Novel approaches for the evaluation of arrhythmic risk

Introduction

Cardiac arrhythmias are major causes of morbidity and mortality. They are the most frequent immediate cause of sudden cardiac death (SCD), which accounts for about 230,000 to 350,000 yearly deaths in the United States. ^, Nuclear cardiology is not customarily thought of as a technique for assessing arrhythmic risk. In the 2008 American Heart Association (AHA)/American College of Cardiology Foundation/Heart Rhythm Society Scientific Statement on noninvasive risk stratification techniques for identifying patients at risk for SCD, the use of imaging was limited to the assessment of left ventricular ejection fraction (LVEF). Since then, radionuclide cardiac imaging, often in conjunction with other noninvasive imaging techniques, has become increasingly recognized as providing important information regarding diagnosis and risk stratification of patients at risk for ventricular arrhythmias. For example, myocardial perfusion imaging (MPI) provides robust quantification of ischemia, scar, and left ventricular (LV) function, which are known to contribute to arrhythmic risk. As described in Chapter 23 , radionuclide imaging also provides quantitative information about myocardial inflammation in patients with inflammatory cardiomyopathies, many of whom present with ventricular arrhythmias, which helps guide patient management. In addition, assessment of LV remodeling and mechanical dyssynchrony using electrocardiogram (ECG)-gated MPI may also help guide management in patients with heart failure (HF) at risk for SCD (see Chapter 27 ). Finally, radionuclide imaging can visualize and quantify cardiac sympathetic nerve function and, in so doing, help identify patients at risk for ventricular arrhythmias and potentially guide therapy, including the use of an implantable cardioverter defibrillator (ICD) and guidance of ventricular ablation.

Risk stratification of arrhythmic risk

Numerous efforts have been made to identify conventional clinical criteria that could effectively risk stratify and select patients with known cardiac dysfunction who are likely to benefit from a primary prevention ICD. In 45,000 primary prevention ICD patients, various so-called shocked predictor variables accurately identified patients at highest risk for death over 3 years. Although ICD discharges were not specifically looked at, the goal was to identify patients at highest risk for nonarrhythmic mortality for whom there would likely be little or no benefit from the device. In another study of 2258 ICD patients, a CHA ₂ DS ₂ -VASc (Congestive heart failure, Hypertension, Age, Diabetes, previous Stroke/transient ischemic attack - vascular disease) score predicted all-cause mortality, again an attempt to identify those patients not likely to benefit from the device.

Numerous ECG parameters associated with arrhythmic risk have been examined in patients after myocardial infarction (MI) or with HF, including ECG Q-waves, an intraventricular conduction delay, spontaneous premature ventricular contractions (PVCs) and nonsustained ventricular tachycardia (NSVT), late potentials on signal-averaged ECG (SAECG), reduced heart rate variability (HRV), and T-wave (repolarization) alternans (TWA), as well as ventricular tachycardia (VT) inducibility on an electrophysiologic study (EPS). Nevertheless, PVCs and NSVT are generally markers of increased risk, SAECG, HRV, and TWA have low positive predictive values and are rarely used in clinical practice, and EPS is invasive and thus not a convenient routinely performed screening procedure to assess arrhythmic risk.

Serum-based biomarkers have been studied for potential screening of arrhythmic risk. A study of 1189 ICD patients found that tumor necrosis factor alpha receptor II, probrain natriuretic peptide (pro-BNP), and cardiac troponin T were independently associated with 1-year mortality, with a net-reclassification improvement of 77.2%.

Despite interesting findings, there are crucial deficiencies with many of the aforementioned analyses. First, they often did not specifically examine arrhythmic events, which is better done using specific ICD-recorded criteria, such as spontaneous sustained (>30 seconds) VT or an appropriate discharge (antitachycardia pacing or defibrillation). ^, At the same time, assessing the ICD record can be misleading because a discharge does not necessarily mean that a patient would have died if not for the device. In addition, an ICD discharge recorded in a patient who has died may be a response to a terminal arrhythmia that occurred as the patient was dying from pump failure.

Second, although various criteria may identify the relatively few patients at highest risk of a lethal arrhythmic event, the majority of patients who die a sudden cardiac death have either undiagnosed disease or are determined to be at low risk based on standard risk markers. Thus, current clinical methods may identify patients most at risk for arrhythmic death but cannot find most of the patients who are at risk.

It is reasonable to expect that more effective ways of assessing ventricular tachyarrhythmic risk employ techniques that directly depict cardiac structures and measure functional parameters, something for which cardiac imaging is ideally suited. Although determination of LVEF using various methods is the most commonly used imaging technique for arrhythmic risk stratification, it is a somewhat crude, global measure of cardiac function that does not directly provide information about underlying arrhythmic origins or mechanisms. Imaging techniques directed at underlying arrhythmic mechanisms are needed for more accurate risk assessment.

Fundamentally, sudden tachyarrhythmias in HF are caused by alterations in the functional expression of ion channels and transporters in conduction tissues, leading to heterogeneous prolongation of action potentials that results in exaggeration of electrical inhomogeneity, particularly temporal and spatial dispersion of repolarization. Alterations in calcium homeostasis also contribute to electrical instability. Ultimately, these electrical perturbations lead to dispersion of electrical impulse conduction through the myocardium, exacerbated by regions with fibrous tissue, resulting in reentrant excitation and ventricular arrhythmias. Although these underlying molecular mechanisms cannot be imaged directly with current clinical techniques, structural changes that make myocardium susceptible to electrical heterogeneity, and outside forces provoking or sustaining it, can be. A convenient way to categorize arrhythmogenic myocardial changes and outside forces is depicted in Fig. 21.1 . Abnormalities in myocardial substrate, such as tissue damage from coronary ischemic events that create areas of potential electrical instability and can lead to myocardial geometric remodeling, infectious damage, immunologically induced damage, a genetic electrical abnormality, and genetic cellular or metabolic abnormalities can all create a heart predisposed to or already exhibiting electrical conduction heterogeneity. Nevertheless, a trigger is required to initiate an arrhythmia, which could be an acute ischemic event imposed on a previously normal heart, an ischemic insult to an already damaged heart, a systemic electrolyte abnormality, a proarrhythmic pharmacologic substance, a hemodynamic or environmental stress, or an autonomic perturbation. Finally, there are modulating factors, such as the state of neurohormonal balance, including direct cardiac autonomic innervation, which can sustain an arrhythmia that has begun or can stop it. Imaging techniques, including radionuclide methods that can depict underlying molecular processes, are well able to assess aspects of all of these categories.

Patient-centered applications of radionuclide and multimodality imaging for the evaluation of arrhythmic risk

Case vignette 1: Screening for coronary artery disease

A 57-year-old male without previous cardiac history presented with exertional chest pain radiating to the left arm with long walks, associated with shortness of breath and palpitations, was referred for an exercise myocardial perfusion single photon emission computed tomography (SPECT) study. His baseline ECG was normal. At about 6 minutes of exercise, the patient developed NSVT with symptoms of chest pain associated with 2 mm of ST-segment depression. The stress/rest ^99m technetium (Tc)-sestamibi images showed a large and severe perfusion defect throughout the anterior and anteroseptal walls, the apical LV segments, and the LV apex, showing complete reversibility ( Fig. 21.2 ). The ECG-gated images demonstrated anterior and anteroseptal hypokinesis with a normal LVEF of 60%. Subsequent coronary angiography showed severe three-vessel obstructive coronary artery disease (CAD), including a 60% left main stenosis. The patient underwent successful coronary artery bypass surgery.

Radionuclide MPI provides accurate quantification of myocardial ischemia, scar, and LVEF, which are known risk factors for ventricular arrhythmias. Indeed, about 80% of SCDs occur in the setting of ischemic heart disease. Half the patients who suffer an out-of-hospital cardiac arrest have evidence of acute MI and more than 50% are found to have significant CAD. For this reason, radionuclide MPI is an effective test to identify patients at risk for arrhythmias associated with CAD. Piccini et al. followed 6383 patients with documented CAD undergoing stress ^99m Tc-sestamibi SPECT MPI and found that the combined extent and severity of scar plus ischemia was significantly associated with SCD independent of LVEF and a clinical morbidity index. They found that the incidence of SCD was greatest (13% at 10 years) in patients with a LVEF of less than 35% and medium or large areas of scar plus ischemia, with an SCD. Conversely, patients with mild or no scar plus ischemia and a LVEF greater than 35% had the lowest risk for SCD.

As illustrated by Case Vignette 1, exercise SPECT MPI can sometimes provoke a potentially lethal arrhythmia, thereby identifying patients at risk for SCD. Conversely, much literature has shown that patients with a normal or near normal SPECT MPI are statistically at extremely low shot-term risk for a lethal event. Thus, provided there is no change in clinical symptoms, a normal or low-risk MPI using SPECT, and presumably also with positron emission tomography (PET) that provides higher diagnostic accuracy and additional ability with quantitative blood flow to exclude high-risk disease, can reasonably exclude the threat of a lethal arrhythmia in the near future.

Once the presence of CAD is established by MPI or other methods, life-threatening ventricular arrhythmias in patients with normal LV function are often the end result of acute cardiac ischemia caused by an acute coronary syndrome. Thus, molecular imaging of atherosclerotic plaque biology may be another approach to identify high-risk patients. As discussed in Chapter 12 , multiple radiotracers targeting different aspects of plaque biology have been successfully used in the identification of at-risk patients, especially when combined with coronary CT angiography (CCTA) and, to a lesser extent, magnetic resonance imaging (MRI).