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Advances in Cardiovascular Imaging
Emerging Role of Multimodality Imaging to Evaluate
Patients at Risk for Sudden Cardiac Death
Matteo Bertini, MD; Martin J. Schalij, MD, PhD; Jeroen J. Bax, MD, PhD; Victoria Delgado, MD, PhD
A
related to SCD such as myocardial ischemia, myocardial scar,
and viability and sympathetic neuronal dysfunction.
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ccurate identification of patients at high risk for sudden cardiac death (SCD) has been one of the objectives of research
in the last years. With an annual incidence between 184 000 and
462000, SCD is a major public-health problem.The most common cause of SCD is a malignant ventricular arrhythmia and,
in the majority of patients with SCD, the underlying anatomic
substrate can be identified.2,3 Ischemic heart disease, idiopathic
dilated cardiomyopathy (DCM), and hypertrophic cardiomyopathy are the most frequent structural heart diseases associated
with SCD. Regardless of the underlying structural heart disease,
the use of implantable cardioverter defibrillators (ICD) for secondary prevention of SCD is supported by extensive evidence
demonstrating the superiority of ICD over antiarrhythmic drug
therapy in reducing SCD and all-cause mortality of patients
resuscitated from cardiac arrest.4 Furthermore, in patients with
ischemic and nonischemic heart failure, the superior efficacy of
ICD over antiarrhythmic therapy for primary prevention of SCD
has been demonstrated in multiple randomized controlled trials
with >6000 patients included.4 However, recommendations for
ICD implantation for primary prevention in patients with other
structural heart diseases such as hypertrophic cardiomyopathy
or right ventricular arrhythmogenic dysplasia rely on prospective registries or retrospectively analyzed series and predictive
markers of SCD have not been definitively established.
Based on inclusion criteria of multicenter ICD trials for primary prevention, left ventricular ejection fraction (LVEF) ≤35%
is one of the major criteria for ICD implantation.However,
patients with reduced LVEF constitute a small proportion of
the individuals who die suddenly and most of the SCD events
occur in patients who do not have symptoms or signs of cardiac disease yet.6 In addition, in the Multicenter Automatic
Defibrillator Implantation Trial II (MADIT II), only 35% of
patients randomized to the ICD arm received appropriate therapy during 3 years’ follow-up.7 These observations underscore
the limited accuracy of LVEF to identify patients at high risk
for SCD. Accordingly, understanding of the underlying mechanisms of SCD is needed to better identify patients with increased
risk of life-threatening arrhythmias who may benefit from ICD
implantation. In clinical practice, noninvasive multimodality
imaging is a valuable tool that provides the most comprehensive information on different pathophysiological mechanisms
Mechanisms of Ventricular Arrhythmia
The pathophysiology of ventricular arrhythmias is complex
and involves the anatomic and functional substrate, transient
factors altering the electrophysiological stability of the substrate and proximate mechanisms of arrhythmia.3 In patients
with structural heart disease (ischemic heart disease, dilated,
and hypertrophic cardiomyopathy), reentry is the most frequent mechanism of ventricular tachycardia/fibrillation (VT/
VF). A central area of conduction block (functional or fixed),
an unidirectional conduction block and a zone of slow conduction, allowing the impulse to re-excite the tissue proximal
to the line of unidirectional block, are prerequisites for reentry
to occur and all require certain spatial heterogeneity of the
tissue.8 In infarcted areas (and their border zones) inexcitable scar tissue is the most common cause of fixed conduction block. Furthermore, the interposition of bundles of scar/
fibrous tissue within layers of viable myocytes enhances the
degree of nonuniform anisotropy, favors electric uncoupling,
and creates areas of unidirectional conduction block and slow
conduction. In addition, cellular hypertrophy and changes in
the density and distribution of gap junction channels impact
strongly on cellular coupling contributing to abnormal conduction and favoring reentrant and focal arrhythymias.9 Current
noninvasive imaging modalities, such as MRI and nuclear
imaging provide important information on extent and location
of myocardial fibrosis. However, the role of noninvasive imaging modalities to evaluate the relative contribution of other
molecular and cellular determinants of abnormal conduction
remains unexplored.
In addition, transient factors that influence the arrhythmogenic substrate may increase the electric heterogeneity.
Myocardial ischemia may enhance regional electric heterogeneity of the myocardium by prolongation of the action potential
duration, alteration of calcium handling and myocyte membrane properties, reduced cellular coupling, and redistribution
of connexines.10 Furthermore, the association between altered
sympathetic innervation and arrhythmia susceptibility is well
established.11 In pathological conditions such as heart failure
Received January 19, 2012; accepted May 1, 2012.
From the Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
Correspondence to Victoria Delgado, MD, PhD, Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The
Netherlands. E-mail [email protected]
(Circ Cardiovasc Imaging. 2012;5:525-535.)
© 2012 American Heart Association, Inc.
Circ Cardiovasc Imaging is available at http://circimaging.ahajournals.org
525
DOI: 10.1161/CIRCIMAGING.110.961532
526 Circ Cardiovasc Imaging July 2012
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Figure 1. Integration of 3-dimensional electroanatomical voltage mapping and contrast-enhanced MRI for characterization of the arrhythmogenic substrate. A, Electroanatomical voltage mapping of a patient with apical myocardial infarction. The different voltages obtained in
the infarct, peri-infarct and remote zone are color-coded. B, Endocardial and epicardial 3-dimensional volume renderings of the left ventricle obtained with MRI. The infarct, peri-infarct and remote zones are also color-coded in purple, orange and green, respectively.
C, The LV 2-chamber view imaged with contrast-enhanced MRI image with the mapping points superimposed. The mapping points in
each area are color-coded as the electroanatomical voltage mapping. Adapted with permission from Wijnmaalen et al 17. Abbreviations:
MRI, magnetic resonance imaging.
or long QT syndrome, sympathetic stimulation enhances
dispersion of repolarization or induces after-depolarizations
contributing to arrhythmogenesis. Also, in ischemic cardiomyopathy, the extent of denervated ventricular myocardium is
strongly related to increased arrhythmogenicity.12,13
In the last years, noninvasive imaging has provided important insight into the identification of patients at risk of SCD
by characterizing the arrhythmogenic substrate and its interaction with different transient factors that modulate mechanisms
of arrhythmia.
Risk of SCD in the Various Cardiomyopathies:
Role of Multimodality Imaging
Coronary Artery Disease and Ischemic
Heart Failure
Ischemic heart disease is the anatomic substrate in 80% of
SCD events. The presence of scar tissue interspersed with
bundles of viable myocardium forms the anatomic substrate
for reentrant VT, the most frequent arrhythmogenic mechanism in patients with chronic heart disease.14,15 The reentrant
wavefront originates from areas of viable myocardium surrounded by fibrous tissue and circulates around scar tissue
that forms functional or anatomically fixed conduction block
areas. These reentrant circuits have been characterized with
3-dimensional catheter-based voltage mapping techniques
(Figure 1).16,17 However, these invasive imaging modalities do
not take into account other transient factors such as ischemia
or activation of the sympathetic nervous system that may influence the anatomic substrate and increase the susceptibility for
VT/VF. Noninvasive imaging permits accurate risk stratification of patients with ischemic heart disease, providing a comprehensive assessment of the anatomic substrate (scar tissue
and viable myocardium) and transient factors (myocardial
ischemia and sympathetic dysfunction).
Myocardial Scar
The extent of myocardial scar is an independent predictor of
ventricular arrhythmias.18–22 Radionuclide techniques (single
photon emission computed tomography [SPECT] and positron emission tomography [PET]), and contrast-enhanced
MRI are the preferred imaging modalities to assess the extent
of scar formation.
With thallium-201 (201Tl) or technetium-99m (99mTc)
sestamibi/tetrofosmin SPECT imaging, myocardial scar is
visualized as fixed perfusion defects (Figure 2). One of the
first studies evaluating the association between myocardial
scar and cardiovascular mortality included 1926 patients
who underwent 201Tl SPECT imaging and demonstrated
that fixed defects were associated with a 21% relative
risk of cardiovascular mortality at long-term follow-up.23
Likewise, in 153 survivors of SCD, the presence of scar tissue on SPECT was independently predictive of arrhythmic
death and VT recurrence (hazard ratios of 4.2, 95% CI 1.3–
14; P=0.02).22 Similarly, myocardial scar tissue is visualized as fixed perfusion defects on PET using oxygen-15
[15O] labeled water, ammonia labeled with nitrogen-13
[13N] and rubidium-82 [82Rb]. Recent work involving 1432
patients undergoing 82Rb PET, revealed that the amount of
myocardial scar was strongly associated with incidence of
cardiac death.24
Delayed contrast-enhanced MRI has the highest spatial resolution for assessment of scar tissue and has further increased
the understanding of the pathophysiology of SCD in patients
with ischemic heart disease.18,25–28 T1-weighted MRI sequences
acquired 10 minutes after intravenous contrast administration
permit detection of scar areas as small as 0.16 g.29 Compared
with normal myocardium, the infarct areas have an increased
extracellular matrix where the contrast agent is trapped. Using
“inversion time scout” or “look locker” sequences, the time
inversion is selected to null myocardial signal permitting differentiation between normal myocardial tissue and scar, which
appears as hyperenhanced, white areas (Figure 2). The extent
and characteristics of scar tissue on contrast-enhanced MRI have
been related to increased risk of cardiac death and v­ entricular
arrhythmias.18,25–28 Initial reports demonstrated the superiority of
myocardial scar burden on contrast-enhanced MRI over LVEF
Bertini et al Imaging for SCD 527
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Figure 2. Assessment of myocardial tissue heterogeneity in ischemic heart failure patients at risk for SCD. Multimodality imaging for
evaluation of a 63-year old man with prior anterior myocardial infarction and LVEF 33% who was referred for ICD implantation for primary prevention. Coronary angiography did not demonstrate significant new coronary stenosis compared with prior angiography. With
2-dimensional speckle tracking echocardiography, regional longitudinal strain could identify the transmural infarct area in the anterior apical region (with a value of longitudinal strain >−5%), the peri-infarct zone (regions surrounding the transmural area) and the remote zone.
In addition, myocardial perfusion imaging with 99mTc-tetrofosmin SPECT showed in the corresponding short-axis (top), vertical long-axis
(middle) and horizontal long-axis (bottom) a fixed defect in the apical segments and mid anterior wall indicating scar formation. There
were no reversible perfusion defects excluding myocardial ischemia. Finally, late gadolinium enhanced MRI (LGE-MRI) confirmed a transmural infarction in the anteroapical region with nontransmural scar in the interventricular septum.
for prediction of ventricular arrhythmias.18 Furthermore, defining different signal intensity thresholds on contrast-enhanced
MRI data permits differentiation and quantification of the core
infarct zone and the peri-infarct or border zone (bundles of viable
myocardium intermingling with fibrous tissue).30 The extent of
the peri-infarct zone emerged as a powerful predictor of cardiac
death and ventricular arrhythmias.26,27 In 144 patients with prior
myocardial infarction, the hazard ratios for all-cause and cardiovascular mortality were 1.42 (95% CI, 1.11–1.81; P=0.005) and
1.49 (95% CI, 1.09–2.03; P=0.014), respectively per each 10%
increment in extent of the peri-infarct zone.28 Subsequently,
Roes et al demonstrated that the extent of the peri-infarct zone
was the only independent predictor of appropriate ICD therapies or cardiac mortality.26 These observations underscore the
need for detailed characterization of the anatomic substrate to
predict ventricular arrhythmias. Particularly, diffusion spectrum MRI tractography is a promising technique that displays
the 3-dimensional myocardial fiber architecture and detects the
presence of a mesh-like network of orthogonally-oriented residual myofibers within the infarct area that may increase the risk
of reentrant VT (Figure 3).31
Other noninvasive imaging modalities have further enabled
tissue and functional characterization of the peri-infarct zone
and infarct core. Recent studies have demonstrated the feasibility of contrast-enhanced multidetector row computed
tomography (MDCT) for tissue characterization.32–34 In addition, the functional properties of the peri-infarct zone have
been evaluated with tagged-MRI and 2-dimensional speckle
tracking echocardiography (Figure 2).35,36 In 424 patients with
ischemic cardiomyopathy referred for ICD implantation to
prevent SCD, the presence of impaired segmental longitudinal
strain in the peri-infarct zone was independently associated
with an increased risk of appropriate ICD therapy for VT/VF
(hazard ratio, 1.22; 95% CI, 1.09–1.36, P<0.001).36
Figure 3. Novel MRI techniques for tissue characterization. Diffusion spectrum
MRI tractography displays the 3-dimensional myocardial fiber architecture
and permits visualization of the microstructural changes that take place after
myocardial infarction. Panel A shows an
example of structurally normal heart. In
contrast, panel B shows the formation of
a mesh-like network of orthogonallyoriented residual myofibers within the
infarct area. Adapted with permission
from Sosnovik et al.31
528 Circ Cardiovasc Imaging July 2012
Figure 4. Neuronal cardiac imaging with 11C-HED PET. A, Myocardial 11C-HED uptake in a healthy subject, showing homogeneous
distribution of the radiotracer in the left ventricle. B, A DCM patient with reduced 11C-HED uptake in the lateral wall of the left ventricle.
C, A patient with ischemic heart disease showing a defect in the apical segment of the left ventricle and reduced 11C-HED uptake in the
septum. Adapted with permission from Pietilä et al.49
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Myocardial Ischemia and Viability
Various studies have shown that myocardial ischemia is an
important trigger of VT/VF whereas coronary revascularization reduced SCD risk.22,37,38 Furthermore, hibernating myocardium has been associated with increased risk of SCD.39,40
SPECT and PET imaging, stress echocardiography and myocardial perfusion MRI provide further risk stratification of
patients with ischemic heart disease by assessing these transient factors (ischemia and viability) that may influence the
arrhythmogenic substrate.21,22,41–43
SPECT myocardial perfusion imaging using 201Tl and 99mTc
as radionuclide tracers provides the largest evidence relating the presence of abnormal myocardial perfusion at peak
stress and the increased risk of VT/VF and SCD.21,22,44,45
Hachamovitch et al demonstrated in 5183 patients who underwent stress/rest dual isotope myocardial perfusion SPECT
that the risk of cardiac death was associated with the severity
of myocardial perfusion abnormalities at peak stress.44 These
results were recently confirmed by Piccini and coworkers, in
a cohort of 6383 patients with known coronary artery disease
who underwent SPECT imaging.21 Increasing summed stress
scores were independently associated with increased risk of
SCD (hazard ratio, 1.16 per 3-U increase; 95% CI, 1.08–
0.125, P<0.0001). Furthermore, SPECT myocardial perfusion
imaging has shown to be an effective method of risk stratification in patients with known coronary artery disease but relatively preserved LVEF (>35%).46 In this group of patients, the
extent of stress myocardial perfusion defects was also associated with an increased risk of SCD (hazard ratio, 1.13 per each
3-U increase in the summed stress score; 95% CI, 1.04–1.23).
These findings highlight the relevance of evaluation of the
arrhythmogenic substrate and transient factors that influence
this substrate, both in patients with low and preserved LVEF.
The association between myocardial viability assessed
with PET and risk of ventricular arrhythmias has also been
explored.24,41 Hibernating myocardium is commonly assessed
in clinical practice with 18-fluorine (18F) fluorodeoxyglucose
PET imaging combined with perfusion imaging. The socalled flow-metabolism mismatch pattern (myocardial hypoperfusion with enhanced glucose myocardial metabolism)
identifies dysfunctional but viable myocardium. In contrast,
hypoperfusion combined with reduced glucose metabolism indicates myocardial scar. In a series of 107 ischemic
heart failure patients undergoing resting myocardial perfusion and metabolic PET imaging with 13N-ammonia and
18
F-fluorodeoxyglucose, respectively, the flow-metabolism
mismatch pattern was related to an increased risk of cardiac
death.41 Patients with an extent of flow-metabolism mismatch >5% of the left ventricle (LV) showed an estimated
annual survival of 50%, significantly lower compared with
the group of patients without flow-metabolism mismatch
(92%; P=0.007).41 More important, the study demonstrated
that revascularization of patients with flow-metabolism mismatch conveyed a superior long-term outcome compared with
patients who were medically treated (annualized survival rate
of 88% versus 50%, P=0.003).41
Other noninvasive imaging modalities such as stress myocardial perfusion MRI and stress echocardiography have also
provided important prognostic information.43,42 Particularly,
integrated myocardial ischemia and scar assessment with
vasodilator stress MRI perfusion and contrast-enhanced MRI
has demonstrated to be a powerful risk stratification tool. In
254 patients with suspected or known coronary artery disease,
the presence of reversible perfusion defect (ischemia) and
contrast-enhanced areas (scar) showed >3-fold independent
association with cardiac death or acute myocardial infarction.43 Similarly, the assessment of ischemia and viable myocardium with dobutamine stress echocardiography has shown
to accurately predict the occurrence of VT.42 In 90 patients
with known coronary artery disease who received an ICD for
primary or secondary prevention, induction of ischemia during stress echocardiography was an independent determinant
of death or ICD therapy at follow-up (hazard ratio, 2.1, 95%
CI, 1.2–3.5, P<0.001).42
Sympathetic Innervation
Cardiac sympathetic innervation imaging has emerged as an
important risk stratification tool for patients with ischemic
heart failure. Using radiolabeled norepinephrine analogs, the
anatomic integrity and function of the sympathetic nerve terminals of the heart can be evaluated with SPECT and PET
imaging.47
Carbon-11 (11C) hydroxyephedrine (HED) is the most
widely used PET tracer to quantify the density of sympathetic nerve terminals and its cardiac uptake correlates
with norepinephrine tissue concentration.48 Reduced retention of 11C-HED on PET images indicates the presence of
regional sympathetic denervation (Figure 4). The prognostic value of 11C-HED PET cardiac innervation imaging was
described by Pietilä and coworkers.49 A total of 46 heart
failure patients, including 33 patients with prior myocardial
infarction, underwent 11C-HED PET imaging. During a mean
follow-up period of 55 months, 11 cardiac deaths (9 SCD)
and 2 heart transplants were recorded. Reduced retention of
Bertini et al Imaging for SCD 529
Figure 5. 123I-MIBG planar and SPECT imaging to assess cardiac sympathetic innervation. A, 123I-MIBG planar imaging permits the
measurement of the late H/M ratio. The regions of interest are located at the mediastinum and including the heart. Example of a heart
failure patient with relatively preserved late H/M ratio (1.77). B, 123I-MIBG SPECT imaging showing an extensive defect in the apical
regions of the left ventricle, indicating, therefore, cardiac denervation of this region. C, Kaplan-Meier estimates of appropriate ICD
therapies in patients with an 123I-MIBG SPECT summed defect score ≤26 and >26. Adapted with permission from Boogers et al.52
C-HED was independently associated with cardiac mortality and heart transplant (hazard ratio, 19.3, 95% CI, 2.6–142;
P=0.014).49 In addition, the presence of denervated myocardial areas with preserved perfusion (perfusion-innervation
mismatch) has been associated with an increased susceptibility for ventricular arrhythmias.50 Combining PET myocardial
perfusion imaging with 13N-ammonia and cardiac innervation
PET imaging with 11C-HED PET in an animal model of myocardial infarction, Sasano et al demonstrated that the extent
of perfusion-innervation mismatch was significantly larger
in the animals with induced monomorphic VT as compared
with the animals without inducible VT (10±4% versus 4±2,
P=0.02).50
PET imaging has a higher temporal and spatial resolution
compared with SPECT imaging. However, because of the limited local availability of this imaging tool, cardiac innervation
is more frequently assessed with SPECT imaging. The SPECT
tracer 123-iodine (123I)-metaiodobenzylguanidine (MIBG)
mimics the uptake, storage and release of norepinephrine in
the sympathetic nerve endings. However, 123I-MIBG is not
metabolized and does not interact with postsynaptic receptors allowing visualization of the sympathetic postganglionic
presynaptic fibers using both planar and SPECT imaging.
From the planar images, global myocardial MIBG uptake
can be assessed using the heart-to-mediastinum (H/M) uptake
ratio and the washout rate. The recent AdreView Myocardial
Imaging for Risk Evaluation in Heart Failure (ADMIRE-HF)
trial, including 961 heart failure patients (68% ischemic cardiomyopathy), demonstrated the independent prognostic
value of 123I-MIBG imaging.51 The occurrence of life-threatening arrhythmic events was prospectively related to cardiac
sympathetic neuronal integrity quantified as the late H/M
uptake ratio on planar MIBG images. The risk of arrhythmic
events at follow-up was significantly higher in patients with
more impaired cardiac sympathetic innervartion, defined by a
late H/M ratio <1.6, compared with patients with a late H/M
ratio ≥1.6 (10.4% versus 3.5%, P<0.001). In addition, using
SPECT images, quantification of regional abnormalities on
123
I-MIBG tracer uptake has also been independently related
to ventricular arrhythmic events (Figure 5).52 In 116 heart failure patients (74% ischemic heart failure) who received an ICD
device for primary or secondary prevention, a late 123I-MIBG
SPECT summed defect score >26 discriminated between
11
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patients with and without increased susceptibility for arrhythmic events. The cumulative event rates at 3 years follow-up
was significantly higher in patients with a late 123I-MIBG
SPECT summed defect score >26 (52% versus 5%, P<0.01)
(Figure 5). At multivariate analysis, late 123I-MIBG SPECT
defect score was an independent predictor of arrhythmic
events (hazard ratio, 1.13; 95% CI, 1.05–1.21; P<0.01) after
adjusting for ICD indication (primary/secondary), heart failure etiology and other myocardial perfusion imaging-derived
parameters.52
These experiences demonstrate that noninvasive imaging
may play an important role in the risk stratification of patients
with chronic ischemic heart disease. An integrated approach
evaluating the anatomic substrate and transient factors that
may precipitate ventricular arrhythmias (myocardial scar,
ischemia and viability and sympathetic innervation) in addition to LVEF may refine risk stratification.
Idiopathic Dilated Cardiomyopathy
Idiopathic dilated cardiomyopathy accounts for 10% of SCD
in the adult population.3 In addition, up to 30% of deaths in
patients with DCM are sudden.53 Pooled analysis from primary and secondary prevention trials including 2110 patients
with DCM showed a statistically significant 31% survival
benefit for ICD over medical therapy (relative risk 0.69; 95%
CI, 0.56–0.86; P=0.002).54 Scar-related reentrant VT, bundle
branch reentrant VT and focal automaticity VT have been proposed as arrhythmogenic mechanisms in DCM.55 In addition,
activation of the sympathetic nervous system and release of
catecholamines may increase ventricular arrhythmias directly
or by enhancing extracellular hypokalemia.10,56 In the last
years, evaluation of arrhythmogenic substrate in DCM has
been directed at the detection and characterization of myocardial scar and sympathetic innervation.25,57–60
Contrast-enhanced MRI has provided important information on the relation between myocardial scar burden, scar location and the risk of ventricular arrhythmias.57,59,61,62 In DCM,
scar tissue usually involves the midwall or shows a patchy distribution. In 26 patients with DCM who were referred for an
electrophysiological study or ICD implantation, Nazarian et
al demonstrated that distribution of myocardial scar assessed
with contrast-enhanced MRI was predictive of (inducible)
sustained monomorphic VT.59 After adjustment for LVEF, scar
530 Circ Cardiovasc Imaging July 2012
Figure 6. Assessment of arrhythmogenic
substrate in hypertrophic cardiomyopathy. A, On 2-dimensional echocardiography, the thickness of the septum >30 mm
is a risk factor for ventricular arrhythmias.
B, On contrast-enhanced MRI thickness
and presence of focal myocardial fibrosis in the interventricular septum can be
assessed (arrow).
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tissue involving 26% to 75% of the myocardial wall thickness
was an independent predictor of inducible VT (odds ratio,
9.125, P=0.02).59 These results were further confirmed in a
study including 101 patients with DCM.57 In as much as 35%
of patients, midwall fibrosis was identified and its presence
was related with an increased risk of VT and SCD (hazard
ratio, 5.2, 95% CI, 1.0–26.9; P=0.03).57 Therefore, this evidence confirms once more the prognostic value of myocardial
scar assessment in patients with DCM.
Regional sympathetic denervation may also occur in DCM
because of scar formation, increasing arrhythmogenic susceptibility.11 Alterations of presynaptic sympathetic innervation in
patients with dilated cardiomyopathy have been demonstrated
using 11C-HED PET.63 In 10 patients with DCM, the presynaptic catecholamine uptake assessed with 11C-HED PET
was significantly reduced as compared with normal controls
(6.8±1.9%/min versus 11.0±0.6%/min, P<0.01) and showed
a heterogeneous distribution with the lowest retention of 11CHED in the apical regions of the left ventricle.63 In 56 DCM
patients, Kasama et al demonstrated that several parameters
measured on 123I-MIBG planar imaging and SPECT (H/M
ratio, wash-out ratio) were associated with the presence of
late ventricular potentials in signal averaged ECG, indicating increased risk of VT and SCD.64 Patients with poor cardiac innervation presented with late ventricular potentials on
advanced ECG testing and, importantly, patients with late ventricular potentials and a high wash-out ratio (≥50%) showed
the highest incidence of SCD (41.2%).64
Based on this evidence, multimodality imaging may
improve our understanding of the underlying mechanisms of
arrhythmia in patients with DCM and refine the therapeutic
strategy.
Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy is the most frequent cause of
SCD in populations younger than 40 years.5 The risk of SCD
is almost 1% annually in patients with hypertrophic cardiomyopathy.65 Compelling evidence has demonstrated that ICD
is an effective life-saving treatment in patients with hypertrophic cardiomyopathy and ≥1 risk factors.66 However, the
heterogeneity in disease presentation and expression with its
relative low prevalence, challenge the identification of hypertrophic cardiomyopathy patients at high risk for SCD. Reentry
is the most common mechanism of VT and may be favored by
the presence of myocardial disarray, increased fibrosis, and
abnormal microvasculature.67 Furthermore, transient factors
such as ischemia or exaggerated response to catecholamines
may enhance the electrophysiological instability of the anatomic substrate, increasing the arrhythmogenic susceptibility.
One of the major risk factors for SCD is an LV thickness
≥30 mm as assessed with echocardiography (Figure 6).67
Ongoing research has been focused on detection of myocardial fibrosis with contrast-enhanced MRI and evaluation of its
predictive value for the occurrence of life-threatening arrhythmias.68–71 Variable patterns of contrast-enhancement can be
observed: transmural and nontransmural contrast-enhancement in focal, multifocal or confluent patterns. The independent association between myocardial fibrosis assessed with
contrast-enhanced MRI and the risk of ventricular arrhythmias
was demonstrated by Adabag and coworkers in 177 patients
with hypertrophic cardiomyopathy.68 Patients with myocardial
fibrosis had 7-fold higher risk of nonsustained VT as compared with patients without myocardial fibrosis (relative risk
7.3; 95% CI, 2.6–20.4; P<0.0001). In multivariate analysis,
after adjustment for age and LV thickness, presence of myocardial fibrosis assessed with contrast-enhanced MRI was the
only independent predictor of ventricular arrhythmias.68 In 217
hypertrophic cardiomyopathy patients, O’Halon et al showed
a higher 3-year cumulative event rate in patients with myocardial fibrosis versus patients without fibrosis (25% versus 7.4%;
hazard ratio, 3.4, P=0.006).71 The incidence of ventricular
arrhythmias was higher in the group of patients with myocardial fibrosis (5.9% versus 1.2%; hazard ratio 4.97, P=0.131).71
However, this difference was not statistically significant and,
therefore, additional evidence may be warranted to establish
myocardial fibrosis as a risk marker for SCD in hypertrophic
cardiomyopathy.
Myocardial ischemia is another transient factor that may
favor ventricular arrhythmias in patients with hypertrophic cardiomyopathy, and has been reported in up to 62%
of patients with hypertrophic cardiomyopathy during stress
myocardial perfusion imaging using SPECT.72 In 158 patients
with hypertrophic cardiomyopathy, the presence of myocardial ischemia was associated with lower 5- and 10-year cardiovascular survival rates compared with patients without
ischemia (88% and 64% versus 99% and 90%, respectively;
P=0.02).72 The presence of myocardial ischemia was an
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Figure 7. Arrhythmogenic right ventricular dysplasia/cardiomyopathy. A, Transthoracic echocardiography shows dilatation of the right
ventricle and aneurysms (arrows) in the mid and apical free wall of a 45-year old man who underwent ICD implantation after presenting
with sustained VT (left bundle branch block morphology). Prior to ICD implantation, MRI was performed confirming moderate RV dilatation and dysfunction with aneurysms in the apex and free wall of the RV and RVOT (B and C). Orthogonal views of the RV are recommended to better detect aneurysms. On late gadolinium enhanced MRI, hyperenhanced areas of the RV free wall were observed (arrows)
indicating fibrosis (D). Finally, the ECG showed inverted negative T wave in right precordial leads (V2–V3) without right bundle branch
block morphology (arrows). Abbreviations: RA, right atrium; RV, right ventricle; RVOT, right ventricular outflow tract.
independent predictor of cardiovascular death (hazard ratio,
1.77; 95% CI, 1.04–3.02; P=0.04).
Finally, an increased myocardial catecholamine concentration may lead to a downregulation of the postsynaptic myocardial β2-adrenoreceptor with subsequent development of heart
failure and ventricular arrhythmias.73 Using PET imaging with
11
C-CGP12177, Choudhury et al demonstrated a reduced density of myocardial β2-adrenoreceptor in patients with hypertrophic cardiomyopathy and preserved LVEF, but the prognostic
implications of these findings require additional studies.73
Arrhythmogenic Right Ventricular
Dysplasia/Cardiomyopathy
Arrhythmogenic right ventricular dysplasia/cardiomyopathy
(ARVD/C) is a genetically determined cardiomyopathy characterized by fibrofatty tissue replacement of the right ventricular
myocardium.74 The genetically-determined disruption of desmosomal integrity may lead to detachment of myocytes at the intercalated discs with progressive myocyte degeneration and death
and subsequent repair with fibrofatty replacement.75 During this
progressive myocyte degeneration, 4 phases can be identified as
1) a subclinical phase with concealed structural abnormalities and
no symptoms; 2) overt right ventricular electric disorder; 3) over
right ventricular failure; and 4) biventricular failure. Sustained
monomorphic VT with left bundle branch morphology is the
most common ventricular arrhythmia.74 Whereas VF can occur
at any phase of the disease, scar-related macro-reentrant VT is
more commonly observed at later stages of the disease. The
available evidence based on observational studies indicates that
ICD is a reasonable therapy for secondary prevention of SCD.5
However, identification of patients with ARVD/C and high risk
for life-threatening arrhythmias to warrant ICD for primary prevention is still challenging.76 Recently, the criteria for diagnosing this cardiomyopathy have been revised and incorporated new
evidence to improve the diagnostic sensitivity while maintaining
specificity.74 Two-dimensional and contrast echocardiography
remain the imaging techniques of choice. However, contrastenhanced MRI has emerged as a valuable tool to characterize
the right ventricular myocardium.77 Regional akinesia or dyskinesia or dyssnchronous right ventricular contraction along with
right ventricular dilatation or impaired systolic function assessed
with MRI are major diagnostic criteria. Furthermore, the presence of fibrous replacement of right ventricular myocardium
(with or without fatty replacement) on endomyocardial biopsy
is another major diagnostic criterion of ARVD/C.74 Contrastenhanced MRI has demonstrated to be a valid alternative to
endomyocardial biopsy.77 This fibrous or fibrofatty replacement of the right ventricular myocardium appears as bright,
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Figure 8. Assessment of mechanical left ventricular dispersion in patients with long-QT syndrome. Segmental LV strain permits evaluation of time to peak longitudinal and circumferential strain and to estimate the mechanical dispersion between the endocardium (as
assessed with longitudinal strain) and the midmyocardium (as assessed with circumferential strain). In this 31-year old woman with long
QT syndrome type 2 who experienced torsade de pointes (shown in the ECG), the mechanical dispersion between the 2 myocardial layers was 155 ms (difference of contraction duration of the basal lateral segment assessed with circumferential [upper panel] and longitudinal [lower panel] strain).
hyperenhanced areas on contrast-enhanced MRI (Figure 7).
Moreover, the relationship between the presence of myocardial
fibrosis on contrast-enhanced MRI and the occurrence of ventricular arrhythmias was demonstrated by Tandri et al in 12 patients
with ARVD/C. Inducible VT on electrophysiological testing was
demonstrated in 6 of 10 patients; all of them showed myocardial
fibrosis of the right ventricle on contrast-enhanced MRI. In contrast, only 1 of 4 patients without inducible VT showed hyperenhancement of the right ventricle (P=0.001). Additional studies
with larger series are needed to confirm these results.
In addition, the potential role of sympathetic innervation on
the genesis of ventricular arrhythmias in this group of patients
has been described.78,79 Loss of sympathetic neurons, increased
synaptic norepinephrine confined in the heart and enhanced
myocardial sensitivity to catecholamines have been proposed
as underlying mechanisms of ventricular arrhythmias.78,79
With the use of 123I-MIBG SPECT, the presence of regionally reduced tracer uptake in the left ventricle was reported in
patients with ARVD/C.78 These areas with reduced 123I-MIBG
uptake, which may correspond to denervated areas, were
located in the basal posteroseptal segments of the left ventricle
and correlated with right ventricular outflow tract origin of VT.
Fibrofatty replacement processes that progress from the epicardium toward the subendocardium may affect the sympathetic
nerves at an early stage of the disease leading to heterogeneous
sympathetic innervation. Furthermore, reduced presynaptic
neuronal catecholamine reuptake and reduced postsynaptic
β2-adrenoreceptor density were demonstrated in 8 patients with
ARVD/C using PET imaging and 11C-HED and 11C-CGP12177
as tracers, respectively.79 This reduced presynaptic reuptake of
norepinephrine results in increased local levels of this catecholamine with subsequent downregulation of the postsynaptic
β2-adrenoreceptor. These findings are relevant given that pharmacological interventions that normalize cardiac sympathetic
innervation may reduce the risk of VT and SCD.
Primary Electric Disorders
Noninvasive cardiac imaging has also provided new insights
in risk stratification of this heterogeneous group of patients
with normal LVEF but electrophysiological myocardial
derangement that predisposes to life-threatening arrhythmias.
Congenital or acquired long-QT syndrome, Wolff-Parkinsonwhite syndrome, Brugada’s syndrome are included in this
group. Particularly, congenital long-QT syndrome is caused by
Bertini et al Imaging for SCD 533
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inherited channelopathies that lead to prolongation of action
potential duration and repolarization, increasing the risk of
early afterdepolarizations and polymorphic VT. Transmural
differences in the action potential duration may increase the
arrhythmogenic susceptibility. These subtle electric derangements may cause mechanical dysfunction. Particularly,
2-dimensional speckle tracking echocardiography has unraveled inhomogeneous myocardial contraction within the left
ventricle in patients with long-QT syndrome.80 This novel
echocardiographic technique permits angle-­
independent
assessment of myocardial deformation in 3 orthogonal directions (longitudinal, radial and circumferential). In 101 genotyped long-QT mutation carriers, including 48 symptomatic
patients with documented ventricular arrhythmias, longitudinal and circumferential LV myocardial strain was measured with 2-dimensional speckle tracking echocardiography.
Longitudinal strain represents the mechanical function of
the subendocardial myofibers whereas circumferential strain
represents the function of the midmyocardium. Indices of
mechanical dispersion, calculated as differences in time to
regional peak strain, were measured in the subendocardium
and midmyocardium (Figure 8). Symptomatic long-QT syndrome mutation carriers showed longer QTc (495±50 ms
versus 460±30 ms, P<0.001) and more pronounced QTc dispersion (56±23 ms versus 48±17 ms, P=0.04) as compared
with asymptomatic carriers. Interestingly, subendocardial
(longitudinal) and midmyocardial (circumferential) mechanical dispersions were significantly larger in symptomatic carriers as compared with asymptomatic carriers (45±13 ms
versus 27±12 ms and 46±22 ms versus 26±21 ms, respectively; P<0.001 for both).80 Therefore, in primary electric
disorders, assessment of LV mechanics with novel echocardiographic techniques may be important tools to risk stratify
these patients.
Conclusions
The limited value of LVEF to identify patients with high risk
for SCD who may benefit from ICD implantation has promoted
research to characterize and visualize the arrhythmogenic substrate and its interaction with transient factors that modulate
basic arrhythmia mechanisms. Noninvasive measurements of
temporal and spatial heterogeneity of dispersion of ventricular repolarization with microvolt T-wave alternans have shown
high negative predictive value (97%) but low positive predictive value (19%) for arrhythmic events.81,82 Signal-averaged
ECG used to detect late potentials has been also associated
with the occurrence of ventricular arrhythmias in postmyocardial infarction and DCM patients. However, several limitations such as a relatively high percentage of inconclusive
tests (20%–40%) and low positive predictive value hamper
the integration of these techniques in clinical practice.81,83
Noninvasive imaging has permitted to directly visualize the
arrhythmogenic substrate and evaluate the transient factors
that may increase the arrhythmic susceptibility. Accurate visualization of myocardial scar or fibrosis with contrast-enhanced
MRI, identification of ischemic and viable myocardium with
echocardiography, MRI or radionuclide imaging and evaluation of cardiac sympathetic innervation with PET and SPECT
imaging may provide a comprehensive assessment of the
arrhythmogenic substrate and the factors that enhance the
risk of life-threatening arrhythmias. A potential strategy to
optimize identification of patients who may benefit from ICD
implantation could be integration of advanced ECG testing
and noninvasive imaging.84 In a small series of 63 patients
with unexplained cardiac arrest and no evidence of cardiac
disease, serial testing (MRI, signal-averaged ECG, exercise
testing, drug challenge, and selective electrophysiological
testing) could identify the underlying cause of cardiac arrest
in >50%.85
In summary, noninvasive imaging has improved the insight
in the mechanisms underlying SCD and integration with LVEF
and advanced ECG testing would help to further improve
identification of patients who may benefit from ICD implantation. The challenge for the future will be to develop accurate
models for risk stratification.
Sources of Funding
The department of Cardiology received research grants from Medtronic,
Boston Scientific, Biotronik, St. Jude Medical & GE Healthcare.
Disclosures
Victoria Delgado received consultant fees from St. Jude Medical and
Medtronic. The remaining authors have no conflicts of interest to
disclose.
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KEY WORDS: single-photon emission computed tomography ◼ sudden
cardiac death ◼ tissue characterization
Emerging Role of Multimodality Imaging to Evaluate Patients at Risk for Sudden Cardiac
Death
Matteo Bertini, Martin J. Schalij, Jeroen J. Bax and Victoria Delgado
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Circ Cardiovasc Imaging. 2012;5:525-535
doi: 10.1161/CIRCIMAGING.110.961532
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