Review ArticleThe role of nuclear cardiac imaging in risk stratification of sudden cardiac death
Introduction
Sudden cardiac death (SCD) currently accounts for up to 60% of all cardiac death in the adult population in the United States.1,2 Despite recent advances in our understanding of cardiovascular disease and in cardiac care, effective primary prevention of SCD in the general population is still an aspiration.3,4 The final common pathway in most cases is malignant ventricular arrhythmia.5 Although the fundamental pathophysiology is complex, an underlying anatomical substrate can be identified in the majority of patients,6 with the most frequent being attributed to ischemic heart disease, idiopathic dilated cardiomyopathy (DCM), and hypertrophic cardiomyopathy (HCM).7
Current guidelines focus on the left ventricular ejection fraction (LVEF) as the primary measure for SCD risk stratification and patient management.8,9 One-third of all SCD occur in patients with moderate to severe left ventricular (LV) systolic dysfunction (LVEF ≤ 35%).10 In this group, primary prevention with an implantable cardioverter defibrillator (ICD) significantly prolongs survival.11,12 However, numerous patients with higher LVEF are still at risk of SCD, but would not qualify for ICD placement according to current guidelines. Furthermore, only 35% of patients randomized for ICD placement in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) received appropriate shock therapy over a 3-year follow-up.13 Taken together, these facts underscore the lack of sensitivity and specificity of LVEF alone in identifying patients who will suffer from SCD and the need for better markers for SCD.
Emerging data support the potential of cardiac imaging to understand the mechanisms of SCD beyond simple LVEF measurement.14 In this review, we will focus on the possible benefits that nuclear cardiology imaging (including myocardial perfusion imaging (MPI), LV function assessment, accurate flow quantification, metabolic imaging and neurohormonal imaging) offers us to improve risk stratification of SCD in patients with ischemic and non-ischemic cardiomyopathy.
Section snippets
Mechanisms of Sudden Cardiac Death
By definition “sudden,” the acute event is not often witnessed, and therefore SCD is difficult to study. In most cases, it is accepted that the final pathway is malignant ventricular arrhythmia.15,16 The underlying mechanisms of ventricular arrhythmogenesis are complex but can simply be considered as the interaction between a structural or anatomic substrate (myocardial scar from prior myocardial infarction) and a functional trigger, such as ischemia.5,6 In the adult population, most SCD occurs
Left Ventricular Function
LVEF is currently the most studied and most commonly used cardiac imaging marker to assess risk for SCD and is used to guide appropriate therapy in both ischemic and non-ischemic cardiomyopathies. Many studies, dating back to the 1980s, quickly established that LVEF is a strong predictor for overall cardiac mortality.24, 25, 26 Not surprisingly, this led to the use of LVEF as a criterion of enrollment in the large clinical trials for the evaluation of ICDs in primary prevention of SCD in the
Ischemia
Ischemia is a well-recognized trigger for ventricular arrhythmias.40,41 Current ICD therapy guidelines recommend optimal revascularization before ICD therapy.31 Moreover, coronary revascularization has been proven to reduce SCD risk.42, 43, 44 Hachamovitch et al, in a large study with 5183 patients who underwent rest/stress dual-isotope (Thallium-201 and Technetium-99m Sestamibi) SPECT MPI, demonstrated that the presence of ischemia yields incremental prognostic data for predicting cardiac
Myocardial Scar and Hibernating Myocardium
Myocardial scar is a complex and powerful substrate for arrhythmogenesis. Changes in tissue composition following an infarct create a heterogeneous zone that leads to depolarization abnormalities, autonomic dysfunction, and repolarization disruption; the presence of viable myocardium adjacent to scar tissue often forms the anatomic substrate for reentrant ventricular tachycardia (VT).55,56 Studies have shown that the extent of scar on SPECT MPI is related to the risk of cardiac death.
Sympathetic Innervation Imaging
Cardiac sympathetic innervation is another novel imaging target in the search for better prediction and prevention of SCD. It plays an important role in cardiac function and may play an important role in future stratification strategies.
The most widely available and studied non-invasive method to assess cardiac sympathetic innervation is currently Iodine-123-metaiodobenzylguanidine (MIBG). MIBG is a guanethidine analog initially developed in the 1980s to study adrenal medulla tumors and other
Idiopathic Dilated Cardiomyopathy (DCM)
According to some studies, SCD accounts for up to 30% of overall death in patients with DCM,96 which accounts for a significant fraction of overall SCD.6 Current guidelines recommend ICD therapy in patients with non-ischemic cardiomyopathy with LVEF ≤ 35% and NYHA class II-III HF,29 while it may be considered in patients with NYHA class I. Evaluation of LV function is thus indicated in these patients. Additionally, studies have shown that sympathetic innervation abnormalities are present in
Future Outlook
Although 11C-HED shows great promise, its use and adoption remain limited because of its short half-life which requires an onsite cyclotron. LMI1195 is a Fluorine-18-based PET tracer with a design similar to MIBG, which could theoretically solve this problem thanks to its longer half-life which allows delivery from a regional cyclotron. Preliminary studies are promising,134,135 and the relationship between myocardial denervation and SCD, along with the potential for an effective
Conclusion
Correctly identifying patients who are at high risk for SCD is of paramount importance since appropriate therapy can be life-saving. While modern medicine has made significant progress in the diagnosis and management of CAD, this is one area where recent progress remains limited. Our current screening process for SCD relies heavily on LVEF assessment, which lacks both sensitivity and specificity. Recent advances in our understanding of the underlying pathophysiology, combined with advances in
Acknowledgments
RSB is a career investigator supported by the Heart and Stroke Foundation of Ontario, a Tier 1 Research Chair supported by the University of Ottawa, and the University of Ottawa Heart Institute Vered Chair in Cardiology. DJ is a Cardiac Imaging Fellow at the University of Ottawa Heart Institute supported by a grant from the CHUM and CHUM Foundation. JK is supported by the Centre of Excellence of Cardiovascular and Metabolic Disease, Academy of Finland.
Disclosures
RSB is or has been a consultant for and
References (140)
- et al.
2012 ACCF/AHA/HRS focused update of the 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines
J Am Coll Cardiol
(2012) - et al.
Population-based analysis of sudden cardiac death with and without left ventricular systolic dysfunction. Two-year findings from the oregon sudden unexpected death study
J Am Coll Cardiol
(2006) - et al.
Sudden cardiac death while wearing a Holter monitor
Am J Cardiol
(1991) - et al.
Myocardial ischemia and ventricular fibrillation: Pathophysiology and clinical implications
Int J Cardiol
(2007) - et al.
Neural modulation of cardiac arrhythmias and sudden cardiac death
Heart Rhythm
(2006) - et al.
Predictors of total mortality and sudden death in mild to moderate heart failure. Captopril-Digoxin Study Group
J Am Coll Cardiol
(1989) - et al.
The association of left ventricular ejection fraction, mortality, and cause of death in stable outpatients with heart failure
J Am Coll Cardiol
(2003) - et al.
Predicting therapeutic benefit from myocardial revascularization procedures: Are measurements of both resting left ventricular ejection fraction and stress-induced myocardial ischemia necessary?
J Nucl Cardiol
(2006) - et al.
Independent and incremental prognostic value of left ventricular ejection fraction determined by stress gated rubidium 82 PET imaging in patients with known or suspected coronary artery disease
J Nucl Cardiol
(2008) - et al.
ACCF/ASNC/ACR/AHA/ASE/SCCT/SCMR/SNM 2009 appropriate use criteria for cardiac radionuclide imaging
J Am Coll Cardiol
(2009)
ASNC imaging guidelines for nuclear cardiology procedures
J Nucl Cardiol.
Gated blood-pool SPECT versus cardiac magnetic resonance imaging for the assessment of left ventricular volumes and ejection fraction
J Nucl Cardiol
Accuracy of radionuclide ventriculography assessed by magnetic resonance imaging in patients with abnormal left ventricles
J Nucl Cardiol
Multiple gated cardiac blood pool imaging for left ventricular ejection fraction: Validation of the technique and assessment of variability
Am J Cardiol
Sudden cardiac death
Cardiovasc Pathol
Surgical coronary revascularization in survivors of prehospital cardiac arrest: Its effect on inducible ventricular arrhythmias and long-term survival
J Am Coll Cardiol
Single-photon emission computed tomography myocardial perfusion imaging and the risk of sudden cardiac death in patients with coronary disease and left ventricular ejection fraction > 35%
J Am Coll Cardiol
Does rubidium-82 PET have superior accuracy to SPECT perfusion imaging for the diagnosis of obstructive coronary disease? A systematic review and meta-analysis
J Am Coll Cardiol.
Cardiac PET perfusion: Prognosis, risk stratification, and clinical management
Semin Nucl Med
Prognostic value of stress myocardial perfusion positron emission tomography
J Am Coll Cardiol
Infarct morphology identifies patients with substrate for sustained ventricular tachycardia
J Am Coll Cardiol
Prognostic value of thallium-201 single-photon emission computed tomographic myocardial perfusion imaging according to extent of myocardial defect: Study in 1,926 patients with foilow-up at 33 months
J Am Coll Cardiol
Risk stratification of patients with prior myocardial infarction and advanced left ventricular dysfunction by gated myocardial perfusion SPECT imaging
J Nucl Cardiol
Long-term survival of patients with coronary artery disease and left ventricular dysfunction: Implications for the role of myocardial viability assessment in management decisions
J Thorac Cardiovasc Surg
Value of metabolic imaging with positron emission tomography for evaluating prognosis in patients with coronary artery disease and left ventricular dysfunction
Am J Cardiol
The extent of perfusion-F18-fluorodeoxyglucose positron emission tomography mismatch determines mortality in medically treated patients with chronic ischemic left ventricular dysfunction
J Am Coll Cardiol
F-18-fluorodeoxyglucose positron emission tomography imaging-assisted management of patients with severe left ventricular dysfunction and suspected coronary disease
J Am Coll Cardiol
Dysinnervated but viable myocardium in ischemic heart disease
J Nucl Cardiol.
Abnormal sympathetic innervation of viable myocardium and the substrate of ventricular tachycardia after myocardial infarction
J Am Coll Cardiol
Myocardial iodine-123 meta-iodobenzylguanidine imaging and cardiac events in heart failure. Results of the prospective ADMIRE-HF (AdreView Myocardial Imaging for Risk Evaluation in Heart Failure) study
J Am Coll Cardiol
Cardiac sympathetic denervation assessed with 123-iodine metaiodobenzylguanidine imaging predicts ventricular arrhythmias in implantable cardioverter-defibrillator patients
J Am Coll Cardiol
Usefulness of cardiac meta-iodobenzylguanidine imaging to identify patients with chronic heart failure and left ventricular ejection fraction < 35% at low risk for sudden cardiac death
Am J Cardiol
Influence of ejection fraction on the prognostic value of sympathetic innervation imaging with iodine-123 MIBG in heart failure
JACC Cardiovasc Imaging.
Cardiac iodine-123 metaiodobenzylguanidine imaging predicts sudden cardiac death independently of left ventricular ejection fraction in patients with chronic heart failure and left ventricular systolic dysfunction: Results from a comparative study with signal-averaged electrocardiogram, heart rate variability, and QT dispersion
J Am Coll Cardiol
Carbon-11 hydroxyephedrine with positron emission tomography for serial assessment of cardiac adrenergic neuronal function after acute myocardial infarction in humans
J Am Coll Cardiol
Regional myocardial sympathetic denervation predicts the risk of sudden cardiac arrest in ischemic cardiomyopathy
J Am Coll Cardiol
Sudden death in idiopathic dilated cardiomyopathy
Am Heart J
Sudden cardiac death in the United States, 1989 to 1998
Circulation
Heart disease and stroke statistics—2015 update: A report from the American Heart Association
Circulation
Interpretation of outcomes of antiarrhythmic clinical trials: Design features and population impact
Circulation
Sudden cardiac death risk stratification
Circ Res
The spectrum of epidemiology underlying sudden cardiac death
Circ Res
Sudden cardiac death
Circulation
Sudden cardiac death: Epidemiology, causes, and mechanisms
Cardiology.
2015 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC) Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC)
Eur Heart J
Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction
N Engl J Med
Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure
N Engl J Med
Long-term clinical course of patients after termination of ventricular tachyarrhythmia by an implanted defibrillator
Circulation
Emerging role of multimodality imaging to evaluate patients at risk for sudden cardiac death
Circ Cardiovasc Imaging.
Long-term recording of cardiac arrhythmias with an implantable cardiac monitor in patients with reduced ejection fraction after acute myocardial infarction the cardiac arrhythmias and risk stratification after acute myocardial infarction (CARISMA) study
Circulation
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