitoring, lasting weeks or even months, is often needed for clinicians to make this diagnosis and initiate appropriate secondary prevention.

Prognosis: Identifying patients at risk

In a patient with known structural or electrical heart disease, ambulatory ECG can be used to stratify risk. This is particularly true in evaluating conditions associated with sudden cardiac death.

For example, hypertrophic cardiomyopathy and arrhythmogenic right ventricular dysplasia or cardiomyopathy are 2 cardiomyopathies that can manifest clinically with ventricular arrhythmias and sudden cardiac death. Ambulatory ECG can detect premature ventricular contractions and ventricular tachycardia and identify their frequency, duration, and anatomic origin. This information is useful in assessing risk of sudden cardiac death and determining the need for an implantable cardioverter-defibrillator.

Similarly, Wolff-Parkinson-White syndrome, involving rapid conduction through an accessory pathway, is associated with increased risk of ventricular fibrillation and sudden cardiac death. Ambulatory ECG monitoring can identify patients who have electrical features that portend the development of ventricular fibrillation.

Also associated with sudden cardiac death are the inherited channelopathies, a heterogeneous group of primary arrhythmic disorders without accompanying structural pathology. Ambulatory ECG monitoring can detect transient electrical changes and nonsustained ventricular arrhythmias that would indicate the patient is at high risk of these disorders.

Assessing arrhythmia treatment

Arrhythmia monitoring using an ambulatory ECG device can also provide data to assess the efficacy of treatment under several circumstances.

The “pill-in-the-pocket” approach to treating atrial fibrillation, for example, involves self-administering a single dose of an antiarrhythmic drug when symptoms occur. Patients with infrequent but bothersome episodes can use an ambulatory ECG device to detect when they are having atrial fibrillation, take their prescribed drug, and see whether it terminates the arrhythmia, all without going to the hospital.

Ambulatory ECG also is useful for assessing pharmacologic or ablative therapy in patients with atrial fibrillation or ventricular tachycardia. Monitoring for several weeks can help clinicians assess the burden of atrial fibrillation when using a rhythm-control strategy; assessing the ventricular rate in real-world situations is useful to determine the success of a rate-control strategy. Shortly after ablation of either atrial fibrillation or ventricular tachycardia, ECG home monitoring for 24 to 48 hours can detect asymptomatic recurrence and treatment failure.

Some antiarrhythmic drugs can prolong the QT interval. Ambulatory ECG devices that feature real-time monitoring can be used during drug initiation, enabling the clinician to monitor the QT interval without admitting the patient to the hospital.

Ultimately, ambulatory ECG monitoring is most commonly used to evaluate symptoms. Because arrhythmias and specific symptoms are unpredictable and transient, extended monitoring in a real-world setting allows for a more comprehensive evaluation than a standard 10-second ECG recording.

Continuous external monitoring: The Holter monitor

Recording is typically done continuously for 24 to 48 hours, although some newer devices can record for longer. Patients can press a button to note when they are experiencing symptoms, allowing for potential correlation with ECG abnormalities. The data are stored on a flash drive that can be uploaded for analysis after recording is complete.

What is its best use? Given its relatively short duration of monitoring, the Holter device is typically used to evaluate symptoms that occur daily or nearly daily. An advantage of the Holter monitor is its ability to record continuously, without requiring the patient to interact with the device. This feature provides “full disclosure,” which is the ability to see arrhythmia data from the entire recording period.

These features make Holter monitoring useful to identify suspected frequently occurring silent arrhythmias or to assess the overall arrhythmia burden. A typical Holter report can contain information on the heart rate (maximum, minimum, and average), ectopic beats, and tachy- and bradyarrhythmias, as well as representative samples.

The Holter device is familiar to most practitioners and remains an effective choice for ambulatory ECG monitoring. However, its use has largely been replaced by newer devices that overcome the Holter’s drawbacks, particularly its short duration of monitoring and the need for postmonitoring analysis. Additionally, although newer Holter devices are more ergonomic, some patients find the wires and gel electrodes uncomfortable or inconvenient.

Intermittent monitoring: Event recorders

Unlike the continuous monitors, intermittent recording devices (also called event recorders), capture and store tracings only during an event.

Intermittent recording monitors are of 2 general types: post-event recorders and loop recorders. These devices can extend the overall duration of observation, which can be especially useful for those whose symptoms and arrhythmias are infrequent.

Post-event recorders are small and self-contained, not requiring electrodes (Figure 1). The device is carried by the patient but not worn continuously. When the patient experiences symptoms, he or she places the device against the chest and presses a button to begin recording. These tracings are stored on the device and can be transmitted by telephone to a data center for analysis. Although post-event recorders allow for monitoring periods typically up to 30 days, they are limited by requiring the patient to act to record an event.

What is its best use? These devices are best used in patients who have infrequent symptoms and are at low risk. Transient or debilitating symptoms, including syncope, can limit the possibility of capturing an event.

Intermittent monitoring: Loop recorders

Loop recorders monitor continuously but record only intermittently. The name refers to the device’s looping memory: ie, to extend how long it can be used and make the most of its limited storage, the device records over previously captured data, saving only the most important data. The device saves the data whenever it detects an abnormal rhythm or the patient experiences symptoms and pushes a button. Data are recorded for a specified time before and after the activation, typically 30 seconds.

Loop recorders come in 2 types: external and implantable.

External loop recorders

External loop recorders look like Holter monitors (Figure 1), but they have the advantage of a much longer observation period—typically up to 1 month. The newest devices have even greater storage capacity and can provide “backward” memory, saving data that were captured just before the patient pushed the button.

In studies of patients with palpitations, presyncope, or syncope, external loop recorders had greater diagnostic yield than traditional 24-hour Holter monitors.^7,8 This finding was supported by a clinical trial that found 30-day monitoring with an external loop recorder led to a 5-fold increase in detecting atrial fibrillation in patients with cryptogenic stroke.⁹

Disadvantages of external loop recorders are limited memory storage, a considerable reliance on patient activation of the device, and wires and electrodes that need to be worn continuously.

What is their best use? External loop recorders are most effective when used to detect an arrhythmia or to correlate infrequent symptoms with an arrhythmia. They are most appropriately used in patients whose symptoms occur more often than every 4 weeks. They are less useful in assessing very infrequent symptoms, overall arrhythmia burden, or responsiveness to therapy.¹⁰

Implantable loop recorders are small devices that contain a pair of sensing electrodes housed within an outer shell (Figure 1). They are implanted subcutaneously, usually in the left parasternal region, using local anesthesia. The subcutaneous location eliminates many of the drawbacks of the skin-electrode interface of external loop recorders.

Similar to the external loop recorder, this device monitors continuously and can be activated to record either by the patient by pressing a button on a separate device, or automatically when an arrhythmia is detected using a preprogrammed algorithm.

In contrast to external devices, many internal loop recorders have a battery life and monitoring capability of up to 3 years. This extended monitoring period has been shown to increase the likelihood of diagnosing syncope or infrequent palpitations.^11,12 Given that paroxysmal atrial fibrillation can be sporadic and reveal itself months after a stroke, internal loop recorders may also have a role in evaluating cryptogenic stroke.^13,14

The most important drawbacks of internal loop recorders are the surgical procedure for insertion, their limited memory storage, and high upfront cost.¹⁵ Furthermore, even though they allow for extended monitoring, there may be diminishing returns for prolonged observation.

What is their best use? For patients with palpitations, intermittent event monitoring has been shown to be cost-effective for the first 2 weeks, but after 3 weeks, the cost per diagnosis increases dramatically.¹⁶ As a result, internal loop recorders are reserved primarily for scenarios in which prolonged external monitoring has not revealed a source of arrhythmia despite a high degree of suspicion.

Mobile cardiac telemetry

Mobile cardiac telemetry builds on other ECG monitoring systems by adding real-time communication and technician evaluation.

Physically, these devices resemble either hand-held event records, with a single-channel sensing unit embedded in the case, or a traditional Holter monitor, with 3 channels, wires, and electrodes  (Figure 1).

The sensor wirelessly communicates with a nearby portable monitor, which continuously observes and analyzes the patient’s heart rhythm. When an abnormal rhythm is detected or when the patient marks the presence of symptoms, data are recorded and sent in real time via a cellular network to a monitoring center; the newest monitors can send data via any Wi-Fi system. The rhythm is then either evaluated by a trained technician or relayed to a physician. If necessary, the patient can be contacted immediately.

Mobile cardiac telemetry is typically used for up to 30 days, which  allows for evaluation of less-frequent symptoms. As a result, it may have a higher diagnostic yield for palpitations, syncope, and presyncope than the 24-hour Holter monitor.¹⁷

Further, perhaps because mobile cardiac telemetry relies less on stored information and requires less patient-device interaction than external loop recorders, it is more effective at symptom evaluation.¹⁸

Mobile cardiac telemetry also has a diagnostic role in evaluating patients with cryptogenic stroke. This is based on studies showing it has a high rate of atrial fibrillation detection in this patient population and is more effective at determining overall atrial fibrillation burden than loop recorders.^18,19

What is its best use? The key advantage of mobile cardiac telemetry is its ability to make rhythm assessments and communicate with technicians in real time. This allows high-risk patients to be immediately alerted to a life-threatening arrhythmia. It also gives providers an opportunity to initiate anticoagulation or titrate antiarrhythmic therapy in the outpatient setting without a delay in obtaining information. This intensive monitoring, however, requires significant manpower, which translates to higher cost, averaging 3 times that of other standard external monitors.¹⁵

Patch monitors

These ultraportable devices are a relatively unobtrusive and easy-to-use alternative for short-term ambulatory ECG monitoring. They monitor continuously with full disclosure, outpatient telemetry, and post-event recording features.

Patch monitors are small, leadless, wireless, and water-resistant (Figure 1). They are affixed to the left pectoral region with a waterproof adhesive and can be worn for 14 to 28 days. Recording is usually done continuously; however, these devices have an event marker button that can be pressed when the user experiences symptoms. They acquire a single channel of data, and each manufacturer has a proprietary algorithm for automated rhythm detection and analysis.²⁰

Several manufacturers produce ECG patch monitors. Two notable devices are the Zio patch (iRhythm Technologies, San Francisco, CA) and the Mobile Cardiac Outpatient Telemetry patch (BioTelemetry, Inc, Malvern, PA).

The Zio patch is a continuous external monitor with full disclosure. It is comparable to the Holter monitor, but has a longer recording period. After completing a 2-week monitoring period, the device is returned for comprehensive rhythm analysis. A typical Zio report contains information on atrial fibrillation burden, ectopic rhythm burden, symptom and rhythm correlation, heart rate trends, and relevant rhythm strips.

The Mobile Cardiac Outpatient Telemetry patch collects data continuously and communicates wirelessly by Bluetooth to send its ECG data to a monitoring center for evaluation.

A principal advantage of patch monitors—and a major selling point for manufacturers—is their low-profile, ergonomic, and patient-friendly design. Patients do not have to manage wires or batteries and are able to shower with their devices. Studies show that these features increase patient satisfaction and compliance, resulting in increased diagnostic yield.^21,22 Additionally, patch monitors have the advantage of a longer continuous monitoring period than traditional Holter devices (2 weeks vs 1 or 2 days), affording an opportunity to capture events that occur less frequently.

Validation studies have reinforced their efficacy and utility in clinical scenarios.^22,23 In large part because of the extended monitoring period, patch monitors have been shown to have greater diagnostic yield than the 24-hour Holter monitor in symptomatic patients undergoing workup for suspected arrhythmia.

The role of patch monitors in evaluating atrial fibrillation is also being established. For patients with cryptogenic stroke, patch monitors have shown better atrial fibrillation detection than the 24-hour Holter monitor.²⁴ Compared with traditional loop monitors, patch monitors have the added advantage of assessing total atrial fibrillation burden. Further, although screening for atrial fibrillation with a traditional 12-lead ECG monitor has not been shown to be effective, clinical studies have found that the patch monitor may be a useful screening tool for high-risk patients.^25,26

Nevertheless, patch monitors have drawbacks. They are not capable of long-term monitoring, owing to battery and adhesive limitations.²⁰ More important, they have  been able to offer only single-channel acquisition, which makes it more difficult to detect an arrhythmia that is characterized by a change in QRS axis or change in QRS width, or to distinguish an arrhythmia from an artifact. This appears to be changing, however, as several manufacturers have recently developed multilead ECG patch monitors or attachments and are attempting to merge this technology with fully capable remote telemetry.

Recent improvements in battery life, memory, detection algorithms, wireless transmission, cellular communication, and adhesives have enabled multiple features to be combined into a single device. Patch monitors, for example, are small devices that now offer full-disclosure recording, extended monitoring, and telemetry transmitting. Automated arrhythmia recognition that triggers recording is central to all modern devices, regardless of type.

As a result of these trends, the traditional features used to differentiate devices may become less applicable. The classic Holter monitor may become obsolete as its advantages (full disclosure, continuous recording) are being incorporated into smaller devices that can record longer. Similarly, external monitors that have the capacity for full disclosure and continuous recording are no longer loop recorders in that they do not record into a circular memory.

It may be preferable to describe all non-Holter devices as event monitors or ambulatory monitors, with the main distinguishing features being the ability to transmit data (telemetry), full disclosure vs patient- or arrhythmia-activated recording, and single-channel or multichannel recording (single-lead or 3-lead ECG).

The following are the main distinguishing features that should influence the choice of device for a given clinical context.

Real-time data evaluation provided by mobile telemetry makes this feature ideal to monitor patients with suspected high-risk arrhythmias and their response to antiarrhythmic therapy.

Full-disclosure recording is necessary to assess the overall burden of an arrhythmia, which is frequently important in making treatment decisions, risk-stratifying, and assessing response to therapy. In contrast, patient- or arrhythmia-activated devices are best used when the goal is simply to establish the presence of an arrhythmia.

Multichannel recording may be better than single-channel recording, as it is needed to determine the anatomic origin of an arrhythmia, as might be the case in risk-stratification in a patient with a ventricular tachycardia.

Long duration. The clinician must have a reasonable estimate of how often the symptoms or arrhythmia occur to determine which device will offer a monitoring duration sufficient to detect an arrhythmia.

NEWER TECHNOLOGIES

The newest ambulatory ECG devices build on the foundational concepts of the older ones. However, with miniaturized electronic circuits, Bluetooth, Wi-Fi, and smartphones, these new devices can capture ECG tracings and diagnose offending arrhythmias on more consumer-friendly devices.

Smartphones and smartwatches have become increasingly powerful. Some have the ability to capture, display, and record the cardiac waveform. One manufacturer to capitalize on these technologies, AliveCor (Mountain View, CA), has developed 2 products capable of generating a single-lead ECG recording using either a smartphone (KardiaMobile) or an Apple watch (KardiaBand).

KardiaMobile has a 2-electrode band that can be carried in a pocket or attached to the back of a smartphone (Figure 1). The user places 1 or 2 fingers from each hand on the electrodes, and the device sends an ultrasound signal that is picked up by the smartphone’s microphone. The signal is digitized to produce a 30-second ECG tracing on the phone’s screen. A proprietary algorithm analyzes the rhythm and generates a description of “normal” or “possible atrial fibrillation.” The ECG is then uploaded to a cloud-based storage system for later access or transmission. KardiaMobile is compatible with both iOS and Android devices.

The KardiaBand is a specialized Apple watch band that has an electrode embedded in it. The user places a thumb on the electrode for 30 seconds, and an ECG tracing is displayed on the watch screen.

The Kardia devices were developed (and advertised) predominantly to assess atrial fibrillation. Studies have validated the accuracy of their algorithm. One study showed that, compared with physician-interpreted ECGs, the algorithm had a 96.6% sensitivity and 94.1% specificity for detecting atrial fibrillation.²⁷ They have been found useful for detecting and evaluating atrial fibrillation in several clinical scenarios, including discharge monitoring in patients after ablation or cardiac surgery.^28,29 In a longer study of patients at risk of stroke, twice-weekly ECG screening using a Kardia device for 1 year was more likely to detect incident atrial fibrillation than routine care alone.³⁰

Also, the Kardia devices can effectively function as post-event recorders when activated by patients when they experience symptoms. In a small study of outpatients with palpitations and a prior nondiagnostic workup, the KardiaMobile device was found to be noninferior to external loop recorders for detecting arrhythmias.³¹ Additional studies are assessing Kardia’s utility in other scenarios, including the evaluation of ST-segment elevation myocardial infarction^32,33 and QT interval for patients receiving antiarrhythmic therapy.³⁴

Cardiio Inc. (Cambridge, MA) has developed technology to screen for atrial fibrillation using an app that requires no additional external hardware. Instead, the app uses a smartphone’s camera and flashlight to perform photo­plethysmography to detect pulsatile changes in blood volume and generate a waveform. Based on waveform variability, a proprietary algorithm attempts to determine whether the user is in atrial fibrillation. It does not produce an ECG tracing. Initial studies suggest it has good diagnostic accuracy and potential utility as a population-based screening tool,^35,36 but it has not been fully validated.

Recently, Apple entered the arena of ambulatory cardiac monitoring with the release of its fourth-generation watch (Apple Watch Series 4 model). This watch has built-in electrodes that can generate a single-lead ECG on the watch screen. Its algorithm can discriminate between atrial fibrillation and sinus rhythm, but it has not been assessed for its ability to evaluate other arrhythmias. Even though it has been “cleared” by the US Food and Drug Administration, it is approved only for informational use, not to make a medical diagnosis.

Integration of ambulatory ECG technology with smartphone and watch technology is an exciting new wearable option for arrhythmia detection. The patient-centered and controlled nature of these devices have the potential to help patients with palpitations or other symptoms determine if their cardiac rhythms are normal.

This technology, however, is still in its infancy and has many limitations. For example, even though these devices can function as post-event recorders, they depend on user-device interactions. Plus, they cannot yet perform continuous arrhythmia monitoring like modern loop recorders.

Additionally, automated analysis has largely been limited to distinguishing atrial fibrillation from normal sinus rhythm. It is uncertain how effective the devices may be in evaluating other arrhythmias. Single-lead ECG recordings, as discussed, have limited interpretability and value. And even though studies have shown utility in certain clinical scenarios, large-scale validation studies are lacking. This technology will likely continue to be developed and its clinical value improved; however, its clinical use requires careful consideration and collaborative physician-patient decision-making.

The development of smartphone and watch ECG technology has led to a rise in direct-to-consumer healthcare delivery. By devising technology that is appealing, useful, and affordable, companies can bypass the insurer and practitioner by targeting increasingly health-literate consumers. For many companies, there is great motivation to enter this healthcare space. Wearable devices are immensely popular and, as a result, generate substantial revenue. One analysis estimates that 1 in 10 Americans (nearly 30 million) owns a wearable, smart-technology device.³⁷

This direct-to-consumer approach has specific implications for cardiology and, more broadly, for healthcare overall. By directly selling to consumers, companies have an opportunity to reach many more people. The Apple Watch Series 4 has taken this a step further: by including this technology in the watch, consumers not necessarily seeking an ambulatory cardiac monitor will have one with a watch purchase. This could lead to increases in monitoring and could alert people to previously undiagnosed disorders.

For consumers, this technology can empower them to choose how and when to be monitored. Further, it gives them personal control of their healthcare data, and helps move the point of care out of hospitals and clinics and into the home.

But wearable medical technology and direct-to-consumer healthcare have risks. First, in the absence of appropriate regulation, patients have to distinguish between products that are well validated and those that are unproven. Consumers also may inappropriately use devices for indications or in scenarios for which the value is uncertain.

Also, there is potential for confusion and misunderstanding of results, including false-positive readings, which could lead to excessive and costly use of unnecessary diagnostic workups. Instead of providing peace of mind, these devices could cause greater worry. This may be especially true with the newest Apple watch, as this product will introduce ambulatory ECG to a younger and healthier segment of the population who are less likely to have true disease.

Further, these devices have algorithms that detect atrial fibrillation, but is it the same as that detected by traditional methods? Sometimes termed “subclinical” atrial fibrillation, it poses uncertainties: ie, Do patients need anticoagulation, pharmacologic therapy, and ablation? The optimal management of subclinical atrial fibrillation, as well as its similarities to and differences from atrial fibrillation diagnosed by traditional methods, are topics that need further study.

Wearable technology is still developing and will continue to do so. Medical practice will have to adapt to it.

FUTURE DIRECTIONS

Changes in technology have led to remarkable advances in the convenience and accuracy of ambulatory ECG monitoring. Ongoing research is expected to lead to even more improvements. Devices will become more ergonomic and technically capable, and they may expand monitoring to include other biologic parameters beyond ECG.

Comfort is important to ensure patient adherence. Newer, flexible electronics embedded in ultrathin materials can potentially improve the wearability of devices that require gel electrodes or adhesive patches.³⁸ Wireless technology may obviate the need for on-skin attachments. Future recording systems may be embedded into clothing or incorporated into wearable vests capable of wirelessly transmitting ECG signals to separate recording stations.³⁹

In addition to becoming smaller and more comfortable, future devices will be more technically capable, leading to a merging of technologies that will further blur the distinctions among devices. Eventually, the features of full disclosure, extended monitoring duration, and telemetric communication will all be present together. Perhaps more important is that ambulatory ECG devices may become fully capable biosensor monitors. These devices would have the potential to monitor respiratory frequency, peripheral oxygen saturation, potassium levels, and arterial pulse pressure.^39,40

A mbulatory electrocardiography (ECG) began in 1949 when Norman “Jeff” Holter developed a monitor that could wirelessly transmit electrophysiologic data.¹ His original device used vacuum tubes, weighed 85 pounds, and had to be carried in a backpack. Furthermore, it could send a signal a distance of only 1 block.²

At the time, it was uncertain if this technology would have any clinical utility. However, in 1952, Holter published the first tracing of abnormal cardiac electrical activity in a patient who had suffered a posterior myocardial infarction.³ By the 1960s, Holter monitoring systems were in full production and use.⁴

Since then, advances in technology have led to small, lightweight devices that enable clinicians to evaluate patients for arrhythmias in a real-world context for extended times, often with the ability to respond in real time.

Many ambulatory devices are available, and choosing the optimal one requires an understanding of which features they have and which are the most appropriate for the specific clinical context. This article reviews the features, indications, advantages, and disadvantages of current devices, and their best use in clinical practice.

INDICATIONS FOR AMBULATORY ECG MONITORING

Diagnosis

The most common diagnostic role of monitoring is to correlate unexplained symptoms, including palpitations, presyncope, and syncope, with a transient cardiac arrhythmia. Monitoring can be considered successful if findings on ECG identify risks for serious arrhythmia and either correlate symptoms with those findings or demonstrate no arrhythmia when symptoms occur.

A range of arrhythmias can cause symptoms. Some, such as premature atrial contractions and premature ventricular contractions, may be benign in many clinical contexts. Others, such as atrial fibrillation, are more serious, and some, such as third-degree heart block and ventricular tachycardia, can be lethal.

Arrhythmia symptoms can vary in frequency and cause differing degrees of debility. The patient’s symptoms, family history, and baseline ECG findings can suggest a more serious or a less serious underlying rhythm. These factors are important when determining which device is most appropriate.

Ambulatory ECG can also be useful in looking for a cause of cryptogenic stroke, ie, an ischemic stroke with an unexplained cause, even after a thorough initial workup. Paroxysmal atrial fibrillation is a frequent cause of cryptogenic stroke, and because it is transient, short-term inpatient telemetry may not be sufficient to detect it. Extended cardiac monitoring, lasting weeks or even months, is often needed for clinicians to make this diagnosis and initiate appropriate secondary prevention.

Prognosis: Identifying patients at risk

In a patient with known structural or electrical heart disease, ambulatory ECG can be used to stratify risk. This is particularly true in evaluating conditions associated with sudden cardiac death.

For example, hypertrophic cardiomyopathy and arrhythmogenic right ventricular dysplasia or cardiomyopathy are 2 cardiomyopathies that can manifest clinically with ventricular arrhythmias and sudden cardiac death. Ambulatory ECG can detect premature ventricular contractions and ventricular tachycardia and identify their frequency, duration, and anatomic origin. This information is useful in assessing risk of sudden cardiac death and determining the need for an implantable cardioverter-defibrillator.

Similarly, Wolff-Parkinson-White syndrome, involving rapid conduction through an accessory pathway, is associated with increased risk of ventricular fibrillation and sudden cardiac death. Ambulatory ECG monitoring can identify patients who have electrical features that portend the development of ventricular fibrillation.

Also associated with sudden cardiac death are the inherited channelopathies, a heterogeneous group of primary arrhythmic disorders without accompanying structural pathology. Ambulatory ECG monitoring can detect transient electrical changes and nonsustained ventricular arrhythmias that would indicate the patient is at high risk of these disorders.

Assessing arrhythmia treatment

Arrhythmia monitoring using an ambulatory ECG device can also provide data to assess the efficacy of treatment under several circumstances.

The “pill-in-the-pocket” approach to treating atrial fibrillation, for example, involves self-administering a single dose of an antiarrhythmic drug when symptoms occur. Patients with infrequent but bothersome episodes can use an ambulatory ECG device to detect when they are having atrial fibrillation, take their prescribed drug, and see whether it terminates the arrhythmia, all without going to the hospital.

Ambulatory ECG also is useful for assessing pharmacologic or ablative therapy in patients with atrial fibrillation or ventricular tachycardia. Monitoring for several weeks can help clinicians assess the burden of atrial fibrillation when using a rhythm-control strategy; assessing the ventricular rate in real-world situations is useful to determine the success of a rate-control strategy. Shortly after ablation of either atrial fibrillation or ventricular tachycardia, ECG home monitoring for 24 to 48 hours can detect asymptomatic recurrence and treatment failure.

Some antiarrhythmic drugs can prolong the QT interval. Ambulatory ECG devices that feature real-time monitoring can be used during drug initiation, enabling the clinician to monitor the QT interval without admitting the patient to the hospital.

Ultimately, ambulatory ECG monitoring is most commonly used to evaluate symptoms. Because arrhythmias and specific symptoms are unpredictable and transient, extended monitoring in a real-world setting allows for a more comprehensive evaluation than a standard 10-second ECG recording.

Continuous external monitoring: The Holter monitor

Recording is typically done continuously for 24 to 48 hours, although some newer devices can record for longer. Patients can press a button to note when they are experiencing symptoms, allowing for potential correlation with ECG abnormalities. The data are stored on a flash drive that can be uploaded for analysis after recording is complete.

What is its best use? Given its relatively short duration of monitoring, the Holter device is typically used to evaluate symptoms that occur daily or nearly daily. An advantage of the Holter monitor is its ability to record continuously, without requiring the patient to interact with the device. This feature provides “full disclosure,” which is the ability to see arrhythmia data from the entire recording period.

These features make Holter monitoring useful to identify suspected frequently occurring silent arrhythmias or to assess the overall arrhythmia burden. A typical Holter report can contain information on the heart rate (maximum, minimum, and average), ectopic beats, and tachy- and bradyarrhythmias, as well as representative samples.

The Holter device is familiar to most practitioners and remains an effective choice for ambulatory ECG monitoring. However, its use has largely been replaced by newer devices that overcome the Holter’s drawbacks, particularly its short duration of monitoring and the need for postmonitoring analysis. Additionally, although newer Holter devices are more ergonomic, some patients find the wires and gel electrodes uncomfortable or inconvenient.

Intermittent monitoring: Event recorders

Unlike the continuous monitors, intermittent recording devices (also called event recorders), capture and store tracings only during an event.

Intermittent recording monitors are of 2 general types: post-event recorders and loop recorders. These devices can extend the overall duration of observation, which can be especially useful for those whose symptoms and arrhythmias are infrequent.

Post-event recorders are small and self-contained, not requiring electrodes (Figure 1). The device is carried by the patient but not worn continuously. When the patient experiences symptoms, he or she places the device against the chest and presses a button to begin recording. These tracings are stored on the device and can be transmitted by telephone to a data center for analysis. Although post-event recorders allow for monitoring periods typically up to 30 days, they are limited by requiring the patient to act to record an event.

What is its best use? These devices are best used in patients who have infrequent symptoms and are at low risk. Transient or debilitating symptoms, including syncope, can limit the possibility of capturing an event.

Intermittent monitoring: Loop recorders

Loop recorders monitor continuously but record only intermittently. The name refers to the device’s looping memory: ie, to extend how long it can be used and make the most of its limited storage, the device records over previously captured data, saving only the most important data. The device saves the data whenever it detects an abnormal rhythm or the patient experiences symptoms and pushes a button. Data are recorded for a specified time before and after the activation, typically 30 seconds.

Loop recorders come in 2 types: external and implantable.

External loop recorders

External loop recorders look like Holter monitors (Figure 1), but they have the advantage of a much longer observation period—typically up to 1 month. The newest devices have even greater storage capacity and can provide “backward” memory, saving data that were captured just before the patient pushed the button.

In studies of patients with palpitations, presyncope, or syncope, external loop recorders had greater diagnostic yield than traditional 24-hour Holter monitors.^7,8 This finding was supported by a clinical trial that found 30-day monitoring with an external loop recorder led to a 5-fold increase in detecting atrial fibrillation in patients with cryptogenic stroke.⁹

Disadvantages of external loop recorders are limited memory storage, a considerable reliance on patient activation of the device, and wires and electrodes that need to be worn continuously.

What is their best use? External loop recorders are most effective when used to detect an arrhythmia or to correlate infrequent symptoms with an arrhythmia. They are most appropriately used in patients whose symptoms occur more often than every 4 weeks. They are less useful in assessing very infrequent symptoms, overall arrhythmia burden, or responsiveness to therapy.¹⁰

Implantable loop recorders are small devices that contain a pair of sensing electrodes housed within an outer shell (Figure 1). They are implanted subcutaneously, usually in the left parasternal region, using local anesthesia. The subcutaneous location eliminates many of the drawbacks of the skin-electrode interface of external loop recorders.

Similar to the external loop recorder, this device monitors continuously and can be activated to record either by the patient by pressing a button on a separate device, or automatically when an arrhythmia is detected using a preprogrammed algorithm.

In contrast to external devices, many internal loop recorders have a battery life and monitoring capability of up to 3 years. This extended monitoring period has been shown to increase the likelihood of diagnosing syncope or infrequent palpitations.^11,12 Given that paroxysmal atrial fibrillation can be sporadic and reveal itself months after a stroke, internal loop recorders may also have a role in evaluating cryptogenic stroke.^13,14

The most important drawbacks of internal loop recorders are the surgical procedure for insertion, their limited memory storage, and high upfront cost.¹⁵ Furthermore, even though they allow for extended monitoring, there may be diminishing returns for prolonged observation.

What is their best use? For patients with palpitations, intermittent event monitoring has been shown to be cost-effective for the first 2 weeks, but after 3 weeks, the cost per diagnosis increases dramatically.¹⁶ As a result, internal loop recorders are reserved primarily for scenarios in which prolonged external monitoring has not revealed a source of arrhythmia despite a high degree of suspicion.

Mobile cardiac telemetry

Mobile cardiac telemetry builds on other ECG monitoring systems by adding real-time communication and technician evaluation.

Physically, these devices resemble either hand-held event records, with a single-channel sensing unit embedded in the case, or a traditional Holter monitor, with 3 channels, wires, and electrodes  (Figure 1).

The sensor wirelessly communicates with a nearby portable monitor, which continuously observes and analyzes the patient’s heart rhythm. When an abnormal rhythm is detected or when the patient marks the presence of symptoms, data are recorded and sent in real time via a cellular network to a monitoring center; the newest monitors can send data via any Wi-Fi system. The rhythm is then either evaluated by a trained technician or relayed to a physician. If necessary, the patient can be contacted immediately.

Mobile cardiac telemetry is typically used for up to 30 days, which  allows for evaluation of less-frequent symptoms. As a result, it may have a higher diagnostic yield for palpitations, syncope, and presyncope than the 24-hour Holter monitor.¹⁷

Further, perhaps because mobile cardiac telemetry relies less on stored information and requires less patient-device interaction than external loop recorders, it is more effective at symptom evaluation.¹⁸

Mobile cardiac telemetry also has a diagnostic role in evaluating patients with cryptogenic stroke. This is based on studies showing it has a high rate of atrial fibrillation detection in this patient population and is more effective at determining overall atrial fibrillation burden than loop recorders.^18,19

What is its best use? The key advantage of mobile cardiac telemetry is its ability to make rhythm assessments and communicate with technicians in real time. This allows high-risk patients to be immediately alerted to a life-threatening arrhythmia. It also gives providers an opportunity to initiate anticoagulation or titrate antiarrhythmic therapy in the outpatient setting without a delay in obtaining information. This intensive monitoring, however, requires significant manpower, which translates to higher cost, averaging 3 times that of other standard external monitors.¹⁵

Patch monitors

These ultraportable devices are a relatively unobtrusive and easy-to-use alternative for short-term ambulatory ECG monitoring. They monitor continuously with full disclosure, outpatient telemetry, and post-event recording features.

Patch monitors are small, leadless, wireless, and water-resistant (Figure 1). They are affixed to the left pectoral region with a waterproof adhesive and can be worn for 14 to 28 days. Recording is usually done continuously; however, these devices have an event marker button that can be pressed when the user experiences symptoms. They acquire a single channel of data, and each manufacturer has a proprietary algorithm for automated rhythm detection and analysis.²⁰

Several manufacturers produce ECG patch monitors. Two notable devices are the Zio patch (iRhythm Technologies, San Francisco, CA) and the Mobile Cardiac Outpatient Telemetry patch (BioTelemetry, Inc, Malvern, PA).

The Zio patch is a continuous external monitor with full disclosure. It is comparable to the Holter monitor, but has a longer recording period. After completing a 2-week monitoring period, the device is returned for comprehensive rhythm analysis. A typical Zio report contains information on atrial fibrillation burden, ectopic rhythm burden, symptom and rhythm correlation, heart rate trends, and relevant rhythm strips.

The Mobile Cardiac Outpatient Telemetry patch collects data continuously and communicates wirelessly by Bluetooth to send its ECG data to a monitoring center for evaluation.

A principal advantage of patch monitors—and a major selling point for manufacturers—is their low-profile, ergonomic, and patient-friendly design. Patients do not have to manage wires or batteries and are able to shower with their devices. Studies show that these features increase patient satisfaction and compliance, resulting in increased diagnostic yield.^21,22 Additionally, patch monitors have the advantage of a longer continuous monitoring period than traditional Holter devices (2 weeks vs 1 or 2 days), affording an opportunity to capture events that occur less frequently.

Validation studies have reinforced their efficacy and utility in clinical scenarios.^22,23 In large part because of the extended monitoring period, patch monitors have been shown to have greater diagnostic yield than the 24-hour Holter monitor in symptomatic patients undergoing workup for suspected arrhythmia.

The role of patch monitors in evaluating atrial fibrillation is also being established. For patients with cryptogenic stroke, patch monitors have shown better atrial fibrillation detection than the 24-hour Holter monitor.²⁴ Compared with traditional loop monitors, patch monitors have the added advantage of assessing total atrial fibrillation burden. Further, although screening for atrial fibrillation with a traditional 12-lead ECG monitor has not been shown to be effective, clinical studies have found that the patch monitor may be a useful screening tool for high-risk patients.^25,26

Nevertheless, patch monitors have drawbacks. They are not capable of long-term monitoring, owing to battery and adhesive limitations.²⁰ More important, they have  been able to offer only single-channel acquisition, which makes it more difficult to detect an arrhythmia that is characterized by a change in QRS axis or change in QRS width, or to distinguish an arrhythmia from an artifact. This appears to be changing, however, as several manufacturers have recently developed multilead ECG patch monitors or attachments and are attempting to merge this technology with fully capable remote telemetry.

Recent improvements in battery life, memory, detection algorithms, wireless transmission, cellular communication, and adhesives have enabled multiple features to be combined into a single device. Patch monitors, for example, are small devices that now offer full-disclosure recording, extended monitoring, and telemetry transmitting. Automated arrhythmia recognition that triggers recording is central to all modern devices, regardless of type.

As a result of these trends, the traditional features used to differentiate devices may become less applicable. The classic Holter monitor may become obsolete as its advantages (full disclosure, continuous recording) are being incorporated into smaller devices that can record longer. Similarly, external monitors that have the capacity for full disclosure and continuous recording are no longer loop recorders in that they do not record into a circular memory.

It may be preferable to describe all non-Holter devices as event monitors or ambulatory monitors, with the main distinguishing features being the ability to transmit data (telemetry), full disclosure vs patient- or arrhythmia-activated recording, and single-channel or multichannel recording (single-lead or 3-lead ECG).

The following are the main distinguishing features that should influence the choice of device for a given clinical context.

Real-time data evaluation provided by mobile telemetry makes this feature ideal to monitor patients with suspected high-risk arrhythmias and their response to antiarrhythmic therapy.

Full-disclosure recording is necessary to assess the overall burden of an arrhythmia, which is frequently important in making treatment decisions, risk-stratifying, and assessing response to therapy. In contrast, patient- or arrhythmia-activated devices are best used when the goal is simply to establish the presence of an arrhythmia.

Multichannel recording may be better than single-channel recording, as it is needed to determine the anatomic origin of an arrhythmia, as might be the case in risk-stratification in a patient with a ventricular tachycardia.

Long duration. The clinician must have a reasonable estimate of how often the symptoms or arrhythmia occur to determine which device will offer a monitoring duration sufficient to detect an arrhythmia.

NEWER TECHNOLOGIES

The newest ambulatory ECG devices build on the foundational concepts of the older ones. However, with miniaturized electronic circuits, Bluetooth, Wi-Fi, and smartphones, these new devices can capture ECG tracings and diagnose offending arrhythmias on more consumer-friendly devices.

Smartphones and smartwatches have become increasingly powerful. Some have the ability to capture, display, and record the cardiac waveform. One manufacturer to capitalize on these technologies, AliveCor (Mountain View, CA), has developed 2 products capable of generating a single-lead ECG recording using either a smartphone (KardiaMobile) or an Apple watch (KardiaBand).

KardiaMobile has a 2-electrode band that can be carried in a pocket or attached to the back of a smartphone (Figure 1). The user places 1 or 2 fingers from each hand on the electrodes, and the device sends an ultrasound signal that is picked up by the smartphone’s microphone. The signal is digitized to produce a 30-second ECG tracing on the phone’s screen. A proprietary algorithm analyzes the rhythm and generates a description of “normal” or “possible atrial fibrillation.” The ECG is then uploaded to a cloud-based storage system for later access or transmission. KardiaMobile is compatible with both iOS and Android devices.

The KardiaBand is a specialized Apple watch band that has an electrode embedded in it. The user places a thumb on the electrode for 30 seconds, and an ECG tracing is displayed on the watch screen.

The Kardia devices were developed (and advertised) predominantly to assess atrial fibrillation. Studies have validated the accuracy of their algorithm. One study showed that, compared with physician-interpreted ECGs, the algorithm had a 96.6% sensitivity and 94.1% specificity for detecting atrial fibrillation.²⁷ They have been found useful for detecting and evaluating atrial fibrillation in several clinical scenarios, including discharge monitoring in patients after ablation or cardiac surgery.^28,29 In a longer study of patients at risk of stroke, twice-weekly ECG screening using a Kardia device for 1 year was more likely to detect incident atrial fibrillation than routine care alone.³⁰

Also, the Kardia devices can effectively function as post-event recorders when activated by patients when they experience symptoms. In a small study of outpatients with palpitations and a prior nondiagnostic workup, the KardiaMobile device was found to be noninferior to external loop recorders for detecting arrhythmias.³¹ Additional studies are assessing Kardia’s utility in other scenarios, including the evaluation of ST-segment elevation myocardial infarction^32,33 and QT interval for patients receiving antiarrhythmic therapy.³⁴

Cardiio Inc. (Cambridge, MA) has developed technology to screen for atrial fibrillation using an app that requires no additional external hardware. Instead, the app uses a smartphone’s camera and flashlight to perform photo­plethysmography to detect pulsatile changes in blood volume and generate a waveform. Based on waveform variability, a proprietary algorithm attempts to determine whether the user is in atrial fibrillation. It does not produce an ECG tracing. Initial studies suggest it has good diagnostic accuracy and potential utility as a population-based screening tool,^35,36 but it has not been fully validated.

Recently, Apple entered the arena of ambulatory cardiac monitoring with the release of its fourth-generation watch (Apple Watch Series 4 model). This watch has built-in electrodes that can generate a single-lead ECG on the watch screen. Its algorithm can discriminate between atrial fibrillation and sinus rhythm, but it has not been assessed for its ability to evaluate other arrhythmias. Even though it has been “cleared” by the US Food and Drug Administration, it is approved only for informational use, not to make a medical diagnosis.

Integration of ambulatory ECG technology with smartphone and watch technology is an exciting new wearable option for arrhythmia detection. The patient-centered and controlled nature of these devices have the potential to help patients with palpitations or other symptoms determine if their cardiac rhythms are normal.

This technology, however, is still in its infancy and has many limitations. For example, even though these devices can function as post-event recorders, they depend on user-device interactions. Plus, they cannot yet perform continuous arrhythmia monitoring like modern loop recorders.

Additionally, automated analysis has largely been limited to distinguishing atrial fibrillation from normal sinus rhythm. It is uncertain how effective the devices may be in evaluating other arrhythmias. Single-lead ECG recordings, as discussed, have limited interpretability and value. And even though studies have shown utility in certain clinical scenarios, large-scale validation studies are lacking. This technology will likely continue to be developed and its clinical value improved; however, its clinical use requires careful consideration and collaborative physician-patient decision-making.

The development of smartphone and watch ECG technology has led to a rise in direct-to-consumer healthcare delivery. By devising technology that is appealing, useful, and affordable, companies can bypass the insurer and practitioner by targeting increasingly health-literate consumers. For many companies, there is great motivation to enter this healthcare space. Wearable devices are immensely popular and, as a result, generate substantial revenue. One analysis estimates that 1 in 10 Americans (nearly 30 million) owns a wearable, smart-technology device.³⁷

This direct-to-consumer approach has specific implications for cardiology and, more broadly, for healthcare overall. By directly selling to consumers, companies have an opportunity to reach many more people. The Apple Watch Series 4 has taken this a step further: by including this technology in the watch, consumers not necessarily seeking an ambulatory cardiac monitor will have one with a watch purchase. This could lead to increases in monitoring and could alert people to previously undiagnosed disorders.

For consumers, this technology can empower them to choose how and when to be monitored. Further, it gives them personal control of their healthcare data, and helps move the point of care out of hospitals and clinics and into the home.

But wearable medical technology and direct-to-consumer healthcare have risks. First, in the absence of appropriate regulation, patients have to distinguish between products that are well validated and those that are unproven. Consumers also may inappropriately use devices for indications or in scenarios for which the value is uncertain.

Also, there is potential for confusion and misunderstanding of results, including false-positive readings, which could lead to excessive and costly use of unnecessary diagnostic workups. Instead of providing peace of mind, these devices could cause greater worry. This may be especially true with the newest Apple watch, as this product will introduce ambulatory ECG to a younger and healthier segment of the population who are less likely to have true disease.

Further, these devices have algorithms that detect atrial fibrillation, but is it the same as that detected by traditional methods? Sometimes termed “subclinical” atrial fibrillation, it poses uncertainties: ie, Do patients need anticoagulation, pharmacologic therapy, and ablation? The optimal management of subclinical atrial fibrillation, as well as its similarities to and differences from atrial fibrillation diagnosed by traditional methods, are topics that need further study.

Wearable technology is still developing and will continue to do so. Medical practice will have to adapt to it.

FUTURE DIRECTIONS

Changes in technology have led to remarkable advances in the convenience and accuracy of ambulatory ECG monitoring. Ongoing research is expected to lead to even more improvements. Devices will become more ergonomic and technically capable, and they may expand monitoring to include other biologic parameters beyond ECG.

Comfort is important to ensure patient adherence. Newer, flexible electronics embedded in ultrathin materials can potentially improve the wearability of devices that require gel electrodes or adhesive patches.³⁸ Wireless technology may obviate the need for on-skin attachments. Future recording systems may be embedded into clothing or incorporated into wearable vests capable of wirelessly transmitting ECG signals to separate recording stations.³⁹

In addition to becoming smaller and more comfortable, future devices will be more technically capable, leading to a merging of technologies that will further blur the distinctions among devices. Eventually, the features of full disclosure, extended monitoring duration, and telemetric communication will all be present together. Perhaps more important is that ambulatory ECG devices may become fully capable biosensor monitors. These devices would have the potential to monitor respiratory frequency, peripheral oxygen saturation, potassium levels, and arterial pulse pressure.^39,40

A mbulatory electrocardiography (ECG) began in 1949 when Norman “Jeff” Holter developed a monitor that could wirelessly transmit electrophysiologic data.¹ His original device used vacuum tubes, weighed 85 pounds, and had to be carried in a backpack. Furthermore, it could send a signal a distance of only 1 block.²

At the time, it was uncertain if this technology would have any clinical utility. However, in 1952, Holter published the first tracing of abnormal cardiac electrical activity in a patient who had suffered a posterior myocardial infarction.³ By the 1960s, Holter monitoring systems were in full production and use.⁴

Since then, advances in technology have led to small, lightweight devices that enable clinicians to evaluate patients for arrhythmias in a real-world context for extended times, often with the ability to respond in real time.

Many ambulatory devices are available, and choosing the optimal one requires an understanding of which features they have and which are the most appropriate for the specific clinical context. This article reviews the features, indications, advantages, and disadvantages of current devices, and their best use in clinical practice.

INDICATIONS FOR AMBULATORY ECG MONITORING

Diagnosis

The most common diagnostic role of monitoring is to correlate unexplained symptoms, including palpitations, presyncope, and syncope, with a transient cardiac arrhythmia. Monitoring can be considered successful if findings on ECG identify risks for serious arrhythmia and either correlate symptoms with those findings or demonstrate no arrhythmia when symptoms occur.

A range of arrhythmias can cause symptoms. Some, such as premature atrial contractions and premature ventricular contractions, may be benign in many clinical contexts. Others, such as atrial fibrillation, are more serious, and some, such as third-degree heart block and ventricular tachycardia, can be lethal.

Arrhythmia symptoms can vary in frequency and cause differing degrees of debility. The patient’s symptoms, family history, and baseline ECG findings can suggest a more serious or a less serious underlying rhythm. These factors are important when determining which device is most appropriate.

Ambulatory ECG can also be useful in looking for a cause of cryptogenic stroke, ie, an ischemic stroke with an unexplained cause, even after a thorough initial workup. Paroxysmal atrial fibrillation is a frequent cause of cryptogenic stroke, and because it is transient, short-term inpatient telemetry may not be sufficient to detect it. Extended cardiac monitoring, lasting weeks or even months, is often needed for clinicians to make this diagnosis and initiate appropriate secondary prevention.

Prognosis: Identifying patients at risk

In a patient with known structural or electrical heart disease, ambulatory ECG can be used to stratify risk. This is particularly true in evaluating conditions associated with sudden cardiac death.

For example, hypertrophic cardiomyopathy and arrhythmogenic right ventricular dysplasia or cardiomyopathy are 2 cardiomyopathies that can manifest clinically with ventricular arrhythmias and sudden cardiac death. Ambulatory ECG can detect premature ventricular contractions and ventricular tachycardia and identify their frequency, duration, and anatomic origin. This information is useful in assessing risk of sudden cardiac death and determining the need for an implantable cardioverter-defibrillator.

Similarly, Wolff-Parkinson-White syndrome, involving rapid conduction through an accessory pathway, is associated with increased risk of ventricular fibrillation and sudden cardiac death. Ambulatory ECG monitoring can identify patients who have electrical features that portend the development of ventricular fibrillation.

Also associated with sudden cardiac death are the inherited channelopathies, a heterogeneous group of primary arrhythmic disorders without accompanying structural pathology. Ambulatory ECG monitoring can detect transient electrical changes and nonsustained ventricular arrhythmias that would indicate the patient is at high risk of these disorders.

Assessing arrhythmia treatment

Arrhythmia monitoring using an ambulatory ECG device can also provide data to assess the efficacy of treatment under several circumstances.

The “pill-in-the-pocket” approach to treating atrial fibrillation, for example, involves self-administering a single dose of an antiarrhythmic drug when symptoms occur. Patients with infrequent but bothersome episodes can use an ambulatory ECG device to detect when they are having atrial fibrillation, take their prescribed drug, and see whether it terminates the arrhythmia, all without going to the hospital.

Ambulatory ECG also is useful for assessing pharmacologic or ablative therapy in patients with atrial fibrillation or ventricular tachycardia. Monitoring for several weeks can help clinicians assess the burden of atrial fibrillation when using a rhythm-control strategy; assessing the ventricular rate in real-world situations is useful to determine the success of a rate-control strategy. Shortly after ablation of either atrial fibrillation or ventricular tachycardia, ECG home monitoring for 24 to 48 hours can detect asymptomatic recurrence and treatment failure.

Some antiarrhythmic drugs can prolong the QT interval. Ambulatory ECG devices that feature real-time monitoring can be used during drug initiation, enabling the clinician to monitor the QT interval without admitting the patient to the hospital.

Ultimately, ambulatory ECG monitoring is most commonly used to evaluate symptoms. Because arrhythmias and specific symptoms are unpredictable and transient, extended monitoring in a real-world setting allows for a more comprehensive evaluation than a standard 10-second ECG recording.

Continuous external monitoring: The Holter monitor

Recording is typically done continuously for 24 to 48 hours, although some newer devices can record for longer. Patients can press a button to note when they are experiencing symptoms, allowing for potential correlation with ECG abnormalities. The data are stored on a flash drive that can be uploaded for analysis after recording is complete.

What is its best use? Given its relatively short duration of monitoring, the Holter device is typically used to evaluate symptoms that occur daily or nearly daily. An advantage of the Holter monitor is its ability to record continuously, without requiring the patient to interact with the device. This feature provides “full disclosure,” which is the ability to see arrhythmia data from the entire recording period.

These features make Holter monitoring useful to identify suspected frequently occurring silent arrhythmias or to assess the overall arrhythmia burden. A typical Holter report can contain information on the heart rate (maximum, minimum, and average), ectopic beats, and tachy- and bradyarrhythmias, as well as representative samples.

The Holter device is familiar to most practitioners and remains an effective choice for ambulatory ECG monitoring. However, its use has largely been replaced by newer devices that overcome the Holter’s drawbacks, particularly its short duration of monitoring and the need for postmonitoring analysis. Additionally, although newer Holter devices are more ergonomic, some patients find the wires and gel electrodes uncomfortable or inconvenient.

Intermittent monitoring: Event recorders

Unlike the continuous monitors, intermittent recording devices (also called event recorders), capture and store tracings only during an event.

Intermittent recording monitors are of 2 general types: post-event recorders and loop recorders. These devices can extend the overall duration of observation, which can be especially useful for those whose symptoms and arrhythmias are infrequent.

Post-event recorders are small and self-contained, not requiring electrodes (Figure 1). The device is carried by the patient but not worn continuously. When the patient experiences symptoms, he or she places the device against the chest and presses a button to begin recording. These tracings are stored on the device and can be transmitted by telephone to a data center for analysis. Although post-event recorders allow for monitoring periods typically up to 30 days, they are limited by requiring the patient to act to record an event.

What is its best use? These devices are best used in patients who have infrequent symptoms and are at low risk. Transient or debilitating symptoms, including syncope, can limit the possibility of capturing an event.

Intermittent monitoring: Loop recorders

Loop recorders monitor continuously but record only intermittently. The name refers to the device’s looping memory: ie, to extend how long it can be used and make the most of its limited storage, the device records over previously captured data, saving only the most important data. The device saves the data whenever it detects an abnormal rhythm or the patient experiences symptoms and pushes a button. Data are recorded for a specified time before and after the activation, typically 30 seconds.

Loop recorders come in 2 types: external and implantable.

External loop recorders

External loop recorders look like Holter monitors (Figure 1), but they have the advantage of a much longer observation period—typically up to 1 month. The newest devices have even greater storage capacity and can provide “backward” memory, saving data that were captured just before the patient pushed the button.

In studies of patients with palpitations, presyncope, or syncope, external loop recorders had greater diagnostic yield than traditional 24-hour Holter monitors.^7,8 This finding was supported by a clinical trial that found 30-day monitoring with an external loop recorder led to a 5-fold increase in detecting atrial fibrillation in patients with cryptogenic stroke.⁹

Disadvantages of external loop recorders are limited memory storage, a considerable reliance on patient activation of the device, and wires and electrodes that need to be worn continuously.

What is their best use? External loop recorders are most effective when used to detect an arrhythmia or to correlate infrequent symptoms with an arrhythmia. They are most appropriately used in patients whose symptoms occur more often than every 4 weeks. They are less useful in assessing very infrequent symptoms, overall arrhythmia burden, or responsiveness to therapy.¹⁰

Implantable loop recorders are small devices that contain a pair of sensing electrodes housed within an outer shell (Figure 1). They are implanted subcutaneously, usually in the left parasternal region, using local anesthesia. The subcutaneous location eliminates many of the drawbacks of the skin-electrode interface of external loop recorders.

Similar to the external loop recorder, this device monitors continuously and can be activated to record either by the patient by pressing a button on a separate device, or automatically when an arrhythmia is detected using a preprogrammed algorithm.

In contrast to external devices, many internal loop recorders have a battery life and monitoring capability of up to 3 years. This extended monitoring period has been shown to increase the likelihood of diagnosing syncope or infrequent palpitations.^11,12 Given that paroxysmal atrial fibrillation can be sporadic and reveal itself months after a stroke, internal loop recorders may also have a role in evaluating cryptogenic stroke.^13,14

The most important drawbacks of internal loop recorders are the surgical procedure for insertion, their limited memory storage, and high upfront cost.¹⁵ Furthermore, even though they allow for extended monitoring, there may be diminishing returns for prolonged observation.

What is their best use? For patients with palpitations, intermittent event monitoring has been shown to be cost-effective for the first 2 weeks, but after 3 weeks, the cost per diagnosis increases dramatically.¹⁶ As a result, internal loop recorders are reserved primarily for scenarios in which prolonged external monitoring has not revealed a source of arrhythmia despite a high degree of suspicion.

Mobile cardiac telemetry

Mobile cardiac telemetry builds on other ECG monitoring systems by adding real-time communication and technician evaluation.

Physically, these devices resemble either hand-held event records, with a single-channel sensing unit embedded in the case, or a traditional Holter monitor, with 3 channels, wires, and electrodes  (Figure 1).

The sensor wirelessly communicates with a nearby portable monitor, which continuously observes and analyzes the patient’s heart rhythm. When an abnormal rhythm is detected or when the patient marks the presence of symptoms, data are recorded and sent in real time via a cellular network to a monitoring center; the newest monitors can send data via any Wi-Fi system. The rhythm is then either evaluated by a trained technician or relayed to a physician. If necessary, the patient can be contacted immediately.

Mobile cardiac telemetry is typically used for up to 30 days, which  allows for evaluation of less-frequent symptoms. As a result, it may have a higher diagnostic yield for palpitations, syncope, and presyncope than the 24-hour Holter monitor.¹⁷

Further, perhaps because mobile cardiac telemetry relies less on stored information and requires less patient-device interaction than external loop recorders, it is more effective at symptom evaluation.¹⁸

Mobile cardiac telemetry also has a diagnostic role in evaluating patients with cryptogenic stroke. This is based on studies showing it has a high rate of atrial fibrillation detection in this patient population and is more effective at determining overall atrial fibrillation burden than loop recorders.^18,19

What is its best use? The key advantage of mobile cardiac telemetry is its ability to make rhythm assessments and communicate with technicians in real time. This allows high-risk patients to be immediately alerted to a life-threatening arrhythmia. It also gives providers an opportunity to initiate anticoagulation or titrate antiarrhythmic therapy in the outpatient setting without a delay in obtaining information. This intensive monitoring, however, requires significant manpower, which translates to higher cost, averaging 3 times that of other standard external monitors.¹⁵

Patch monitors

These ultraportable devices are a relatively unobtrusive and easy-to-use alternative for short-term ambulatory ECG monitoring. They monitor continuously with full disclosure, outpatient telemetry, and post-event recording features.

Patch monitors are small, leadless, wireless, and water-resistant (Figure 1). They are affixed to the left pectoral region with a waterproof adhesive and can be worn for 14 to 28 days. Recording is usually done continuously; however, these devices have an event marker button that can be pressed when the user experiences symptoms. They acquire a single channel of data, and each manufacturer has a proprietary algorithm for automated rhythm detection and analysis.²⁰

Several manufacturers produce ECG patch monitors. Two notable devices are the Zio patch (iRhythm Technologies, San Francisco, CA) and the Mobile Cardiac Outpatient Telemetry patch (BioTelemetry, Inc, Malvern, PA).

The Zio patch is a continuous external monitor with full disclosure. It is comparable to the Holter monitor, but has a longer recording period. After completing a 2-week monitoring period, the device is returned for comprehensive rhythm analysis. A typical Zio report contains information on atrial fibrillation burden, ectopic rhythm burden, symptom and rhythm correlation, heart rate trends, and relevant rhythm strips.

The Mobile Cardiac Outpatient Telemetry patch collects data continuously and communicates wirelessly by Bluetooth to send its ECG data to a monitoring center for evaluation.

A principal advantage of patch monitors—and a major selling point for manufacturers—is their low-profile, ergonomic, and patient-friendly design. Patients do not have to manage wires or batteries and are able to shower with their devices. Studies show that these features increase patient satisfaction and compliance, resulting in increased diagnostic yield.^21,22 Additionally, patch monitors have the advantage of a longer continuous monitoring period than traditional Holter devices (2 weeks vs 1 or 2 days), affording an opportunity to capture events that occur less frequently.

Validation studies have reinforced their efficacy and utility in clinical scenarios.^22,23 In large part because of the extended monitoring period, patch monitors have been shown to have greater diagnostic yield than the 24-hour Holter monitor in symptomatic patients undergoing workup for suspected arrhythmia.

The role of patch monitors in evaluating atrial fibrillation is also being established. For patients with cryptogenic stroke, patch monitors have shown better atrial fibrillation detection than the 24-hour Holter monitor.²⁴ Compared with traditional loop monitors, patch monitors have the added advantage of assessing total atrial fibrillation burden. Further, although screening for atrial fibrillation with a traditional 12-lead ECG monitor has not been shown to be effective, clinical studies have found that the patch monitor may be a useful screening tool for high-risk patients.^25,26

Nevertheless, patch monitors have drawbacks. They are not capable of long-term monitoring, owing to battery and adhesive limitations.²⁰ More important, they have  been able to offer only single-channel acquisition, which makes it more difficult to detect an arrhythmia that is characterized by a change in QRS axis or change in QRS width, or to distinguish an arrhythmia from an artifact. This appears to be changing, however, as several manufacturers have recently developed multilead ECG patch monitors or attachments and are attempting to merge this technology with fully capable remote telemetry.

Recent improvements in battery life, memory, detection algorithms, wireless transmission, cellular communication, and adhesives have enabled multiple features to be combined into a single device. Patch monitors, for example, are small devices that now offer full-disclosure recording, extended monitoring, and telemetry transmitting. Automated arrhythmia recognition that triggers recording is central to all modern devices, regardless of type.

As a result of these trends, the traditional features used to differentiate devices may become less applicable. The classic Holter monitor may become obsolete as its advantages (full disclosure, continuous recording) are being incorporated into smaller devices that can record longer. Similarly, external monitors that have the capacity for full disclosure and continuous recording are no longer loop recorders in that they do not record into a circular memory.

It may be preferable to describe all non-Holter devices as event monitors or ambulatory monitors, with the main distinguishing features being the ability to transmit data (telemetry), full disclosure vs patient- or arrhythmia-activated recording, and single-channel or multichannel recording (single-lead or 3-lead ECG).

The following are the main distinguishing features that should influence the choice of device for a given clinical context.

Real-time data evaluation provided by mobile telemetry makes this feature ideal to monitor patients with suspected high-risk arrhythmias and their response to antiarrhythmic therapy.

Full-disclosure recording is necessary to assess the overall burden of an arrhythmia, which is frequently important in making treatment decisions, risk-stratifying, and assessing response to therapy. In contrast, patient- or arrhythmia-activated devices are best used when the goal is simply to establish the presence of an arrhythmia.

Multichannel recording may be better than single-channel recording, as it is needed to determine the anatomic origin of an arrhythmia, as might be the case in risk-stratification in a patient with a ventricular tachycardia.

Long duration. The clinician must have a reasonable estimate of how often the symptoms or arrhythmia occur to determine which device will offer a monitoring duration sufficient to detect an arrhythmia.

NEWER TECHNOLOGIES

The newest ambulatory ECG devices build on the foundational concepts of the older ones. However, with miniaturized electronic circuits, Bluetooth, Wi-Fi, and smartphones, these new devices can capture ECG tracings and diagnose offending arrhythmias on more consumer-friendly devices.

Smartphones and smartwatches have become increasingly powerful. Some have the ability to capture, display, and record the cardiac waveform. One manufacturer to capitalize on these technologies, AliveCor (Mountain View, CA), has developed 2 products capable of generating a single-lead ECG recording using either a smartphone (KardiaMobile) or an Apple watch (KardiaBand).

KardiaMobile has a 2-electrode band that can be carried in a pocket or attached to the back of a smartphone (Figure 1). The user places 1 or 2 fingers from each hand on the electrodes, and the device sends an ultrasound signal that is picked up by the smartphone’s microphone. The signal is digitized to produce a 30-second ECG tracing on the phone’s screen. A proprietary algorithm analyzes the rhythm and generates a description of “normal” or “possible atrial fibrillation.” The ECG is then uploaded to a cloud-based storage system for later access or transmission. KardiaMobile is compatible with both iOS and Android devices.

The KardiaBand is a specialized Apple watch band that has an electrode embedded in it. The user places a thumb on the electrode for 30 seconds, and an ECG tracing is displayed on the watch screen.

The Kardia devices were developed (and advertised) predominantly to assess atrial fibrillation. Studies have validated the accuracy of their algorithm. One study showed that, compared with physician-interpreted ECGs, the algorithm had a 96.6% sensitivity and 94.1% specificity for detecting atrial fibrillation.²⁷ They have been found useful for detecting and evaluating atrial fibrillation in several clinical scenarios, including discharge monitoring in patients after ablation or cardiac surgery.^28,29 In a longer study of patients at risk of stroke, twice-weekly ECG screening using a Kardia device for 1 year was more likely to detect incident atrial fibrillation than routine care alone.³⁰

Also, the Kardia devices can effectively function as post-event recorders when activated by patients when they experience symptoms. In a small study of outpatients with palpitations and a prior nondiagnostic workup, the KardiaMobile device was found to be noninferior to external loop recorders for detecting arrhythmias.³¹ Additional studies are assessing Kardia’s utility in other scenarios, including the evaluation of ST-segment elevation myocardial infarction^32,33 and QT interval for patients receiving antiarrhythmic therapy.³⁴

Cardiio Inc. (Cambridge, MA) has developed technology to screen for atrial fibrillation using an app that requires no additional external hardware. Instead, the app uses a smartphone’s camera and flashlight to perform photo­plethysmography to detect pulsatile changes in blood volume and generate a waveform. Based on waveform variability, a proprietary algorithm attempts to determine whether the user is in atrial fibrillation. It does not produce an ECG tracing. Initial studies suggest it has good diagnostic accuracy and potential utility as a population-based screening tool,^35,36 but it has not been fully validated.

Recently, Apple entered the arena of ambulatory cardiac monitoring with the release of its fourth-generation watch (Apple Watch Series 4 model). This watch has built-in electrodes that can generate a single-lead ECG on the watch screen. Its algorithm can discriminate between atrial fibrillation and sinus rhythm, but it has not been assessed for its ability to evaluate other arrhythmias. Even though it has been “cleared” by the US Food and Drug Administration, it is approved only for informational use, not to make a medical diagnosis.

Integration of ambulatory ECG technology with smartphone and watch technology is an exciting new wearable option for arrhythmia detection. The patient-centered and controlled nature of these devices have the potential to help patients with palpitations or other symptoms determine if their cardiac rhythms are normal.

This technology, however, is still in its infancy and has many limitations. For example, even though these devices can function as post-event recorders, they depend on user-device interactions. Plus, they cannot yet perform continuous arrhythmia monitoring like modern loop recorders.

Additionally, automated analysis has largely been limited to distinguishing atrial fibrillation from normal sinus rhythm. It is uncertain how effective the devices may be in evaluating other arrhythmias. Single-lead ECG recordings, as discussed, have limited interpretability and value. And even though studies have shown utility in certain clinical scenarios, large-scale validation studies are lacking. This technology will likely continue to be developed and its clinical value improved; however, its clinical use requires careful consideration and collaborative physician-patient decision-making.

The development of smartphone and watch ECG technology has led to a rise in direct-to-consumer healthcare delivery. By devising technology that is appealing, useful, and affordable, companies can bypass the insurer and practitioner by targeting increasingly health-literate consumers. For many companies, there is great motivation to enter this healthcare space. Wearable devices are immensely popular and, as a result, generate substantial revenue. One analysis estimates that 1 in 10 Americans (nearly 30 million) owns a wearable, smart-technology device.³⁷

This direct-to-consumer approach has specific implications for cardiology and, more broadly, for healthcare overall. By directly selling to consumers, companies have an opportunity to reach many more people. The Apple Watch Series 4 has taken this a step further: by including this technology in the watch, consumers not necessarily seeking an ambulatory cardiac monitor will have one with a watch purchase. This could lead to increases in monitoring and could alert people to previously undiagnosed disorders.

For consumers, this technology can empower them to choose how and when to be monitored. Further, it gives them personal control of their healthcare data, and helps move the point of care out of hospitals and clinics and into the home.

But wearable medical technology and direct-to-consumer healthcare have risks. First, in the absence of appropriate regulation, patients have to distinguish between products that are well validated and those that are unproven. Consumers also may inappropriately use devices for indications or in scenarios for which the value is uncertain.

Also, there is potential for confusion and misunderstanding of results, including false-positive readings, which could lead to excessive and costly use of unnecessary diagnostic workups. Instead of providing peace of mind, these devices could cause greater worry. This may be especially true with the newest Apple watch, as this product will introduce ambulatory ECG to a younger and healthier segment of the population who are less likely to have true disease.

Further, these devices have algorithms that detect atrial fibrillation, but is it the same as that detected by traditional methods? Sometimes termed “subclinical” atrial fibrillation, it poses uncertainties: ie, Do patients need anticoagulation, pharmacologic therapy, and ablation? The optimal management of subclinical atrial fibrillation, as well as its similarities to and differences from atrial fibrillation diagnosed by traditional methods, are topics that need further study.

Wearable technology is still developing and will continue to do so. Medical practice will have to adapt to it.

FUTURE DIRECTIONS

Changes in technology have led to remarkable advances in the convenience and accuracy of ambulatory ECG monitoring. Ongoing research is expected to lead to even more improvements. Devices will become more ergonomic and technically capable, and they may expand monitoring to include other biologic parameters beyond ECG.

Comfort is important to ensure patient adherence. Newer, flexible electronics embedded in ultrathin materials can potentially improve the wearability of devices that require gel electrodes or adhesive patches.³⁸ Wireless technology may obviate the need for on-skin attachments. Future recording systems may be embedded into clothing or incorporated into wearable vests capable of wirelessly transmitting ECG signals to separate recording stations.³⁹

In addition to becoming smaller and more comfortable, future devices will be more technically capable, leading to a merging of technologies that will further blur the distinctions among devices. Eventually, the features of full disclosure, extended monitoring duration, and telemetric communication will all be present together. Perhaps more important is that ambulatory ECG devices may become fully capable biosensor monitors. These devices would have the potential to monitor respiratory frequency, peripheral oxygen saturation, potassium levels, and arterial pulse pressure.^39,40

In Reply: We thank Dr. Antonios for his comments regarding the current shortcomings of the ICD-9 and ICD-10 coding systems in describing the acute MI types as defined in the universal definition. We share his concern that accurate and consistent coding of MIs may be difficult when the definition of MI changes over a short period of time. Such changes create a disconnect not only between our clinical terminology and coding systems, but also potentially between our conventional sense of a “heart attack” as an acute coronary syndrome or a clinically significant infarction rather than a small troponin elevation from demand ischemia. This has consequences not only for quality measures and reporting, but also for clinical research trials and clinical care. This is exemplified by reports of recent trials that were possibly prematurely discontinued, as the use of troponin thresholds may conflate large MIs with clinically insignificant ones.¹

Recently, the Society for Cardiovascular Angiography and Interventions published a new definition of “clinically relevant” MI after revascularization.² Rather than relying on troponins, which are elevated in as many as 24.3% of uncomplicated percutaneous coronary interventions and in 42% to 82% of uncomplicated coronary artery bypass grafting procedures (based on the 2007 universal definition), they point to extensive literature documenting that only patients with elevated creatine kinase MB more than 10 times the upper limit of normal after revascularization have a worsened prognosis. We favor this clinically relevant MI definition for post-revascularization MI. We also favor the use of creatine kinase MB as a less sensitive but more specific confirmatory marker for acute coronary syndromes (type 1) or clinically significant supply-demand (type 2) MI, when the symptoms or electrocardiographic signs are nondiagnostic, as they often are.³ However, until there is a consensus around a single definition, clinicians are effectively walking around a Tower of Babel and must take care to be specific when documenting an MI.

In Reply: We thank Dr. Antonios for his comments regarding the current shortcomings of the ICD-9 and ICD-10 coding systems in describing the acute MI types as defined in the universal definition. We share his concern that accurate and consistent coding of MIs may be difficult when the definition of MI changes over a short period of time. Such changes create a disconnect not only between our clinical terminology and coding systems, but also potentially between our conventional sense of a “heart attack” as an acute coronary syndrome or a clinically significant infarction rather than a small troponin elevation from demand ischemia. This has consequences not only for quality measures and reporting, but also for clinical research trials and clinical care. This is exemplified by reports of recent trials that were possibly prematurely discontinued, as the use of troponin thresholds may conflate large MIs with clinically insignificant ones.¹

Recently, the Society for Cardiovascular Angiography and Interventions published a new definition of “clinically relevant” MI after revascularization.² Rather than relying on troponins, which are elevated in as many as 24.3% of uncomplicated percutaneous coronary interventions and in 42% to 82% of uncomplicated coronary artery bypass grafting procedures (based on the 2007 universal definition), they point to extensive literature documenting that only patients with elevated creatine kinase MB more than 10 times the upper limit of normal after revascularization have a worsened prognosis. We favor this clinically relevant MI definition for post-revascularization MI. We also favor the use of creatine kinase MB as a less sensitive but more specific confirmatory marker for acute coronary syndromes (type 1) or clinically significant supply-demand (type 2) MI, when the symptoms or electrocardiographic signs are nondiagnostic, as they often are.³ However, until there is a consensus around a single definition, clinicians are effectively walking around a Tower of Babel and must take care to be specific when documenting an MI.

In Reply: We thank Dr. Antonios for his comments regarding the current shortcomings of the ICD-9 and ICD-10 coding systems in describing the acute MI types as defined in the universal definition. We share his concern that accurate and consistent coding of MIs may be difficult when the definition of MI changes over a short period of time. Such changes create a disconnect not only between our clinical terminology and coding systems, but also potentially between our conventional sense of a “heart attack” as an acute coronary syndrome or a clinically significant infarction rather than a small troponin elevation from demand ischemia. This has consequences not only for quality measures and reporting, but also for clinical research trials and clinical care. This is exemplified by reports of recent trials that were possibly prematurely discontinued, as the use of troponin thresholds may conflate large MIs with clinically insignificant ones.¹

Recently, the Society for Cardiovascular Angiography and Interventions published a new definition of “clinically relevant” MI after revascularization.² Rather than relying on troponins, which are elevated in as many as 24.3% of uncomplicated percutaneous coronary interventions and in 42% to 82% of uncomplicated coronary artery bypass grafting procedures (based on the 2007 universal definition), they point to extensive literature documenting that only patients with elevated creatine kinase MB more than 10 times the upper limit of normal after revascularization have a worsened prognosis. We favor this clinically relevant MI definition for post-revascularization MI. We also favor the use of creatine kinase MB as a less sensitive but more specific confirmatory marker for acute coronary syndromes (type 1) or clinically significant supply-demand (type 2) MI, when the symptoms or electrocardiographic signs are nondiagnostic, as they often are.³ However, until there is a consensus around a single definition, clinicians are effectively walking around a Tower of Babel and must take care to be specific when documenting an MI.

In 2012, a task force of the European Society of Cardiology, the American College of Cardiology Foundation, the American Heart Association, and the World Heart Federation released its “third universal definition” of myocardial infarction (MI),¹ replacing the previous (2007) definition. The new consensus definition reflects the increasing sensitivity of available troponin assays, which are commonly elevated in other conditions and after uncomplicated percutaneous coronary intervention or cardiac surgery. With a more appropriate definition of the troponin threshold after these procedures, benign myocardial injury can be differentiated from pathologic MI.

TROPONINS: THE PREFERRED MARKERS

Symptoms of MI such as nausea, chest pain, epigastric discomfort, syncope, and diaphoresis may be nonspecific, and findings on electrocardiography or imaging studies may be nondiagnostic. We thus rely on biomarker elevations to identify patients who need treatment.

Cardiac troponin I and cardiac troponin T have become the preferred markers for detecting MI, as they are more sensitive and tissue-specific than their main competitor, the MB fraction of creatine kinase (CK-MB).² But the newer troponin assays, which are even more sensitive than earlier ones, have raised concerns about their ability to differentiate patients who truly have acute coronary syndromes from those with other causes of troponin elevation. This can have major effects on treatment, patient psyche, and hospital costs.

Troponin elevations can occur in patients with heart failure, end-stage renal disease, sepsis, acute pulmonary embolism, myopericarditis, arrhythmias, and many other conditions. As noted by the task force, these cases of elevated troponin in the absence of clinical supportive evidence should not be labeled as an MI but rather as myocardial injury.

Troponins bind actin and myosin filaments in a trimeric complex composed of troponins I, C, and T. Troponins are present in all muscle cells, but the cardiac isoforms are specific to myocardial tissue.

As a result, both cardiac troponin I and cardiac troponin T, as measured by fourth-generation assays, are highly sensitive (75.2%, 95% confidence interval [CI] 66.8%–83.4%) and specific (94.6%, 95% CI 93.4%–96.3%) for detecting pathologic processes involving the heart.^3,4 Nonetheless, increases in cardiac troponin T (but not I) have been documented in patients with disease of skeletal muscles, likely secondary to re-expressed isoforms of the troponin C gene present in both cardiac and skeletal myocytes.³ There has been no evidence to suggest that either cardiac troponin I nor cardiac troponin T is superior to the other as a marker of MI.

Serum troponin levels detectably rise by 2 to 3 hours after myocardial injury. This temporal pattern is similar to that of CK-MB, which rises at about 2 hours and reaches a peak in 4 to 6 hours. However, troponins are more sensitive than CK-MB during this early time period, since a greater proportion is released from the heart during times of cardiac injury.

The definition of an abnormal troponin value is set by the precision of each individual assay. The task force has designated the optimal precision for troponin assays to be at a coefficient of variation of less than 10% when describing a value exceeding the 99th percentile in a reference population. The 99th percentile, which is the upper reference limit, corresponds to a value near 0.035 μg/L for fourth-generation troponin I and troponin T assays.⁵ Most assays have been adapted to ensure that they meet such criteria.

High-sensitivity assays

Over the past few years, “high-sensitivity” assays have been developed that can detect nanogram levels of troponin.

In one study, an algorithm that incorporated high-sensitivity cardiac troponin T levels was able to rule in or rule out acute MI in 77% of patients with chest pain within 1 hour.⁶ The algorithm had a sensitivity and negative predictive value of 100%.

Other studies have shown a sensitivity of 100.0%, a specificity of 34.0%, and a negative predictive value of 100.0% when using a cardiac troponin T cutoff of 3 ng/L, while a cutoff of 14 ng/L yielded a sensitivity of 85.4%, a specificity of 82.4%, and a negative predictive value of 96.1%.⁴ With cutoffs as low as 3 ng/L, some assays detect elevated troponin in up to 90% of people in normal reference populations without MI.⁷

Physicians thus need to be aware that high-sensitivity troponin assays should mainly be used to rule out acute coronary syndrome, as their high sensitivity substantially compromises their specificity. The appropriate thresholds for various patient populations, the appropriate testing procedures with high-sensitivity assays as compared with the fourth-generation troponin assays (ie, frequency of testing, change in level, and rise), and the cost and clinical outcomes of care based on algorithms that use these values remain unclear and will require further study.^8,9

TYPES OF MYOCARDIAL INFARCTION

The task force defines the following categories of MI (Table 1):

Type 1: Spontaneous myocardial infarction

Type 1, or “spontaneous” MI, is an acute coronary syndrome, colloquially called a “heart attack.” It is primarily the result of rupture, fissuring, erosion, or dissection of atherosclerotic plaque. Most are the result of underlying atherosclerotic coronary artery disease, although some (ie, those caused by coronary dissection) are not.

To diagnose type 1 MI, a blood sample must detect a rise or fall (or both) of cardiac biomarker values (preferably cardiac troponin), with at least one value above the 99th percentile. However, an elevated troponin level is not sufficient. At least one of the following criteria must also be met:

• Symptoms of ischemia
• New ST-segment or T-wave changes or new left bundle branch block
• Development of pathologic Q waves
• Imaging evidence of new loss of viable myocardium or new wall-motion abnormality
• Finding of an intracoronary thrombus by angiography or autopsy.

Type 1 MI therapy requires antithrombotic drugs and, with the additional findings, revascularization.

Type 2 MI is caused by a supply-demand imbalance in myocardial perfusion, resulting in ischemic damage. This specifically excludes acute coronary thrombosis, but can result from marked changes in demand or supply (eg, sepsis) or from a combination of acute changes and chronic conditions (eg, tachycardia with baseline coronary artery disease). Baseline stable coronary artery disease, left ventricular hypertrophy, endothelial dysfunction, coronary artery spasm, coronary embolism, arrhythmias, anemia, respiratory failure, hypotension, and hypertension can all contribute to a supply-demand mismatch sufficient to cause permanent myocardial damage.

The criteria for diagnosing type 2 MI are the same as for type 1: both elevated troponin levels and one of the clinical criteria (symptoms of ischemia, electrocardiographic changes, new wall-motion abnormality, or intracoronary thrombus) must be present.

Of importance, unlike those with type 1 MI, most patients with type 2 MI are unlikely to immediately benefit from antithrombotic therapy, as they typically have no acute thrombosis (except in cases of coronary embolism). Therapy should instead be directed at the underlying supply-demand imbalance and may include volume resuscitation, blood pressure support or control, or control of tachyarrhythmias.

In the long term, treatment to resolve or prevent supply-demand imbalances may also include revascularization or antithrombotic drugs, but these may be contraindicated in the acute setting.

Type 3: Sudden cardiac death from MI

The third type of MI occurs when myocardial ischemia results in sudden cardiac death before blood samples can be obtained. Before dying, the patient should have had symptoms suggesting myocardial ischemia and should have had presumed new ischemic electrocardiographic changes or new left bundle branch block.

This definition of MI is not very useful clinically but is important for population-based research studies.

Type 4a: Due to percutaneous coronary intervention

A rise in CK-MB levels after percutaneous coronary intervention has been associated with a higher rate of death or recurrent MI.¹⁰ Previously, type 4 MI was defined as an elevation of cardiac biomarker values (> 3 times the 99th percentile) after percutaneous coronary intervention in a patient who had a normal baseline value (< 99th percentile).¹¹

Unfortunately, using troponin at this threshold, the number of cases is five times higher than when CK-MB is used, without a consistent correlation with the outcomes of death or complications.¹² Currently, the increase in cardiac troponin after percutaneous coronary intervention is best interpreted as a marker of the patient’s atherothrombotic burden more than as a predictor of adverse outcomes.¹³

The updated definition of MI associated with percutaneous coronary intervention now requires an elevation of cardiac troponin values greater than 5 times the 99th percentile in a patient who had normal baseline values or an increase of more than 20% from baseline within 48 hours of the procedure. As this value has been arbitrarily assigned rather than based on an established threshold with clinical outcomes, a true MI must further meet one of the following criteria:

• Symptoms suggesting myocardial ischemia
• New ischemic electrocardiographic changes or new left bundle branch block
• Angiographic loss of patency of a major coronary artery or a side branch or persistent slow-flow or no-flow or embolization
• Imaging evidence of a new loss of viable myocardium or a new wall-motion abnormality.

Given that troponin levels may be elevated in up to 65% of patients after uncomplicated percutaneous coronary intervention and this elevation may be unavoidable,¹⁴ a higher troponin threshold to diagnose MI and the clear requirement of clinical correlates may resonate with physicians as a more appropriate definition. In turn, such guidelines may better identify those with an adverse event, while partly reducing unnecessary hospitalization and observation time in those for whom it is not necessary.

Type 4b: Due to stent thrombosis

Type 4b MI is MI caused by stent thrombosis. The thrombosis must be detected by coronary angiography or autopsy in the setting of myocardial ischemia and a rise or fall of cardiac biomarker values, with at least one value above the 99th percentile.

Type 4c: Due to restenosis

Proposed is the addition of type 4c MI, ie, MI resulting from restenosis of more than 50%, because restenosis after percutaneous coronary intervention can lead to MI without thrombosis.¹⁵

Type 5: After coronary artery bypass grafting

Similar to the situation after percutaneous coronary intervention, increased CK-MB levels after coronary artery bypass graft surgery are associated with poor outcomes.¹⁶ Although some studies have indicated that increased troponin levels within 24 hours of this surgery are associated with higher death rates, no study has established a troponin threshold that correlates with outcomes.¹⁷

The task force acknowledged this lack of prognostic value but arbitrarily defined type 5 MI as requiring biomarker elevations greater than 10 times the 99th percentile during the first 48 hours after surgery, with a normal baseline value. One of the following additional criteria must also be met:

• New pathologic Q waves or new left bundle branch block
• Angiographically documented new occlusion in the graft or native coronary artery
• Imaging evidence of new loss of viable myocardium or new wall-motion abnormality.

CHANGES FROM THE 2007 DEFINITIONS

Updates to the definitions of the MI types since the 2007 task force definition can be found in Table 1.

In type 1 and 2 MI, the finding of an intracoronary thrombus by angiography or autopsy was added as one of the possible criteria for evidence of myocardial ischemia.

In type 3 MI, the definition was simplified by deleting the former criterion of finding a fresh thrombus by angiography or autopsy.

In type 4a MI, by requiring clinical correlates, the updated definition in particular moves away from relying solely on troponin levels to diagnose an infarction after percutaneous coronary intervention, as was the case in 2007. Other changes from the 2007 definition: the troponin MI threshold was previously 3 times the 99th percentile, now it is 5 times. Also, if the patient had an elevated baseline value, he or she can now still qualify as having an MI if the level increases by more than 20%.

In type 5 MI, changes to the definition similarly reflect the need to address overly sensitive troponin values when diagnosing an MI after coronary artery bypass grafting. To address such concerns, the required cardiac biomarker values were increased from more than 5 to more than 10 times the 99th percentile.

The task force raised the troponin thresholds for type 4 and type 5 MI in response to evidence showing that troponins are excessively sensitive to minimal myocardial damage during revascularization, and the lack of a troponin threshold that correlates with clinical outcomes.¹² Although higher, these values remain arbitrary, so physicians will need to exercise clinical judgment when deciding whether patients are experiencing benign myocardial injury or rather a true MI after revascularization procedures.

OTHER CONDITIONS THAT RAISE TROPONIN LEVELS

As troponin is a marker not only for MI but also for any form of cardiac injury, its levels are elevated in numerous conditions, such as heart failure, renal failure, and left ventricular hypertrophy. The task force identifies distinct troponin elevations above basal levels as the best indication of new pathology, yet several conditions other than acute coronary syndromes can also cause dynamic changes in troponin levels.

Troponin is a sensitive marker for ruling out MI and has tissue specificity for cardiac injury, but it is not specific for acute coronary syndrome as the cause of such injury. Troponin assays were tested and validated in patients in whom there was a high clinical suspicion of acute coronary syndrome, but when ordered indiscriminately, they have a poor positive predictive value (53%) for this disorder.¹⁸

Physicians must distinguish between acute coronary syndrome and other causes when deciding to give antithrombotics. Table 2 lists common causes of increased troponin other than acute coronary syndrome.

Heart failure

Some patients with acute congestive heart failure have elevated troponin levels. In one study, 6.2% of such patients had troponin I levels of 1 μg/L or higher or troponin T levels of 0.1 μg/L or higher, and these patients had poorer outcomes and more severe symptoms.¹⁹ Levels can also be elevated in patients with chronic heart failure, in whom they correlate with impaired hemodynamics, progressive ventricular dysfunction, and death.²⁰ In an overview of two large trials of patients with chronic congestive heart failure, 86% and 98% tested positive for cardiac troponin using high-sensitivity assays.²¹

Troponin levels can rise from baseline and subsequently fall in congestive heart failure due to small amounts of myocardial injury, which may be very difficult to distinguish from MI based on the similar presenting symptoms of dyspnea and chest pressure.^1,22 The increased troponin levels in chronic congestive heart failure may reflect apoptosis secondary to wall stretch or direct cell toxicity by neurohormones, alcohol, chemotherapy agents, or infiltrative disorders.^23–26

End-stage renal disease

Troponin levels are increased in end-stage renal disease, with 25% to 75% of patients having elevated levels using currently available assays.^27–29 With the advent of high-sensitivity assays, however, cardiac troponin T levels higher than the 99th percentile are found in 100% of patients who have end-stage renal disease without cardiac symptoms.³⁰

Troponin values above the 99th percentile are therefore not diagnostic of MI in this population. Rather, a diagnosis of MI in patients with end-stage renal disease requires clinical signs and symptoms and serial changes in troponin levels from baseline levels. The task force and the National Academy of Clinical Biochemistry recommend requiring an elevation of more than 20% from baseline, representing a change in troponin of more than 3 standard deviations.³¹

Increases in troponin in renal failure are thought to be the result of chronic cardiac structural changes such as coronary artery disease, left ventricular hypertrophy, and elevated left ventricular end-diastolic pressure, rather than decreased clearance.^32,33

In stable patients with end-stage renal disease, those who have high levels of cardiac troponin T have a higher mortality rate.³⁴ Although the mechanism is not completely clear, decreased clearance of uremic toxins may contribute to myocardial damage beyond that of the cardiac structural changes.³⁴

Sepsis

Approximately 50% of patients admitted to an intensive care unit with sepsis without acute coronary syndrome have elevated troponin levels.³⁵

Elevated troponin in sepsis patients has been associated with left ventricular dysfunction, most likely from hemodynamic stress, direct cytotoxicity of bacterial endotoxins, and reperfusion injury.^35,36 Critical illness places high demands on the myocardium, while oxygen supply may be diminished by hypotension, pulmonary edema, and intravascular volume depletion. This supply-demand mismatch is similar to the physiology of type 2 MI, with clinical signs and symptoms of MI potentially being the only differentiating factor.

Elevated troponin levels may represent either reversible or irreversible myocardial injury in patients with sepsis and are a predictor of severe illness and death.³⁷ However, what to do about elevated troponin in patients with sepsis is not clear. When patients are in the intensive care unit with single-organ or multi-organ failure, the diagnosis and treatment of troponin elevations may not take priority.¹ Diagnosing MI is further complicated by the inability of critically ill patients to communicate signs and symptoms. Physicians should also remember that diagnostic testing (electrocardiography, echocardiography) is often necessary to meet the clinical criteria for a type 1 or 2 MI in critically ill patients, and that treatment options may be limited.

Pulmonary embolism

Pulmonary embolism is a leading noncardiac cause of troponin elevation in patients in whom the clinical suspicion of acute coronary syndrome is initially high.³⁸ It is thought that increased troponin levels in patients with pulmonary embolism are caused by increased right ventricular strain secondary to increased pulmonary artery resistance.

The signs and symptoms of MI and of pulmonary embolism overlap, and troponin can be elevated in both conditions, making the initial diagnosis difficult. Electrocardiography and early bedside echocardiography can identify the predominant right-sided dilatation and strain in the heart secondary to pulmonary embolism. Computed tomography should be performed if there is even a moderate clinical suspicion of pulmonary embolism.

The appropriate use of thrombolytics in a normotensive patient with pulmonary embolism remains controversial. The significant risks of hemorrhage need to be balanced with the risk of hemodynamic deterioration. For these patients, the combination of cardiac troponin I measurement and echocardiography provides more prognostic information than each does individually.³⁹ Troponin elevation may therefore be a marker for poor outcomes without aggressive treatment with thrombolytics.

However, single troponin measurements in patients hospitalized early with pulmonary embolism can lead to substantial risk of misdiagnosing them with MI. Although the intensity of the peak is not particularly useful in the setting of pulmonary embolism, two consecutive troponin values 8 hours apart will allow for more appropriate risk stratification for pulmonary embolism patients, who may have a delay between right heart injury and troponin release.⁴⁰

It is reasonable to expect that myocarditis—inflammation of the myocardium—would cause release of troponin from myocytes.⁴¹ Interestingly, however, troponin levels can also be elevated in pericarditis.⁴² The reasons are not clear but have been hypothesized as being caused by nonspecific inflammation during pericarditis that also includes the superficial myocardium—hence, “myopericarditis.”

We have only limited data on the outcomes of patients who have pericarditis with troponin elevation, but troponin levels did correlate with an adverse prognosis in one study.⁴³

Arrhythmias

A number of arrhythmias have been associated with elevated troponin levels. Some studies have shown arrhythmias to be the most common cause of high troponin levels in patients who are not experiencing an acute coronary syndrome.^44,45

The reasons proposed for increased troponins in tachyarrhythmia are similar to those in other conditions of oxygen supply-demand mismatch.⁴⁶ Tachycardia alone may lead to troponin release in the absence of myodepressive factors, inflammatory mediators, or coronary artery disease.⁴⁶

Studies have provided only mixed data as to whether troponin levels predict newonset arrhythmias or recurrence of arrhythmias.^47,48 Nonetheless, elevated troponin (≥ 0.040 μg/L) in patients with atrial fibrillation has independently correlated with increased risk of stroke or systemic embolism, death, and other cardiovascular events. This is clinically important, as troponin elevations higher than these levels adds prognostic information to that given by the CHADS2 stroke score (congestive heart failure, hypertension, age ≥ 75 years diabetes mellitus, and prior stroke or transient ischemic attack) and thus can inform appropriate anticoagulation therapy.⁴⁹

USE OF TROPONIN VALUES

Troponins are highly sensitive assays with high tissue specificity for myocardial injury, but levels can be elevated in non-MI conditions and in MIs other than type 1. As with any diagnostic test applied to a population with a low prevalence of the disease, troponin elevation has a low positive predictive value—53% for acute coronary syndrome.¹⁸

Unfortunately, in clinical practice, troponins are measured in up to 50% of admitted patients, a small proportion of whom have clinical signs or symptoms of MI.⁵⁰ Often, clinicians are left with a positive troponin of unknown significance, potentially leading to unnecessary diagnostic testing that detracts from the primary diagnosis.

Dynamic changes in troponin values (eg, a change of more than 20% in a patient with end-stage renal disease) are helpful in distinguishing acute from chronic causes of troponin elevation. However, such changes can also occur with acute or chronic congestive heart failure, tachycardia, hypotension, or other conditions other than acute coronary syndrome.

The absolute numerical value of troponin can help assess the significance of troponin elevation. In most non-MI and non-acute coronary syndrome causes of troponin elevation, the troponin level tends to be lower than 1 μg/mL (Figure 1). Occasional exceptions occur, especially when multiple conditions coexist (end-stage renal disease and congestive heart failure, for example). In contrast, most patients with acute coronary syndromes have either clear symptoms or electrocardiographic changes consistent with MI and a troponin that rises above 0.5 μg/mL.

The task force discourages the use of secondary thresholds for MI, as there is no level of troponin that is considered benign. While any troponin elevation carries a negative prognosis, such prognostic knowledge may not be particularly helpful in deciding whether to anticoagulate patients or attempt revascularization procedures.

We thus recommend using a threshold higher than the 99th percentile to distinguish acute coronary syndromes from other causes of troponin elevations. The particular threshold for decision-making should vary, depending on how strongly one clinically suspects an acute coronary syndrome. For instance, a cardiac troponin I level of 0.2 μg/mL in an otherwise healthy patient with chest pain and ST-segment depression is more than sufficient to diagnose acute coronary syndrome. In contrast, an end-stage renal disease patient with hypertensive cardiomyopathy who presents only with nausea should have a level markedly higher than his or her baseline value (and likely > 0.8 μg/mL) before acute coronary syndrome should be diagnosed.

CK-MB’S ROLE IN THE TROPONIN ERA

Some proponents of troponin assays, including those on the task force, have suggested that CK-MB may no longer be necessary in the evaluation of acute MI.⁵¹ In the past, CK-MB had more research supporting its use in quantifying myocardial damage and in diagnosing reinfarction, but some data suggest that troponin may be equally useful for these applications.^52,53

These comments aside, CK-MB measurements are still widely ordered with troponin, a probable response to the clinical difficulty of determining the cause and significance of troponin elevations. Although likely less common with recent assays, a small subgroup of patients with acute coronary syndrome will be CK-MB–positive and troponin-negative and at higher risk of morbidity and death than those who are troponin- and CK-MB–negative.^54,55

Troponin levels are elevated in many chronic conditions, whereas CK-MB levels may be unaffected or less affected. In some cases, such as congestive heart failure or renal failure, troponins may be both chronically elevated and more than 20% higher than at baseline. In a clinical context in which a false-positive troponin assay is likely, the addition of a CK-MB assay may help determine if a rise (and possibly a subsequent fall) in the troponin level represents true MI. More importantly, deciding on antithrombotic therapy or revascularization is often based on whether a patient has acute coronary syndrome, rather than a small MI from demand ischemia. CK-MB may thus serve as a less sensitive but more specific marker for the larger amount of myocardial damage that one might expect from an acute coronary syndrome.

CK-MB testing also may help determine the acuity of an acute coronary syndrome for patients with known causes of increased troponin. A negative CK-MB value in the presence of a troponin value elevated above baseline could indicate an event a few days prior.

Finally, the approach of ordering both troponin and CK-MB may be particularly helpful in diagnosing type 4 and 5 MIs, as current guidelines suggest that more research is needed to determine whether current troponin thresholds lead to clinical outcomes.

CLINICAL JUDGMENT IS NECESSARY

The updated definition raises the biomarker threshold required to diagnose MI after revascularization procedures and reemphasizes the need to look for other signs of infarction. This change reflects the sometimes excessive sensitivity of troponin assays for minimal and often unavoidable myocardial damage that occurs in numerous conditions.

With sensitive troponin assays, clinical judgment is essential for separating true MI from myocardial injury, and acute coronary syndrome from demand ischemia. Clinicians will now be forced to be cognizant of their suspicion for acute coronary syndrome in the presence of multiple noncoronary causes of increased troponin with little practical guideline guidance. In settings in which troponin elevation is expected (eg, congestive heart failure, end-stage renal failure, shock), a higher cardiac troponin threshold or CK-MB may be useful as a less sensitive but more specific marker of significant myocardial damage requiring aggressive treatment.

In 2012, a task force of the European Society of Cardiology, the American College of Cardiology Foundation, the American Heart Association, and the World Heart Federation released its “third universal definition” of myocardial infarction (MI),¹ replacing the previous (2007) definition. The new consensus definition reflects the increasing sensitivity of available troponin assays, which are commonly elevated in other conditions and after uncomplicated percutaneous coronary intervention or cardiac surgery. With a more appropriate definition of the troponin threshold after these procedures, benign myocardial injury can be differentiated from pathologic MI.

TROPONINS: THE PREFERRED MARKERS

Symptoms of MI such as nausea, chest pain, epigastric discomfort, syncope, and diaphoresis may be nonspecific, and findings on electrocardiography or imaging studies may be nondiagnostic. We thus rely on biomarker elevations to identify patients who need treatment.

Cardiac troponin I and cardiac troponin T have become the preferred markers for detecting MI, as they are more sensitive and tissue-specific than their main competitor, the MB fraction of creatine kinase (CK-MB).² But the newer troponin assays, which are even more sensitive than earlier ones, have raised concerns about their ability to differentiate patients who truly have acute coronary syndromes from those with other causes of troponin elevation. This can have major effects on treatment, patient psyche, and hospital costs.

Troponin elevations can occur in patients with heart failure, end-stage renal disease, sepsis, acute pulmonary embolism, myopericarditis, arrhythmias, and many other conditions. As noted by the task force, these cases of elevated troponin in the absence of clinical supportive evidence should not be labeled as an MI but rather as myocardial injury.

Troponins bind actin and myosin filaments in a trimeric complex composed of troponins I, C, and T. Troponins are present in all muscle cells, but the cardiac isoforms are specific to myocardial tissue.

As a result, both cardiac troponin I and cardiac troponin T, as measured by fourth-generation assays, are highly sensitive (75.2%, 95% confidence interval [CI] 66.8%–83.4%) and specific (94.6%, 95% CI 93.4%–96.3%) for detecting pathologic processes involving the heart.^3,4 Nonetheless, increases in cardiac troponin T (but not I) have been documented in patients with disease of skeletal muscles, likely secondary to re-expressed isoforms of the troponin C gene present in both cardiac and skeletal myocytes.³ There has been no evidence to suggest that either cardiac troponin I nor cardiac troponin T is superior to the other as a marker of MI.

Serum troponin levels detectably rise by 2 to 3 hours after myocardial injury. This temporal pattern is similar to that of CK-MB, which rises at about 2 hours and reaches a peak in 4 to 6 hours. However, troponins are more sensitive than CK-MB during this early time period, since a greater proportion is released from the heart during times of cardiac injury.

The definition of an abnormal troponin value is set by the precision of each individual assay. The task force has designated the optimal precision for troponin assays to be at a coefficient of variation of less than 10% when describing a value exceeding the 99th percentile in a reference population. The 99th percentile, which is the upper reference limit, corresponds to a value near 0.035 μg/L for fourth-generation troponin I and troponin T assays.⁵ Most assays have been adapted to ensure that they meet such criteria.

High-sensitivity assays

Over the past few years, “high-sensitivity” assays have been developed that can detect nanogram levels of troponin.

In one study, an algorithm that incorporated high-sensitivity cardiac troponin T levels was able to rule in or rule out acute MI in 77% of patients with chest pain within 1 hour.⁶ The algorithm had a sensitivity and negative predictive value of 100%.

Other studies have shown a sensitivity of 100.0%, a specificity of 34.0%, and a negative predictive value of 100.0% when using a cardiac troponin T cutoff of 3 ng/L, while a cutoff of 14 ng/L yielded a sensitivity of 85.4%, a specificity of 82.4%, and a negative predictive value of 96.1%.⁴ With cutoffs as low as 3 ng/L, some assays detect elevated troponin in up to 90% of people in normal reference populations without MI.⁷

Physicians thus need to be aware that high-sensitivity troponin assays should mainly be used to rule out acute coronary syndrome, as their high sensitivity substantially compromises their specificity. The appropriate thresholds for various patient populations, the appropriate testing procedures with high-sensitivity assays as compared with the fourth-generation troponin assays (ie, frequency of testing, change in level, and rise), and the cost and clinical outcomes of care based on algorithms that use these values remain unclear and will require further study.^8,9

TYPES OF MYOCARDIAL INFARCTION

The task force defines the following categories of MI (Table 1):

Type 1: Spontaneous myocardial infarction

Type 1, or “spontaneous” MI, is an acute coronary syndrome, colloquially called a “heart attack.” It is primarily the result of rupture, fissuring, erosion, or dissection of atherosclerotic plaque. Most are the result of underlying atherosclerotic coronary artery disease, although some (ie, those caused by coronary dissection) are not.

To diagnose type 1 MI, a blood sample must detect a rise or fall (or both) of cardiac biomarker values (preferably cardiac troponin), with at least one value above the 99th percentile. However, an elevated troponin level is not sufficient. At least one of the following criteria must also be met:

• Symptoms of ischemia
• New ST-segment or T-wave changes or new left bundle branch block
• Development of pathologic Q waves
• Imaging evidence of new loss of viable myocardium or new wall-motion abnormality
• Finding of an intracoronary thrombus by angiography or autopsy.

Type 1 MI therapy requires antithrombotic drugs and, with the additional findings, revascularization.

Type 2 MI is caused by a supply-demand imbalance in myocardial perfusion, resulting in ischemic damage. This specifically excludes acute coronary thrombosis, but can result from marked changes in demand or supply (eg, sepsis) or from a combination of acute changes and chronic conditions (eg, tachycardia with baseline coronary artery disease). Baseline stable coronary artery disease, left ventricular hypertrophy, endothelial dysfunction, coronary artery spasm, coronary embolism, arrhythmias, anemia, respiratory failure, hypotension, and hypertension can all contribute to a supply-demand mismatch sufficient to cause permanent myocardial damage.

The criteria for diagnosing type 2 MI are the same as for type 1: both elevated troponin levels and one of the clinical criteria (symptoms of ischemia, electrocardiographic changes, new wall-motion abnormality, or intracoronary thrombus) must be present.

Of importance, unlike those with type 1 MI, most patients with type 2 MI are unlikely to immediately benefit from antithrombotic therapy, as they typically have no acute thrombosis (except in cases of coronary embolism). Therapy should instead be directed at the underlying supply-demand imbalance and may include volume resuscitation, blood pressure support or control, or control of tachyarrhythmias.

In the long term, treatment to resolve or prevent supply-demand imbalances may also include revascularization or antithrombotic drugs, but these may be contraindicated in the acute setting.

Type 3: Sudden cardiac death from MI

The third type of MI occurs when myocardial ischemia results in sudden cardiac death before blood samples can be obtained. Before dying, the patient should have had symptoms suggesting myocardial ischemia and should have had presumed new ischemic electrocardiographic changes or new left bundle branch block.

This definition of MI is not very useful clinically but is important for population-based research studies.

Type 4a: Due to percutaneous coronary intervention

A rise in CK-MB levels after percutaneous coronary intervention has been associated with a higher rate of death or recurrent MI.¹⁰ Previously, type 4 MI was defined as an elevation of cardiac biomarker values (> 3 times the 99th percentile) after percutaneous coronary intervention in a patient who had a normal baseline value (< 99th percentile).¹¹

Unfortunately, using troponin at this threshold, the number of cases is five times higher than when CK-MB is used, without a consistent correlation with the outcomes of death or complications.¹² Currently, the increase in cardiac troponin after percutaneous coronary intervention is best interpreted as a marker of the patient’s atherothrombotic burden more than as a predictor of adverse outcomes.¹³

The updated definition of MI associated with percutaneous coronary intervention now requires an elevation of cardiac troponin values greater than 5 times the 99th percentile in a patient who had normal baseline values or an increase of more than 20% from baseline within 48 hours of the procedure. As this value has been arbitrarily assigned rather than based on an established threshold with clinical outcomes, a true MI must further meet one of the following criteria:

• Symptoms suggesting myocardial ischemia
• New ischemic electrocardiographic changes or new left bundle branch block
• Angiographic loss of patency of a major coronary artery or a side branch or persistent slow-flow or no-flow or embolization
• Imaging evidence of a new loss of viable myocardium or a new wall-motion abnormality.

Given that troponin levels may be elevated in up to 65% of patients after uncomplicated percutaneous coronary intervention and this elevation may be unavoidable,¹⁴ a higher troponin threshold to diagnose MI and the clear requirement of clinical correlates may resonate with physicians as a more appropriate definition. In turn, such guidelines may better identify those with an adverse event, while partly reducing unnecessary hospitalization and observation time in those for whom it is not necessary.

Type 4b: Due to stent thrombosis

Type 4b MI is MI caused by stent thrombosis. The thrombosis must be detected by coronary angiography or autopsy in the setting of myocardial ischemia and a rise or fall of cardiac biomarker values, with at least one value above the 99th percentile.

Type 4c: Due to restenosis

Proposed is the addition of type 4c MI, ie, MI resulting from restenosis of more than 50%, because restenosis after percutaneous coronary intervention can lead to MI without thrombosis.¹⁵

Type 5: After coronary artery bypass grafting

Similar to the situation after percutaneous coronary intervention, increased CK-MB levels after coronary artery bypass graft surgery are associated with poor outcomes.¹⁶ Although some studies have indicated that increased troponin levels within 24 hours of this surgery are associated with higher death rates, no study has established a troponin threshold that correlates with outcomes.¹⁷

The task force acknowledged this lack of prognostic value but arbitrarily defined type 5 MI as requiring biomarker elevations greater than 10 times the 99th percentile during the first 48 hours after surgery, with a normal baseline value. One of the following additional criteria must also be met:

• New pathologic Q waves or new left bundle branch block
• Angiographically documented new occlusion in the graft or native coronary artery
• Imaging evidence of new loss of viable myocardium or new wall-motion abnormality.

CHANGES FROM THE 2007 DEFINITIONS

Updates to the definitions of the MI types since the 2007 task force definition can be found in Table 1.

In type 1 and 2 MI, the finding of an intracoronary thrombus by angiography or autopsy was added as one of the possible criteria for evidence of myocardial ischemia.

In type 3 MI, the definition was simplified by deleting the former criterion of finding a fresh thrombus by angiography or autopsy.

In type 4a MI, by requiring clinical correlates, the updated definition in particular moves away from relying solely on troponin levels to diagnose an infarction after percutaneous coronary intervention, as was the case in 2007. Other changes from the 2007 definition: the troponin MI threshold was previously 3 times the 99th percentile, now it is 5 times. Also, if the patient had an elevated baseline value, he or she can now still qualify as having an MI if the level increases by more than 20%.

In type 5 MI, changes to the definition similarly reflect the need to address overly sensitive troponin values when diagnosing an MI after coronary artery bypass grafting. To address such concerns, the required cardiac biomarker values were increased from more than 5 to more than 10 times the 99th percentile.

The task force raised the troponin thresholds for type 4 and type 5 MI in response to evidence showing that troponins are excessively sensitive to minimal myocardial damage during revascularization, and the lack of a troponin threshold that correlates with clinical outcomes.¹² Although higher, these values remain arbitrary, so physicians will need to exercise clinical judgment when deciding whether patients are experiencing benign myocardial injury or rather a true MI after revascularization procedures.

OTHER CONDITIONS THAT RAISE TROPONIN LEVELS

As troponin is a marker not only for MI but also for any form of cardiac injury, its levels are elevated in numerous conditions, such as heart failure, renal failure, and left ventricular hypertrophy. The task force identifies distinct troponin elevations above basal levels as the best indication of new pathology, yet several conditions other than acute coronary syndromes can also cause dynamic changes in troponin levels.

Troponin is a sensitive marker for ruling out MI and has tissue specificity for cardiac injury, but it is not specific for acute coronary syndrome as the cause of such injury. Troponin assays were tested and validated in patients in whom there was a high clinical suspicion of acute coronary syndrome, but when ordered indiscriminately, they have a poor positive predictive value (53%) for this disorder.¹⁸

Physicians must distinguish between acute coronary syndrome and other causes when deciding to give antithrombotics. Table 2 lists common causes of increased troponin other than acute coronary syndrome.

Heart failure

Some patients with acute congestive heart failure have elevated troponin levels. In one study, 6.2% of such patients had troponin I levels of 1 μg/L or higher or troponin T levels of 0.1 μg/L or higher, and these patients had poorer outcomes and more severe symptoms.¹⁹ Levels can also be elevated in patients with chronic heart failure, in whom they correlate with impaired hemodynamics, progressive ventricular dysfunction, and death.²⁰ In an overview of two large trials of patients with chronic congestive heart failure, 86% and 98% tested positive for cardiac troponin using high-sensitivity assays.²¹

Troponin levels can rise from baseline and subsequently fall in congestive heart failure due to small amounts of myocardial injury, which may be very difficult to distinguish from MI based on the similar presenting symptoms of dyspnea and chest pressure.^1,22 The increased troponin levels in chronic congestive heart failure may reflect apoptosis secondary to wall stretch or direct cell toxicity by neurohormones, alcohol, chemotherapy agents, or infiltrative disorders.^23–26

End-stage renal disease

Troponin levels are increased in end-stage renal disease, with 25% to 75% of patients having elevated levels using currently available assays.^27–29 With the advent of high-sensitivity assays, however, cardiac troponin T levels higher than the 99th percentile are found in 100% of patients who have end-stage renal disease without cardiac symptoms.³⁰

Troponin values above the 99th percentile are therefore not diagnostic of MI in this population. Rather, a diagnosis of MI in patients with end-stage renal disease requires clinical signs and symptoms and serial changes in troponin levels from baseline levels. The task force and the National Academy of Clinical Biochemistry recommend requiring an elevation of more than 20% from baseline, representing a change in troponin of more than 3 standard deviations.³¹

Increases in troponin in renal failure are thought to be the result of chronic cardiac structural changes such as coronary artery disease, left ventricular hypertrophy, and elevated left ventricular end-diastolic pressure, rather than decreased clearance.^32,33

In stable patients with end-stage renal disease, those who have high levels of cardiac troponin T have a higher mortality rate.³⁴ Although the mechanism is not completely clear, decreased clearance of uremic toxins may contribute to myocardial damage beyond that of the cardiac structural changes.³⁴

Sepsis

Approximately 50% of patients admitted to an intensive care unit with sepsis without acute coronary syndrome have elevated troponin levels.³⁵

Elevated troponin in sepsis patients has been associated with left ventricular dysfunction, most likely from hemodynamic stress, direct cytotoxicity of bacterial endotoxins, and reperfusion injury.^35,36 Critical illness places high demands on the myocardium, while oxygen supply may be diminished by hypotension, pulmonary edema, and intravascular volume depletion. This supply-demand mismatch is similar to the physiology of type 2 MI, with clinical signs and symptoms of MI potentially being the only differentiating factor.

Elevated troponin levels may represent either reversible or irreversible myocardial injury in patients with sepsis and are a predictor of severe illness and death.³⁷ However, what to do about elevated troponin in patients with sepsis is not clear. When patients are in the intensive care unit with single-organ or multi-organ failure, the diagnosis and treatment of troponin elevations may not take priority.¹ Diagnosing MI is further complicated by the inability of critically ill patients to communicate signs and symptoms. Physicians should also remember that diagnostic testing (electrocardiography, echocardiography) is often necessary to meet the clinical criteria for a type 1 or 2 MI in critically ill patients, and that treatment options may be limited.

Pulmonary embolism

Pulmonary embolism is a leading noncardiac cause of troponin elevation in patients in whom the clinical suspicion of acute coronary syndrome is initially high.³⁸ It is thought that increased troponin levels in patients with pulmonary embolism are caused by increased right ventricular strain secondary to increased pulmonary artery resistance.

The signs and symptoms of MI and of pulmonary embolism overlap, and troponin can be elevated in both conditions, making the initial diagnosis difficult. Electrocardiography and early bedside echocardiography can identify the predominant right-sided dilatation and strain in the heart secondary to pulmonary embolism. Computed tomography should be performed if there is even a moderate clinical suspicion of pulmonary embolism.

The appropriate use of thrombolytics in a normotensive patient with pulmonary embolism remains controversial. The significant risks of hemorrhage need to be balanced with the risk of hemodynamic deterioration. For these patients, the combination of cardiac troponin I measurement and echocardiography provides more prognostic information than each does individually.³⁹ Troponin elevation may therefore be a marker for poor outcomes without aggressive treatment with thrombolytics.

However, single troponin measurements in patients hospitalized early with pulmonary embolism can lead to substantial risk of misdiagnosing them with MI. Although the intensity of the peak is not particularly useful in the setting of pulmonary embolism, two consecutive troponin values 8 hours apart will allow for more appropriate risk stratification for pulmonary embolism patients, who may have a delay between right heart injury and troponin release.⁴⁰

It is reasonable to expect that myocarditis—inflammation of the myocardium—would cause release of troponin from myocytes.⁴¹ Interestingly, however, troponin levels can also be elevated in pericarditis.⁴² The reasons are not clear but have been hypothesized as being caused by nonspecific inflammation during pericarditis that also includes the superficial myocardium—hence, “myopericarditis.”

We have only limited data on the outcomes of patients who have pericarditis with troponin elevation, but troponin levels did correlate with an adverse prognosis in one study.⁴³

Arrhythmias

A number of arrhythmias have been associated with elevated troponin levels. Some studies have shown arrhythmias to be the most common cause of high troponin levels in patients who are not experiencing an acute coronary syndrome.^44,45

The reasons proposed for increased troponins in tachyarrhythmia are similar to those in other conditions of oxygen supply-demand mismatch.⁴⁶ Tachycardia alone may lead to troponin release in the absence of myodepressive factors, inflammatory mediators, or coronary artery disease.⁴⁶

Studies have provided only mixed data as to whether troponin levels predict newonset arrhythmias or recurrence of arrhythmias.^47,48 Nonetheless, elevated troponin (≥ 0.040 μg/L) in patients with atrial fibrillation has independently correlated with increased risk of stroke or systemic embolism, death, and other cardiovascular events. This is clinically important, as troponin elevations higher than these levels adds prognostic information to that given by the CHADS2 stroke score (congestive heart failure, hypertension, age ≥ 75 years diabetes mellitus, and prior stroke or transient ischemic attack) and thus can inform appropriate anticoagulation therapy.⁴⁹

USE OF TROPONIN VALUES

Troponins are highly sensitive assays with high tissue specificity for myocardial injury, but levels can be elevated in non-MI conditions and in MIs other than type 1. As with any diagnostic test applied to a population with a low prevalence of the disease, troponin elevation has a low positive predictive value—53% for acute coronary syndrome.¹⁸

Unfortunately, in clinical practice, troponins are measured in up to 50% of admitted patients, a small proportion of whom have clinical signs or symptoms of MI.⁵⁰ Often, clinicians are left with a positive troponin of unknown significance, potentially leading to unnecessary diagnostic testing that detracts from the primary diagnosis.

Dynamic changes in troponin values (eg, a change of more than 20% in a patient with end-stage renal disease) are helpful in distinguishing acute from chronic causes of troponin elevation. However, such changes can also occur with acute or chronic congestive heart failure, tachycardia, hypotension, or other conditions other than acute coronary syndrome.

The absolute numerical value of troponin can help assess the significance of troponin elevation. In most non-MI and non-acute coronary syndrome causes of troponin elevation, the troponin level tends to be lower than 1 μg/mL (Figure 1). Occasional exceptions occur, especially when multiple conditions coexist (end-stage renal disease and congestive heart failure, for example). In contrast, most patients with acute coronary syndromes have either clear symptoms or electrocardiographic changes consistent with MI and a troponin that rises above 0.5 μg/mL.

The task force discourages the use of secondary thresholds for MI, as there is no level of troponin that is considered benign. While any troponin elevation carries a negative prognosis, such prognostic knowledge may not be particularly helpful in deciding whether to anticoagulate patients or attempt revascularization procedures.

We thus recommend using a threshold higher than the 99th percentile to distinguish acute coronary syndromes from other causes of troponin elevations. The particular threshold for decision-making should vary, depending on how strongly one clinically suspects an acute coronary syndrome. For instance, a cardiac troponin I level of 0.2 μg/mL in an otherwise healthy patient with chest pain and ST-segment depression is more than sufficient to diagnose acute coronary syndrome. In contrast, an end-stage renal disease patient with hypertensive cardiomyopathy who presents only with nausea should have a level markedly higher than his or her baseline value (and likely > 0.8 μg/mL) before acute coronary syndrome should be diagnosed.

CK-MB’S ROLE IN THE TROPONIN ERA

Some proponents of troponin assays, including those on the task force, have suggested that CK-MB may no longer be necessary in the evaluation of acute MI.⁵¹ In the past, CK-MB had more research supporting its use in quantifying myocardial damage and in diagnosing reinfarction, but some data suggest that troponin may be equally useful for these applications.^52,53

These comments aside, CK-MB measurements are still widely ordered with troponin, a probable response to the clinical difficulty of determining the cause and significance of troponin elevations. Although likely less common with recent assays, a small subgroup of patients with acute coronary syndrome will be CK-MB–positive and troponin-negative and at higher risk of morbidity and death than those who are troponin- and CK-MB–negative.^54,55

Troponin levels are elevated in many chronic conditions, whereas CK-MB levels may be unaffected or less affected. In some cases, such as congestive heart failure or renal failure, troponins may be both chronically elevated and more than 20% higher than at baseline. In a clinical context in which a false-positive troponin assay is likely, the addition of a CK-MB assay may help determine if a rise (and possibly a subsequent fall) in the troponin level represents true MI. More importantly, deciding on antithrombotic therapy or revascularization is often based on whether a patient has acute coronary syndrome, rather than a small MI from demand ischemia. CK-MB may thus serve as a less sensitive but more specific marker for the larger amount of myocardial damage that one might expect from an acute coronary syndrome.

CK-MB testing also may help determine the acuity of an acute coronary syndrome for patients with known causes of increased troponin. A negative CK-MB value in the presence of a troponin value elevated above baseline could indicate an event a few days prior.

Finally, the approach of ordering both troponin and CK-MB may be particularly helpful in diagnosing type 4 and 5 MIs, as current guidelines suggest that more research is needed to determine whether current troponin thresholds lead to clinical outcomes.

CLINICAL JUDGMENT IS NECESSARY

The updated definition raises the biomarker threshold required to diagnose MI after revascularization procedures and reemphasizes the need to look for other signs of infarction. This change reflects the sometimes excessive sensitivity of troponin assays for minimal and often unavoidable myocardial damage that occurs in numerous conditions.

With sensitive troponin assays, clinical judgment is essential for separating true MI from myocardial injury, and acute coronary syndrome from demand ischemia. Clinicians will now be forced to be cognizant of their suspicion for acute coronary syndrome in the presence of multiple noncoronary causes of increased troponin with little practical guideline guidance. In settings in which troponin elevation is expected (eg, congestive heart failure, end-stage renal failure, shock), a higher cardiac troponin threshold or CK-MB may be useful as a less sensitive but more specific marker of significant myocardial damage requiring aggressive treatment.

In 2012, a task force of the European Society of Cardiology, the American College of Cardiology Foundation, the American Heart Association, and the World Heart Federation released its “third universal definition” of myocardial infarction (MI),¹ replacing the previous (2007) definition. The new consensus definition reflects the increasing sensitivity of available troponin assays, which are commonly elevated in other conditions and after uncomplicated percutaneous coronary intervention or cardiac surgery. With a more appropriate definition of the troponin threshold after these procedures, benign myocardial injury can be differentiated from pathologic MI.

TROPONINS: THE PREFERRED MARKERS

Symptoms of MI such as nausea, chest pain, epigastric discomfort, syncope, and diaphoresis may be nonspecific, and findings on electrocardiography or imaging studies may be nondiagnostic. We thus rely on biomarker elevations to identify patients who need treatment.

Cardiac troponin I and cardiac troponin T have become the preferred markers for detecting MI, as they are more sensitive and tissue-specific than their main competitor, the MB fraction of creatine kinase (CK-MB).² But the newer troponin assays, which are even more sensitive than earlier ones, have raised concerns about their ability to differentiate patients who truly have acute coronary syndromes from those with other causes of troponin elevation. This can have major effects on treatment, patient psyche, and hospital costs.

Troponin elevations can occur in patients with heart failure, end-stage renal disease, sepsis, acute pulmonary embolism, myopericarditis, arrhythmias, and many other conditions. As noted by the task force, these cases of elevated troponin in the absence of clinical supportive evidence should not be labeled as an MI but rather as myocardial injury.

Troponins bind actin and myosin filaments in a trimeric complex composed of troponins I, C, and T. Troponins are present in all muscle cells, but the cardiac isoforms are specific to myocardial tissue.

As a result, both cardiac troponin I and cardiac troponin T, as measured by fourth-generation assays, are highly sensitive (75.2%, 95% confidence interval [CI] 66.8%–83.4%) and specific (94.6%, 95% CI 93.4%–96.3%) for detecting pathologic processes involving the heart.^3,4 Nonetheless, increases in cardiac troponin T (but not I) have been documented in patients with disease of skeletal muscles, likely secondary to re-expressed isoforms of the troponin C gene present in both cardiac and skeletal myocytes.³ There has been no evidence to suggest that either cardiac troponin I nor cardiac troponin T is superior to the other as a marker of MI.

Serum troponin levels detectably rise by 2 to 3 hours after myocardial injury. This temporal pattern is similar to that of CK-MB, which rises at about 2 hours and reaches a peak in 4 to 6 hours. However, troponins are more sensitive than CK-MB during this early time period, since a greater proportion is released from the heart during times of cardiac injury.

The definition of an abnormal troponin value is set by the precision of each individual assay. The task force has designated the optimal precision for troponin assays to be at a coefficient of variation of less than 10% when describing a value exceeding the 99th percentile in a reference population. The 99th percentile, which is the upper reference limit, corresponds to a value near 0.035 μg/L for fourth-generation troponin I and troponin T assays.⁵ Most assays have been adapted to ensure that they meet such criteria.

High-sensitivity assays

Over the past few years, “high-sensitivity” assays have been developed that can detect nanogram levels of troponin.

In one study, an algorithm that incorporated high-sensitivity cardiac troponin T levels was able to rule in or rule out acute MI in 77% of patients with chest pain within 1 hour.⁶ The algorithm had a sensitivity and negative predictive value of 100%.

Other studies have shown a sensitivity of 100.0%, a specificity of 34.0%, and a negative predictive value of 100.0% when using a cardiac troponin T cutoff of 3 ng/L, while a cutoff of 14 ng/L yielded a sensitivity of 85.4%, a specificity of 82.4%, and a negative predictive value of 96.1%.⁴ With cutoffs as low as 3 ng/L, some assays detect elevated troponin in up to 90% of people in normal reference populations without MI.⁷

Physicians thus need to be aware that high-sensitivity troponin assays should mainly be used to rule out acute coronary syndrome, as their high sensitivity substantially compromises their specificity. The appropriate thresholds for various patient populations, the appropriate testing procedures with high-sensitivity assays as compared with the fourth-generation troponin assays (ie, frequency of testing, change in level, and rise), and the cost and clinical outcomes of care based on algorithms that use these values remain unclear and will require further study.^8,9

TYPES OF MYOCARDIAL INFARCTION

The task force defines the following categories of MI (Table 1):

Type 1: Spontaneous myocardial infarction

Type 1, or “spontaneous” MI, is an acute coronary syndrome, colloquially called a “heart attack.” It is primarily the result of rupture, fissuring, erosion, or dissection of atherosclerotic plaque. Most are the result of underlying atherosclerotic coronary artery disease, although some (ie, those caused by coronary dissection) are not.

To diagnose type 1 MI, a blood sample must detect a rise or fall (or both) of cardiac biomarker values (preferably cardiac troponin), with at least one value above the 99th percentile. However, an elevated troponin level is not sufficient. At least one of the following criteria must also be met:

• Symptoms of ischemia
• New ST-segment or T-wave changes or new left bundle branch block
• Development of pathologic Q waves
• Imaging evidence of new loss of viable myocardium or new wall-motion abnormality
• Finding of an intracoronary thrombus by angiography or autopsy.

Type 1 MI therapy requires antithrombotic drugs and, with the additional findings, revascularization.

Type 2 MI is caused by a supply-demand imbalance in myocardial perfusion, resulting in ischemic damage. This specifically excludes acute coronary thrombosis, but can result from marked changes in demand or supply (eg, sepsis) or from a combination of acute changes and chronic conditions (eg, tachycardia with baseline coronary artery disease). Baseline stable coronary artery disease, left ventricular hypertrophy, endothelial dysfunction, coronary artery spasm, coronary embolism, arrhythmias, anemia, respiratory failure, hypotension, and hypertension can all contribute to a supply-demand mismatch sufficient to cause permanent myocardial damage.

The criteria for diagnosing type 2 MI are the same as for type 1: both elevated troponin levels and one of the clinical criteria (symptoms of ischemia, electrocardiographic changes, new wall-motion abnormality, or intracoronary thrombus) must be present.

Of importance, unlike those with type 1 MI, most patients with type 2 MI are unlikely to immediately benefit from antithrombotic therapy, as they typically have no acute thrombosis (except in cases of coronary embolism). Therapy should instead be directed at the underlying supply-demand imbalance and may include volume resuscitation, blood pressure support or control, or control of tachyarrhythmias.

In the long term, treatment to resolve or prevent supply-demand imbalances may also include revascularization or antithrombotic drugs, but these may be contraindicated in the acute setting.

Type 3: Sudden cardiac death from MI

The third type of MI occurs when myocardial ischemia results in sudden cardiac death before blood samples can be obtained. Before dying, the patient should have had symptoms suggesting myocardial ischemia and should have had presumed new ischemic electrocardiographic changes or new left bundle branch block.

This definition of MI is not very useful clinically but is important for population-based research studies.

Type 4a: Due to percutaneous coronary intervention

A rise in CK-MB levels after percutaneous coronary intervention has been associated with a higher rate of death or recurrent MI.¹⁰ Previously, type 4 MI was defined as an elevation of cardiac biomarker values (> 3 times the 99th percentile) after percutaneous coronary intervention in a patient who had a normal baseline value (< 99th percentile).¹¹

Unfortunately, using troponin at this threshold, the number of cases is five times higher than when CK-MB is used, without a consistent correlation with the outcomes of death or complications.¹² Currently, the increase in cardiac troponin after percutaneous coronary intervention is best interpreted as a marker of the patient’s atherothrombotic burden more than as a predictor of adverse outcomes.¹³

The updated definition of MI associated with percutaneous coronary intervention now requires an elevation of cardiac troponin values greater than 5 times the 99th percentile in a patient who had normal baseline values or an increase of more than 20% from baseline within 48 hours of the procedure. As this value has been arbitrarily assigned rather than based on an established threshold with clinical outcomes, a true MI must further meet one of the following criteria:

• Symptoms suggesting myocardial ischemia
• New ischemic electrocardiographic changes or new left bundle branch block
• Angiographic loss of patency of a major coronary artery or a side branch or persistent slow-flow or no-flow or embolization
• Imaging evidence of a new loss of viable myocardium or a new wall-motion abnormality.

Given that troponin levels may be elevated in up to 65% of patients after uncomplicated percutaneous coronary intervention and this elevation may be unavoidable,¹⁴ a higher troponin threshold to diagnose MI and the clear requirement of clinical correlates may resonate with physicians as a more appropriate definition. In turn, such guidelines may better identify those with an adverse event, while partly reducing unnecessary hospitalization and observation time in those for whom it is not necessary.

Type 4b: Due to stent thrombosis

Type 4b MI is MI caused by stent thrombosis. The thrombosis must be detected by coronary angiography or autopsy in the setting of myocardial ischemia and a rise or fall of cardiac biomarker values, with at least one value above the 99th percentile.

Type 4c: Due to restenosis

Proposed is the addition of type 4c MI, ie, MI resulting from restenosis of more than 50%, because restenosis after percutaneous coronary intervention can lead to MI without thrombosis.¹⁵

Type 5: After coronary artery bypass grafting

Similar to the situation after percutaneous coronary intervention, increased CK-MB levels after coronary artery bypass graft surgery are associated with poor outcomes.¹⁶ Although some studies have indicated that increased troponin levels within 24 hours of this surgery are associated with higher death rates, no study has established a troponin threshold that correlates with outcomes.¹⁷

The task force acknowledged this lack of prognostic value but arbitrarily defined type 5 MI as requiring biomarker elevations greater than 10 times the 99th percentile during the first 48 hours after surgery, with a normal baseline value. One of the following additional criteria must also be met:

• New pathologic Q waves or new left bundle branch block
• Angiographically documented new occlusion in the graft or native coronary artery
• Imaging evidence of new loss of viable myocardium or new wall-motion abnormality.

CHANGES FROM THE 2007 DEFINITIONS

Updates to the definitions of the MI types since the 2007 task force definition can be found in Table 1.

In type 1 and 2 MI, the finding of an intracoronary thrombus by angiography or autopsy was added as one of the possible criteria for evidence of myocardial ischemia.

In type 3 MI, the definition was simplified by deleting the former criterion of finding a fresh thrombus by angiography or autopsy.

In type 4a MI, by requiring clinical correlates, the updated definition in particular moves away from relying solely on troponin levels to diagnose an infarction after percutaneous coronary intervention, as was the case in 2007. Other changes from the 2007 definition: the troponin MI threshold was previously 3 times the 99th percentile, now it is 5 times. Also, if the patient had an elevated baseline value, he or she can now still qualify as having an MI if the level increases by more than 20%.

In type 5 MI, changes to the definition similarly reflect the need to address overly sensitive troponin values when diagnosing an MI after coronary artery bypass grafting. To address such concerns, the required cardiac biomarker values were increased from more than 5 to more than 10 times the 99th percentile.

The task force raised the troponin thresholds for type 4 and type 5 MI in response to evidence showing that troponins are excessively sensitive to minimal myocardial damage during revascularization, and the lack of a troponin threshold that correlates with clinical outcomes.¹² Although higher, these values remain arbitrary, so physicians will need to exercise clinical judgment when deciding whether patients are experiencing benign myocardial injury or rather a true MI after revascularization procedures.

OTHER CONDITIONS THAT RAISE TROPONIN LEVELS

As troponin is a marker not only for MI but also for any form of cardiac injury, its levels are elevated in numerous conditions, such as heart failure, renal failure, and left ventricular hypertrophy. The task force identifies distinct troponin elevations above basal levels as the best indication of new pathology, yet several conditions other than acute coronary syndromes can also cause dynamic changes in troponin levels.

Troponin is a sensitive marker for ruling out MI and has tissue specificity for cardiac injury, but it is not specific for acute coronary syndrome as the cause of such injury. Troponin assays were tested and validated in patients in whom there was a high clinical suspicion of acute coronary syndrome, but when ordered indiscriminately, they have a poor positive predictive value (53%) for this disorder.¹⁸

Physicians must distinguish between acute coronary syndrome and other causes when deciding to give antithrombotics. Table 2 lists common causes of increased troponin other than acute coronary syndrome.

Heart failure

Some patients with acute congestive heart failure have elevated troponin levels. In one study, 6.2% of such patients had troponin I levels of 1 μg/L or higher or troponin T levels of 0.1 μg/L or higher, and these patients had poorer outcomes and more severe symptoms.¹⁹ Levels can also be elevated in patients with chronic heart failure, in whom they correlate with impaired hemodynamics, progressive ventricular dysfunction, and death.²⁰ In an overview of two large trials of patients with chronic congestive heart failure, 86% and 98% tested positive for cardiac troponin using high-sensitivity assays.²¹

Troponin levels can rise from baseline and subsequently fall in congestive heart failure due to small amounts of myocardial injury, which may be very difficult to distinguish from MI based on the similar presenting symptoms of dyspnea and chest pressure.^1,22 The increased troponin levels in chronic congestive heart failure may reflect apoptosis secondary to wall stretch or direct cell toxicity by neurohormones, alcohol, chemotherapy agents, or infiltrative disorders.^23–26

End-stage renal disease

Troponin levels are increased in end-stage renal disease, with 25% to 75% of patients having elevated levels using currently available assays.^27–29 With the advent of high-sensitivity assays, however, cardiac troponin T levels higher than the 99th percentile are found in 100% of patients who have end-stage renal disease without cardiac symptoms.³⁰

Troponin values above the 99th percentile are therefore not diagnostic of MI in this population. Rather, a diagnosis of MI in patients with end-stage renal disease requires clinical signs and symptoms and serial changes in troponin levels from baseline levels. The task force and the National Academy of Clinical Biochemistry recommend requiring an elevation of more than 20% from baseline, representing a change in troponin of more than 3 standard deviations.³¹

Increases in troponin in renal failure are thought to be the result of chronic cardiac structural changes such as coronary artery disease, left ventricular hypertrophy, and elevated left ventricular end-diastolic pressure, rather than decreased clearance.^32,33

In stable patients with end-stage renal disease, those who have high levels of cardiac troponin T have a higher mortality rate.³⁴ Although the mechanism is not completely clear, decreased clearance of uremic toxins may contribute to myocardial damage beyond that of the cardiac structural changes.³⁴

Sepsis

Approximately 50% of patients admitted to an intensive care unit with sepsis without acute coronary syndrome have elevated troponin levels.³⁵

Elevated troponin in sepsis patients has been associated with left ventricular dysfunction, most likely from hemodynamic stress, direct cytotoxicity of bacterial endotoxins, and reperfusion injury.^35,36 Critical illness places high demands on the myocardium, while oxygen supply may be diminished by hypotension, pulmonary edema, and intravascular volume depletion. This supply-demand mismatch is similar to the physiology of type 2 MI, with clinical signs and symptoms of MI potentially being the only differentiating factor.

Elevated troponin levels may represent either reversible or irreversible myocardial injury in patients with sepsis and are a predictor of severe illness and death.³⁷ However, what to do about elevated troponin in patients with sepsis is not clear. When patients are in the intensive care unit with single-organ or multi-organ failure, the diagnosis and treatment of troponin elevations may not take priority.¹ Diagnosing MI is further complicated by the inability of critically ill patients to communicate signs and symptoms. Physicians should also remember that diagnostic testing (electrocardiography, echocardiography) is often necessary to meet the clinical criteria for a type 1 or 2 MI in critically ill patients, and that treatment options may be limited.

Pulmonary embolism

Pulmonary embolism is a leading noncardiac cause of troponin elevation in patients in whom the clinical suspicion of acute coronary syndrome is initially high.³⁸ It is thought that increased troponin levels in patients with pulmonary embolism are caused by increased right ventricular strain secondary to increased pulmonary artery resistance.

The signs and symptoms of MI and of pulmonary embolism overlap, and troponin can be elevated in both conditions, making the initial diagnosis difficult. Electrocardiography and early bedside echocardiography can identify the predominant right-sided dilatation and strain in the heart secondary to pulmonary embolism. Computed tomography should be performed if there is even a moderate clinical suspicion of pulmonary embolism.

The appropriate use of thrombolytics in a normotensive patient with pulmonary embolism remains controversial. The significant risks of hemorrhage need to be balanced with the risk of hemodynamic deterioration. For these patients, the combination of cardiac troponin I measurement and echocardiography provides more prognostic information than each does individually.³⁹ Troponin elevation may therefore be a marker for poor outcomes without aggressive treatment with thrombolytics.

However, single troponin measurements in patients hospitalized early with pulmonary embolism can lead to substantial risk of misdiagnosing them with MI. Although the intensity of the peak is not particularly useful in the setting of pulmonary embolism, two consecutive troponin values 8 hours apart will allow for more appropriate risk stratification for pulmonary embolism patients, who may have a delay between right heart injury and troponin release.⁴⁰

It is reasonable to expect that myocarditis—inflammation of the myocardium—would cause release of troponin from myocytes.⁴¹ Interestingly, however, troponin levels can also be elevated in pericarditis.⁴² The reasons are not clear but have been hypothesized as being caused by nonspecific inflammation during pericarditis that also includes the superficial myocardium—hence, “myopericarditis.”

We have only limited data on the outcomes of patients who have pericarditis with troponin elevation, but troponin levels did correlate with an adverse prognosis in one study.⁴³

Arrhythmias

A number of arrhythmias have been associated with elevated troponin levels. Some studies have shown arrhythmias to be the most common cause of high troponin levels in patients who are not experiencing an acute coronary syndrome.^44,45

The reasons proposed for increased troponins in tachyarrhythmia are similar to those in other conditions of oxygen supply-demand mismatch.⁴⁶ Tachycardia alone may lead to troponin release in the absence of myodepressive factors, inflammatory mediators, or coronary artery disease.⁴⁶

Studies have provided only mixed data as to whether troponin levels predict newonset arrhythmias or recurrence of arrhythmias.^47,48 Nonetheless, elevated troponin (≥ 0.040 μg/L) in patients with atrial fibrillation has independently correlated with increased risk of stroke or systemic embolism, death, and other cardiovascular events. This is clinically important, as troponin elevations higher than these levels adds prognostic information to that given by the CHADS2 stroke score (congestive heart failure, hypertension, age ≥ 75 years diabetes mellitus, and prior stroke or transient ischemic attack) and thus can inform appropriate anticoagulation therapy.⁴⁹

USE OF TROPONIN VALUES

Troponins are highly sensitive assays with high tissue specificity for myocardial injury, but levels can be elevated in non-MI conditions and in MIs other than type 1. As with any diagnostic test applied to a population with a low prevalence of the disease, troponin elevation has a low positive predictive value—53% for acute coronary syndrome.¹⁸

Unfortunately, in clinical practice, troponins are measured in up to 50% of admitted patients, a small proportion of whom have clinical signs or symptoms of MI.⁵⁰ Often, clinicians are left with a positive troponin of unknown significance, potentially leading to unnecessary diagnostic testing that detracts from the primary diagnosis.

Dynamic changes in troponin values (eg, a change of more than 20% in a patient with end-stage renal disease) are helpful in distinguishing acute from chronic causes of troponin elevation. However, such changes can also occur with acute or chronic congestive heart failure, tachycardia, hypotension, or other conditions other than acute coronary syndrome.

The absolute numerical value of troponin can help assess the significance of troponin elevation. In most non-MI and non-acute coronary syndrome causes of troponin elevation, the troponin level tends to be lower than 1 μg/mL (Figure 1). Occasional exceptions occur, especially when multiple conditions coexist (end-stage renal disease and congestive heart failure, for example). In contrast, most patients with acute coronary syndromes have either clear symptoms or electrocardiographic changes consistent with MI and a troponin that rises above 0.5 μg/mL.

The task force discourages the use of secondary thresholds for MI, as there is no level of troponin that is considered benign. While any troponin elevation carries a negative prognosis, such prognostic knowledge may not be particularly helpful in deciding whether to anticoagulate patients or attempt revascularization procedures.

We thus recommend using a threshold higher than the 99th percentile to distinguish acute coronary syndromes from other causes of troponin elevations. The particular threshold for decision-making should vary, depending on how strongly one clinically suspects an acute coronary syndrome. For instance, a cardiac troponin I level of 0.2 μg/mL in an otherwise healthy patient with chest pain and ST-segment depression is more than sufficient to diagnose acute coronary syndrome. In contrast, an end-stage renal disease patient with hypertensive cardiomyopathy who presents only with nausea should have a level markedly higher than his or her baseline value (and likely > 0.8 μg/mL) before acute coronary syndrome should be diagnosed.

CK-MB’S ROLE IN THE TROPONIN ERA

Some proponents of troponin assays, including those on the task force, have suggested that CK-MB may no longer be necessary in the evaluation of acute MI.⁵¹ In the past, CK-MB had more research supporting its use in quantifying myocardial damage and in diagnosing reinfarction, but some data suggest that troponin may be equally useful for these applications.^52,53

These comments aside, CK-MB measurements are still widely ordered with troponin, a probable response to the clinical difficulty of determining the cause and significance of troponin elevations. Although likely less common with recent assays, a small subgroup of patients with acute coronary syndrome will be CK-MB–positive and troponin-negative and at higher risk of morbidity and death than those who are troponin- and CK-MB–negative.^54,55

Troponin levels are elevated in many chronic conditions, whereas CK-MB levels may be unaffected or less affected. In some cases, such as congestive heart failure or renal failure, troponins may be both chronically elevated and more than 20% higher than at baseline. In a clinical context in which a false-positive troponin assay is likely, the addition of a CK-MB assay may help determine if a rise (and possibly a subsequent fall) in the troponin level represents true MI. More importantly, deciding on antithrombotic therapy or revascularization is often based on whether a patient has acute coronary syndrome, rather than a small MI from demand ischemia. CK-MB may thus serve as a less sensitive but more specific marker for the larger amount of myocardial damage that one might expect from an acute coronary syndrome.

CK-MB testing also may help determine the acuity of an acute coronary syndrome for patients with known causes of increased troponin. A negative CK-MB value in the presence of a troponin value elevated above baseline could indicate an event a few days prior.

Finally, the approach of ordering both troponin and CK-MB may be particularly helpful in diagnosing type 4 and 5 MIs, as current guidelines suggest that more research is needed to determine whether current troponin thresholds lead to clinical outcomes.

CLINICAL JUDGMENT IS NECESSARY

The updated definition raises the biomarker threshold required to diagnose MI after revascularization procedures and reemphasizes the need to look for other signs of infarction. This change reflects the sometimes excessive sensitivity of troponin assays for minimal and often unavoidable myocardial damage that occurs in numerous conditions.

With sensitive troponin assays, clinical judgment is essential for separating true MI from myocardial injury, and acute coronary syndrome from demand ischemia. Clinicians will now be forced to be cognizant of their suspicion for acute coronary syndrome in the presence of multiple noncoronary causes of increased troponin with little practical guideline guidance. In settings in which troponin elevation is expected (eg, congestive heart failure, end-stage renal failure, shock), a higher cardiac troponin threshold or CK-MB may be useful as a less sensitive but more specific marker of significant myocardial damage requiring aggressive treatment.