Revascularization in Patients With Severe Left Ventricular Dysfunction

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 67, NO. 24, 2016

ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER

http://dx.doi.org/10.1016/j.jacc.2016.03.571

THE PRESENT AND FUTURE STATE-OF-THE-ART REVIEW

Revascularization in Patients With Severe Left Ventricular Dysfunction Is the Assessment of Viability Still Viable? Nandan S. Anavekar, MB, BCH,a Panithaya Chareonthaitawee, MD,b Jagat Narula, MD, PHD,b Bernard J. Gersh, MB, BCH, DPHILa

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assess myocardial viability including their advantages, disadvantages, and limitations; and 3) discuss the current body of knowledge regarding

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the role of noninvasive viability testing in the setting of ischemic heart disease with associated left ventricular dysfunction, including the limitations of applicability and generalizability of these studies to the wider patient population.

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From the aDivision of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota; and the bDivision of Cardiovascular Diseases,

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monitoring boards for Mount Sinai St. Luke’s, Boston Scientific, Teva Pharmaceutical Industries, Janssen Scientific Affairs, St. Jude Medical, Janssen Research & Development, Baxter Healthcare, the Cardiovascular Research Foundation, Medtronic Inc., Xenon Pharmaceuticals, Cipla Limited, the Thrombosis Research Institute, and Armetheon Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Robert Beanlands, MD, served as Guest Editor for this paper. Manuscript received December 23, 2015; revised manuscript received February 18, 2016, accepted March 18, 2016.

Anavekar et al.

JACC VOL. 67, NO. 24, 2016 JUNE 21, 2016:2874–87

Revascularization in Severe LV Dysfunction

Revascularization in Patients With Severe Left Ventricular Dysfunction Is the Assessment of Viability Still Viable? Nandan S. Anavekar, MB, BCH,a Panithaya Chareonthaitawee, MD,b Jagat Narula, MD, PHD,b Bernard J. Gersh, MB, BCH, DPHILa

ABSTRACT Myocardial viability assessment is typically reserved for patients with coronary artery disease and significant left ventricular dysfunction. In this setting, there is myocardial adaptation to an altered physiological state that is potentially reversible. Imaging can characterize different parameters of cardiac function; however, despite previously published appraisals of different imaging modalities, there is still uncertainty regarding the role of these tests in clinical practice. The purpose of this review is to reflect on the physiological basis of myocardial viability, discuss the imaging tests available that characterize myocardial viability, and summarize the current published reports on the use of these tests in clinical practice. (J Am Coll Cardiol 2016;67:2874–87) © 2016 by the American College of Cardiology Foundation.

M

yocardial injury occurs through varied

THE PIVOTAL IMPORTANCE OF

mechanisms,

VENTRICULAR DYSFUNCTION AND PROGNOSIS

most

commonly

in

the

setting of coronary artery disease (CAD).

Cardiac dysfunction consequently leads to a cascade of molecular events to maintain physiological equi-

It has been known for close to half a century that left

librium. Clinical heart failure may ensue secondary

ventricular (LV) function is of prognostic significance

to pump dysfunction and arrhythmias, causing sig-

in cardiovascular disease. In a 10-year follow up of

nificant morbidity and mortality. Therapy is multi-

survival in CASS (Coronary Artery Surgery Study),

faceted, including revascularization paralleled with

admittedly in an era when advances in medical

ancillary pharmacological and nonpharmacological

therapeutics were only in their infancy, the presence

strategies.

of

The

pharmacological

armamentarium

LV

dysfunction

represented

an

important

focuses on altering the neurohormonal response;

discriminant for benefit from bypass graft surgery (1).

the nonpharmacological approaches, primarily car-

A striking finding in the same study was the relatively

diac resynchronization therapy, focus on improving

low 10-year mortality of patients who had a normal

electrical

optimize

ejection fraction (EF), irrespective of the number of

cardiovascular function, prevent progressive remod-

diseased coronary vessels (1). The importance of

eling, allay symptoms of heart failure, and improve

ventricular function has been borne out in multiple

survival.

investigations spanning several decades; the pur-

synchrony.

The

goal

is

to

A challenging clinical scenario remains: the patient

ported mechanisms of benefit post-revascularization

with severe cardiac dysfunction receiving optimal

being manifold, extending beyond the treatment of

medical therapy (OMT) and carrying significant sur-

ischemia alone (Figure 1) (1–10).

gical risk. Can we improve symptoms? Can we

After injury, the heart undergoes adaptive changes

improve survival? Is there a role for viability testing?

with alterations in geometry and function. The pro-

Is there a standalone test, or should different mo-

cess of remodeling is dictated by hemodynamic and

dalities be used complementarily?

neurohormonal factors (11), which trigger a cascade of

This review aims to elaborate on these issues that

events that alter the interaction of myocytes with

are emerging in contemporary practice. We will

each other and with the extracellular matrix. Macro-

review the pathophysiological events in ischemic

scopically this manifests in changes in size, shape,

cardiac dysfunction, noninvasive strategies to image

and wall thickness of the heart. Although initially

viable

published

adaptive, if unchecked, the continued stimulus for

reports regarding patient outcomes with decisions

these changes leads to deleterious effects in the

aided by viability testing.

setting of pre-existing CAD, including progression to

myocardium,

and

the

current

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Revascularization in Severe LV Dysfunction

ABBREVIATIONS

symptomatic heart failure and worsening

utility could be more powerful in combination (19),

AND ACRONYMS

ischemia. Multiple neurohormonal mecha-

allowing for a more complete characterization of the

nisms established in the pathogenesis of

entire myocardial substrate. Such an approach has

heart failure currently serve as important

been found to be of clinical utility in a small pilot study

targets in medical therapy (12–17). The

(19); however, multimodality imaging in the evalua-

importance of these neurohormonal mecha-

tion of myocardial viability has not been studied sys-

nisms is underscored by a recent study (18)

tematically and is not currently recommended.

CABG = coronary artery bypass graft

CAD = coronary artery disease CMR = cardiac magnetic resonance

quantifying inhomogeneity in myocardial

EF = ejection fraction FDG =

18

sympathetic

F-fluorodeoxyglucose

LV = left ventricle/ventricular LVEF = left ventricular ejection

innervation

using

positron

MYOCARDIAL VIABILITY:

emission tomography (PET), which found

STUNNING, HIBERNATION,

this to be predictive of cardiac arrest. The

AND THE MYOCARDIAL SUBSTRATE

study comprised 204 subjects with moderate

fraction

OMT = optimal medical therapy PET = positron emission

to severe reduction in LV function. Myocar-

Pathophysiologically, myocardial viability refers to

dial sympathetic denervation was quantified

those cardiomyocytes that are “alive,” defined by

using the tracer

tomography

11

C-meta-hydroxyephedrine

cellular,

metabolic,

and

microscopic

contractile

and was predictive of sudden cardiac arrest.

function (7,20). Clinically, hibernating and stunned

emission computed

Interestingly, other multivariate predictors

myocardium are subdivisions with differing but

tomography

of sudden cardiac arrest included end-

sometimes overlapping characteristics (Figure 2).

SPECT = single-photon

diastolic volume, serum creatinine, and the absence

The first description of myocardial response to

of angiotensin inhibition. These findings emphasize

acute coronary occlusion was in a dog model in 1935

that the physiological milieu is critical in predicting

(21). In this experiment, ligation of a large coronary

outcomes in patients with ischemic cardiomyopathy

branch vessel resulted in a cyanotic and dilated heart

and that evaluation of such patients must extend

with alterations in contractile function. Nearly half a

beyond ischemia testing alone.

century subsequent to this description, the notion

Cardiac function is not a dichotomous variable;

of the “stunned” myocardium was born (22,23).

aspects of function measured using one modality

Abruptly reduced blood flow initially causes con-

might not be measureable using another. In the area of

tractile dysfunction that persists after blood flow is

myocardial

reports

restored, and this was initially referred as the “hit,

regarding the indications for revascularization in the

run, and stun” phenomenon (22). Although the exact

context of the extent of potentially reversible LV

mechanism remains unclear, it likely represents the

dysfunction remain controversial. Under the rubric of

response of the myocardium to metabolic aberrations

viability, is it the EF, extent of remodeling, extent of

created by acute ischemia. This view is supported by

scar, extent of ischemia, duration of dysfunction, or

the lack of ultrastructural changes in myocyte

a combination that should drive the strategy to treat?

appearance (23,24) and the observation of recovery of

In isolation, these parameters are useful, but their

function, typically over hours to days (7).

viability

testing,

published

It is clear that markedly depressed LV function in the setting of ischemic cardiomyopathy can be

F I G U R E 1 Benefits of Revascularization

reversed with revascularization (9,25). Moreover, those patients with ischemic symptoms and the most

Potential benefits

severe LV dysfunction appear to benefit most from surgical revascularization. In this scenario, a high periprocedural risk must be weighed against an

in resting LVEF

Inducible ischemia

improvement in late mortality (Central Illustration)

Ventricular remodeling

10-year follow-up of patients with ischemic cardio-

Diastolic dysfunction

myopathy, LV dysfunction (LVEF <35%), and CAD

(26). These findings were recently confirmed in a Prevention of ventricular arrhythmias

amenable to coronary artery bypass graft (CABG) (27). In this study, the rate of death of any cause over 10 symptoms of CHF

years was significantly reduced by an absolute difference of 8% in patients who underwent CABG in

Schematic illustration of the purported benefits of revascularization in the setting of coronary artery disease with left ventricular dysfunction. CHF ¼ congestive heart failure; LVEF ¼ left ventricular ejection fraction.

addition to OMT compared with those receiving optimal contemporary medical therapy alone (27). Hibernating myocardium was initially considered to represent an adaptation to a persistent reduction in

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blood flow, significant enough to impair function but

F I G U R E 2 Hibernation and Stunning

not to produce infarction per se (23). This postulate was

supported

by

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Revascularization in Severe LV Dysfunction

findings

of

reduced

resting Mechanistic differences and similarities

myocardial blood flow in dysfunctional myocardial segments, as measured by cardiac magnetic resonance (CMR) and PET imaging techniques (28,29). other investigations suggest that the pathogenesis of

Adverse effect of ischemic injury No histopathologic abnormalities

myocardial hibernation might be nonlinear, with examples of reductions in coronary blood flow that follow

LV

dysfunction

rather

than

precede

Hibernation

Stunning

However, this mechanism is not definitive, because

it

Presumably protective to adaptation flow or ischemia

Severely reduced CFR

(23,30,31). Biopsy specimens of hibernating myocarRepetitive stunning ?

dium demonstrate alterations in both cellular and extracellular structure. Observations at the cellular

Maintain viability Histopathologic changes – progressive and dynamic

level include dedifferentiation to a more embryonic phenotype characterized by loss of sarcomeres and myofibrils, as well as increased storage glycogen

Myocardial hibernation and stunning in the pathophysiology of reversible left ventricular

(23,32–34). These cellular changes are coupled with

dysfunction. These pathophysiological entities appear to lie on a spectrum of cellular and

fibrotic changes in the extracellular matrix. The

molecular adaptations to reduced myocardial blood flow. CFR ¼ coronary flow reserve.

extent of extracellular fibrosis could be linked to reversibility of hibernation, with areas of reduced or absent fibrosis predictive of functional recovery after

stress perfusion, as well as contractile function, with

revascularization (23,34,35). In contradistinction to

dobutamine as the stress agent (19). Contractile

stunned myocardium, functional recovery of the hi-

reserve was assessed with image acquisition during

bernating myocardium is more variable and is likely

low-dose

determined by the severity of derangements incurred

myocardial dysfunction were defined. Myocardial

at the microscopic level. The time of recovery can be

hibernation was defined as segments with severe

as little as 10 days when the structural abnormalities

systolic dysfunction with evidence of hypoperfusion

dobutamine

infusion.

Four

states

of

are minor, or to 6 months and beyond when there is

at rest; myocardial stunning was defined as the

severe ultrastructural derangement, with one study

presence of contractile dysfunction in the setting of

documenting functional improvement extending to

normal perfusion. Myocardial remodeling included

14 months (32,36,37).

segments with regional dysfunction, with only mild

Although conceptually, the distinction between

to

moderate

resting

perfusion

defects

and

no

stunned and hibernating myocardium has important

dobutamine-inducible ischemia. Finally, myocardial

clinical implications, both can coexist, and indeed,

scarring included segments with regional dysfunction

hibernation might represent an adaptation to repeti-

and severe fixed perfusion defects at rest and stress.

tive stunning (Figure 2) (7). Revascularization in pa-

This study (19) demonstrated that even after the strict

tients with significant viability has been shown to

use of these definitions to distinguish myocardial

improve outcomes, cardiac function, and functional

substrate

class in many observational studies (38). In patients

coexist within the same patient, and even within the

characteristics,

different

states

could

with significant viable myocardium (>20%) in the

same vascular territory. Moreover, each of these

setting of ventricular dysfunction, mortality in-

varied pathophysiological states will have differing

creases when the therapeutic strategy is medical

tendencies to recover after revascularization, which

therapy alone (39), which underscores the importance

further challenges the ability to predict response to

of identifying these patients to provide effective

therapy. Similarly, in a substudy comprising 399 pa-

therapy.

tients (40), the presence of inducible ischemia in the

Myocardial substrate characterization could help

setting of moderate to severe LV dysfunction was not

stratify patients who might benefit from revasculari-

found to predict better outcomes with surgical

zation. In a pilot study that used single-photon

revascularization compared with OMT. These find-

emission computed tomography (SPECT) to charac-

ings held regardless of intention-to-treat, as-treated,

terize myocardial function (19), the spectrum of

or per-protocol analysis. In a very large observational

myocardial abnormalities proved to be complex. In

study comprising close to 14,000 patients (41) that

this study, a unique 4-step imaging protocol was

used adenosine or exercise SPECT imaging, the

implemented that took into account regional rest and

presence of significant ischemia in patients in the

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Revascularization in Severe LV Dysfunction

C E N T R A L IL L U ST R A T I O N Revascularization in Patients With Severe LV Dysfunction: Prognosis of Patients With LV Dysfunction and CAD

Patient with left ventricular (LV) dysfunction

Myocardial viability imaging Viable myocardium: The muscular wall of the heart, does not contract normally at rest but has the potential to recover its function • Positron emission tomography (PET) Assess myocardial perfusion and metabolism • Single-photon emission computed tomography (SPECT) Estimate resting perfusion, stress-induced ischemia, scarring and cardiac function • Echocardiography Assess cardiac size, shape, wall thickness and wall motion • Cardiac MRI Assess myocardial scarring as evidence of nonviable tissue

Does patient have viable myocardium?

Revascularization improves outcomes, cardiac function and functional class

Revascularization does not predict better outcomes than optimal medical therapy (OMT) alone

Mortality increases with OMT alone

Patients with severe LV dysfunction benefit most from revascularization; a high peri-procedural risk must be balanced against late mortality benefit.

Anavekar, N.S. et al. J Am Coll Cardiol. 2016;67(24):2874–87.

Both the extent or severity of coronary artery disease (CAD) and the severity of left ventricular (LV) dysfunction are inter-related. Patients with the most severe dysfunction will have the greatest benefit, at the cost of a high periprocedural risk. MRI ¼ magnetic resonance imaging; OMT ¼ optimal medical therapy; PET ¼ positron emission tomography; SPECT ¼ single-photon emission computed tomography.

setting of reduced scar burden (defined as <10% of

neurohormonal pathway modification. Currently, a

the myocardium) predicted survival after early

single imaging modality cannot both define these al-

revascularization. This was in contradistinction to

terations and categorize them pathophysiologically.

those patients who had ischemia with large scar

By identifying and characterizing abnormal myocar-

burden, for whom a benefit from revascularization

dium, complementary multimodality imaging pro-

was not observed. These studies (19,40,41) highlight

vides an opportunity to help determine candidacy for

the importance of myocardial substrate characteriza-

revascularization therapies.

tion in the assessment of patients with severe ischemic heart disease. Management remains chal-

TESTS TO DETERMINE

lenging, because a mixed picture of scarred, hiber-

MYOCARDIAL VIABILITY

nating,

stunned,

and

remodeled

myocardium

might confound the purported benefits of revascu-

The spectrum of viability testing includes nu-

larization alone, which emphasizes the importance of

clear, ultrasound, and magnetic resonance–based

Anavekar et al.

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Revascularization in Severe LV Dysfunction

F I G U R E 3 Range of Sensitivity, Specificity, PPV, and NPV of Currently Available Viability Testing Modalities

100 92

90 80

87

87 83

84

80

83 78 75

74

74

76

65

79

72

70 63

78

67 63

60 54

50 40 30 20 10 0 Sensitivity

Specificity DSE

18

FDG PET

PPV Tc-99m

MRI

NPV

TI-201

F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging offers the greatest sensitivity, with comparable specificity to other

modalities. Dobutamine echocardiography offers the greatest specificity at the cost of reduced sensitivity. The positive predictive value (PPV) is similar among the imaging modalities; however, PET appears to have a greater negative predictive value (NPV) in this pooled dataset. Data on cardiac magnetic resonance are limited by the reduced number of available studies. Adapted with permission from Schinkel et al. (64). DSE ¼ dobutamine stress echocardiography; Tc ¼ technetium.

techniques. These tests have variable sensitivity and

PET AND SPECT: DOCUMENTATION OF INTACT

specificity ranges and technical limitations; avail-

MYOCARDIAL PERFUSION AND METABOLISM. PET

ability also influences their use in clinical practice

identifies segments with reduced perfusion but

(Figure 3, Tables 1 and 2).

preserved metabolism, thereby identifying viable

T A B L E 1 Comparison of the Ability of Imaging Techniques to Assess Ventricular Function and Characterize Myocardial Infarct Size

Technique

Ventricular Functional Assessment

Scar Characterization

Echocardiography

 Assesses both RV and LV systolic and diastolic function with quantitative and qualitative measures  Delineates contractile reserve with low-dose dobutamine  Strain imaging emerging as a complement to functional assessment  Can be performed at the bedside

 Scar determination based on qualitative measures including myocardial thinning, echogenicity, and regional contractility

Nuclear cardiac imaging

 Assesses LV function with well-validated quantitative measures

 Scar quantitation techniques most robust in available published data

Magnetic resonance imaging

 Assesses both RV and LV function  Currently reference standard for volumetric assessment of RV and LV  Delineates contractile reserve with low-dose dobutamine

 Scar quantitation is well validated and considered reference standard  Both infarct size and transmurality can be assessed  Assessment of RV involvement in the infarct  Microvascular obstruction assessment

Cardiac CT

 Strength in quantifying ventricular volumes

 Investigational

CT ¼ computed tomography; LV ¼ left ventricle; RV ¼ right ventricle.

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Revascularization in Severe LV Dysfunction

T A B L E 2 Comparison of Imaging Modalities Used to Test Myocardial Viability

Imaging Modality 201

Radiation Exposure

Perfusion Imaging

Stress-Induced Ischemia

Yes

Yes

Yes

 Sarcolemmal integrity

 Limited spatial resolution  Highest radiation exposure

TI SPECT

99m

Assessment of Viability

Limitations

Yes

Yes

Yes

 Mitochondrial membrane integrity

 Limited spatial resolution

Cardiac PET

Yes

Yes

Yes

 Cellular glucose uptake capacity

 Limited spatial resolution  Not widely available

Dobutamine echocardiography

No

Not approved

Yes

 Contractile reserve

 Limited acoustic windows  Interobserver variability

CMR

No

Yes

Yes

 Contractile reserve

 Avoid in patients with cardiac devices  Avoid in patients with GFR <30 ml/min/1.73 m 2  Body habitus  Not widely available

PET CT*

Yes

Yes

Yes

 Cellular glucose uptake capacity

 Need studies

PET CMR*

Yes

Yes

Yes

 Cellular glucose uptake capacity  Contractile reserve

 Need studies

Tc SPECT

*PET CT and PET CMR are emerging hybrid imaging modalities that have yet to be studied. PET CT could add value by decreasing attenuation artifact by coregistration of anatomic information provided by CT with the metabolic and perfusion data provided by PET. PET CMR holds promise in its potential to combine perfusion, metabolic, and contractile information. CMR ¼ cardiac magnetic resonance; CT ¼ computed tomography; GFR ¼ glomerular filtration rate; PET ¼ positron emission tomography; SPECT ¼ single-photon emission computed tomography; Tc ¼ technetium; Tl ¼ thallium.

myocardium. PET has robust built-in attenuation

relatively preserved or increased FDG uptake. This

correction, traditionally with line or rod sources and

pattern suggests the presence of viable, hibernating

more recently with CT, which is particularly useful

myocardium. A second pattern includes regions of

when imaging obese patients and female patients.

normal

Advances in PET technology have led to further re-

dysfunctional segments. In this setting, the myocar-

ductions in radiation dose per scan, improved spatial

dium may be normal or stunned, and in the setting of

resolution, and gated sequences for accurate mea-

a dilated ventricle, the pattern may represent a

surement of cardiac function (23,42).

remodeled heart. The distinction between stunned

perfusion

and

normal

metabolism

in

The PET imaging protocol is divided into 2 parts:

myocardium and the remodeled ventricle might not

the first assesses myocardial perfusion; the second

be clear from rest perfusion and metabolism images

assesses

alone, and in this scenario, ischemia testing can help

myocardial

commonly

used

identify ischemic segments that typify stunned

rubidium 82 and N-13 ammonia, the uptake of which

myocardium. A third pattern comprises segments of

is proportional to myocardial blood flow. Metabolic

reduced perfusion and metabolism, which usually

18

perfusion

Radionuclides include

imaging with

in

metabolism.

imaging

F-fluorodeoxyglucose (FDG) relies on

indicate presence of scar. The latter is associated with

a physiological milieu in which the myocardium uti-

an inverse relation to improvement in LV function

lizes glucose as the metabolic substrate. Under

after revascularization (43). A final pattern, referred

normal circumstances, the myocardium utilizes free

to as a reversed mismatch, demonstrates normal

fatty acids as the most efficient and readily available

perfusion but reduced FDG uptake. Such a scenario

energy source; however, alterations imposed by

has been observed in the setting of revascularization

chronic ischemia favor a substrate switch to glucose.

early after myocardial infarction, left bundle branch

The same carrier that transports glucose transports

block, right ventricular pacing, nonischemic cardio-

FDG into the cell; FDG uptake therefore represents a

myopathy, and diabetes mellitus (23). Given the

marker of glucose utilization, which will be normal or

presence of normal perfusion, these findings are

increased in viable myocardium. Traditionally, PET

typically interpreted to mean presence of viable

viability imaging is performed under resting condi-

myocardium.

tions;

however,

assessment

of

stress-induced

The radionuclides used in SPECT imaging include

ischemia can be added to the protocol, because its

thallium-201 and technetium-99m. Although SPECT

presence affects outcomes with revascularization.

imaging is widely available and provides estimates of

With PET viability imaging, there are 4 patterns

resting perfusion, stress-induced ischemia, extent of

that need consideration. The most important is a

scar, and cardiac function, it underestimates the

perfusion-metabolism mismatch: reduced myocardial

presence of viability. For example, a fixed defect on

perfusion and contractile function in the setting of

stress–4-h

redistribution

thallium-201

SPECT

or

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Revascularization in Severe LV Dysfunction

stress-rest technetium-99m SPECT could represent

that appeared to be fixed on later redistribution in

either severe hypoperfusion or scar (44,45). The

18 patients (55). Among patients who had thallium-201

initial uptake of thallium is flow dependent, with a

reinjection performed immediately after 3- to 4-h

high

first-pass

myocardial

extraction

fraction

redistribution and subsequently underwent coronary

across physiological ranges of myocardial blood

artery revascularization, 87% of regions identified as

flow. The myocardial uptake of thallium-201 is a

viable by reinjection studies had normal thallium-201

sarcolemmal membrane sodium-potassium adeno-

uptake and improved regional wall motion after

sine triphosphatase–dependent active process that

revascularization. In contrast, all regions with fixed

requires cell membrane integrity and is therefore

defects after reinjection had persistent wall motion

indicative of myocardial viability. Regions demon-

abnormalities after revascularization (56).

strating redistribution of thallium correlate with

Sestamibi and tetrofosmin are tracer agents that are

regions of FDG uptake on PET imaging (46,47). There

taken up and retained in the mitochondria, reflecting

are several available protocols for viability assessment

intact mitochondrial membranes and implying integ-

using

rity of mitochondrial function, and thus are markers of

thallium-201.

Rest-redistribution

protocols

depend on the initial flow-dependent kinetics of

cellular

thallium-201. A defect seen on an image taken soon

thallium-201 is that these agents show minimal redis-

after a rest injection is related to the resting myocar-

tribution within the myocardium. With a few excep-

dial blood flow; however, a significant percentage of

tions (57–69), studies comparing viability detection

resting thallium-201 defects show redistribution

with technetium-99m–labeled radiotracers versus

when reimaged several hours after injection (48,49).

thallium-201 and FDG PET have generally demon-

Segments that show a reversible resting thallium-201

strated that technetium-99m tracers underestimate

defect often have improved function after revascu-

myocardial

larization,

myocardial

viability assessment with technetium-99m agents

viability. Stress-redistribution imaging protocols may

could be achieved through nitrate administration

demonstrate stress-induced thallium defects that

before rest radiotracer injection and quantification of

normalize on serial imaging several hours after initial

regional radiotracer uptake (60,61).

which

suggests

regional

image acquisition, thereby indicating viability (50). Late-distribution imaging is predicated on the fact that under some circumstances, the redistribution of thallium-201 takes longer than the 4 h typically used in standard stress-redistribution protocols. This observation led to the development of late-redistribution protocols, which generally involve redistribution imaging 18 to 24 h after thallium-201 injection. With these protocols, thallium-201 redistribution is seen in a significant number of perfusion defects deemed fixed by imaging at 4 h (51–54). Late thallium-201 redistribution has been validated as an accurate predictor of viability, with up to 95% of segments with late redistribution showing improved stress perfusion after revascularization (54). However, as with early (3 to 4 h) redistribution, the absence of late redistribution underestimates the presence of viable myocardium in up to 37% of segments that show an improvement in function after revascularization (54). This suggests that some ischemic but viable myocardial segments might never redistribute, even with late imaging, unless blood levels of thallium-201 are increased. To circumvent some of the problems associated with redistribution imaging related to blood levels of thallium-201, reinjection protocols have also been established. Thallium reinjection performed

viability.

A

viability;

significant

however,

ECHOCARDIOGRAPHY:

difference

from

improvement

DOCUMENTATION

in

OF

MYOCARDIAL CONTRACTILE RESERVE. The echo-

cardiographic evaluation of myocardial viability includes assessment of cardiac size, shape, and wall thickness combined with regional wall motion. Areas of wall thinning and akinesis usually represent presence of scar. The addition of dobutamine infusion assesses contractile reserve, a crucial component of the examination to determine viability in dysfunctional segments. A biphasic response, which refers to an initial improvement in contractile function with low-dose dobutamine followed by deterioration with higher doses, is the most significant finding to predict recovery after revascularization (62). Myocardial

contrast

echocardiography

has

advanced our ability to assess wall motion and myocardial perfusion. In one study, myocardial contrast echocardiography improved identification of ischemia in the left anterior descending territory and in multivessel disease compared with wall motion assessment alone (63). However, myocardial contrast echocardiography is not yet approved for myocardial perfusion imaging, and its utility in the evaluation of myocardial viability imaging is still to be determined. CMR: DOCUMENTATION OF MYOCARDIAL SCAR AS

immediately after late (24 h) redistribution in 30

EVIDENCE OF NONVIABLE TISSUE. CMR has an

patients showed defect reversibility in 40% of regions

emerging role in the assessment of myocardial

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Revascularization in Severe LV Dysfunction

viability. A systematic approach that uses CMR first

associated with worse outcomes, and conversely,

includes an evaluation of cardiac shape, size, wall

those patients with viability detected by noninvasive

thickness, and derivation of cardiac volumes and

testing, including SPECT, FDG-PET, and echocardi-

mass. Second is the assessment of global and regional

ography, demonstrate significantly improved survival

wall motion abnormalities. The addition of low-dose

with revascularization compared with medical ther-

dobutamine can assess contractile reserve similar to

apy alone (6–8,68–70). However, in these non-

that used in echocardiography (64). Real-time perfu-

randomized

sion imaging with intravenous gadolinium contrast

standardized, and adherence was not described

allows assessment of perfusion defects. The funda-

(6,71). More recently, viability testing with CMR has

mental component of the examination involves

paralleled the findings observed with the other

assessment for the presence of delayed myocardial

modalities. In a report of 144 patients with ischemic

enhancement after intravenous gadolinium adminis-

cardiomyopathy

tration. The high spatial resolution of CMR allows

deemed to have viable myocardium treated medically

delineation of transmural extent of scar, which is

fared worse than those who underwent revasculari-

currently not possible with nuclear cardiac imaging or

zation (72). Second, published reports suggest that

echocardiography (65). The probability of improve-

the presence of myocardial viability on noninvasive

ment of regional contractile function after revascu-

testing predicts improvement in regional LV function,

larization

of

as well as heart failure symptoms and exercise ca-

transmural viability. These data suggest that recovery

pacity after revascularization (7,64,73); however, the

of function after revascularization is a continuum

relationship between improvement in indexes of

and is coupled to the ratio of viable to scarred

ventricular performance and functional performance

myocardium within the dysfunctional myocardial

remains

region

is

and

directly

also

related

correlates

to

the

with

extent

findings

of

nuclear-based imaging techniques (66).

studies,

who

unclear.

medical

therapy

underwent

Furthermore,

CMR,

was

not

patients

gradations

of

myocardial viability that could predict functional improvement, as measured by exercise capacity, remain to be delineated and may differ among the

ROLE OF VIABILITY TESTING IN THE

techniques.

MANAGEMENT OF PATIENTS WITH

The role of noninvasive viability testing in clinical

ISCHEMIC CARDIOMYOPATHY

decision making has been evaluated in only a few prospective clinical trials. CHRISTMAS (Carvedilol

Published data encompassing viability testing are

Hibernation Reversible Ischemia Trial: Marker of

weighted

Success) was a double-blind, randomized trial of

by

small,

single-center,

observational

studies during an era when medical therapies for

medical therapy in chronic LV dysfunction (74,75).

ischemic heart disease have expanded markedly (8).

This trial assessed the efficacy of carvedilol treatment

Studies in the field have limitations in design, which

in patients with hibernation or ischemia using both

results in challenges in their applicability to clinical

nuclear and echocardiographic techniques to identify

practice. These limitations arise mostly because of

the presence and extent of hibernation. The study

differences in definition of viability, cutoffs for clin-

found that the volume of myocardium affected by

ical endpoints, and differences in inclusion criteria

hibernation, ischemia, or both is an important deter-

for these studies. Furthermore, in complex CAD, a

minant of the improvement of LV function (as

description of the completeness of revascularization

assessed by LVEF) with carvedilol treatment (75),

is important to understanding the outcomes of

with little or no increase in LVEF in the absence of

revascularization (67) and could influence the utility

viability (75). Patients in the placebo arm demon-

of upstream viability testing. Further challenges are

strated an increase in the number of segments with

posed by the complexity of myocardial substrate

reduced viability over time, including segments that

abnormalities,

stunned,

were previously classified as hibernating (75). This

hibernating, remodeled, and scarred myocardium

highlights the complexity and heterogeneity of the

commonly being identified in the same patient (19).

myocardial substrate underlying LV dysfunction

Therefore, there continue to be large knowledge gaps

caused by CAD. The role of revascularization was not

regarding application of noninvasive viability testing

specifically studied in this trial (75).

with

combinations

of

in patients with complex CAD and LV dysfunction.

The PARR-1 (Positron Emission Tomography and

Nevertheless, despite these challenges, 2 impor-

Recovery Following Revascularization) study was

tant initial concepts have surfaced. First, in patients

a prospective multicenter cohort study (43). In

with ischemic cardiomyopathy and viability noted on

this study, extent of scar was an independent

noninvasive testing, medical treatment alone is

predictor of ventricular functional recovery after

Anavekar et al.

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Revascularization in Severe LV Dysfunction

T A B L E 3 Comparison of the PARR-2 and STICH Trials

Study design Premise

PARR-2

STICH (Viability Substudy)

Randomized controlled trial

Randomized controlled trial

Comparison of an imaging-guided strategy to standard care for ischemic cardiomyopathy

Number of patients Centers

430

601

Multicenter (9 centers)

Multicenter (99 centers)

Enrollment period

2000-2004

2002-2007

PET

Echocardiography SPECT

Primary: occurrence of cardiac death, MI, or hospital stays for cardiac cause Secondary: time to occurrence of the primary endpoint and time to cardiac death

Primary: rate of death due to any cause Secondary: rate of death due to cardiovascular causes and rate of death due to any cause or hospitalization for cardiovascular causes

CABG/PCI

CABG

Viability test Study endpoints

Outcome of revascularization vs. optimal medical therapy for ischemic cardiomyopathy

Intervention Patient characteristics, n or n (%) % Female

16

13

Baseline LVEF, %

27

27

NYHA functional class II to IV

352 (82)

574 (96)

CCS II-IV

198 (46)

271 (45)

Prior CABG

80 (19)

16 (3)

Prior MI

346 (80)

481 (80)

Chronic renal insufficiency

146 (34)

43 (7)

Diabetes mellitus

167 (39)

224 (37)

1

5.1

Caveats

Median follow-up, yrs

 25% of the FDG-PET study group were not managed according to imaging recommendations  Patients assigned to CABG had lower rates of cardiovascular death and of the composite endpoint of death of any cause or hospitalization for cardiovascular causes

 Viability study nonrandomized  83% of subjects in the viability substudy were Caucasian compared with 54% of subjects in the STICH trial who did not have a viability test  Subgroups of patients assigned to the FDG PET group who had recent angiography or who adhered to imaging recommendations had better outcomes

Main result

No difference between an imaging-guided strategy and standard care

No incremental benefit of revascularization strategy over optimal medical therapy

CABG ¼ coronary artery bypass graft; CCS ¼ Canadian Cardiovascular Society; FDG ¼ fluorodeoxyglucose; LVEF ¼ left ventricular ejection fraction; MI ¼ myocardial infarction; NYHA ¼ New York Heart Association; PARR ¼ Positron Emission Tomography and Recovery Following Revascularization; PCI ¼ percutaneous coronary intervention; STICH ¼ Surgical Treatment for Ischemic Heart Failure; other abbreviations as in Table 2.

revascularization, with smaller scar scores predicting

according to imaging recommendations, primarily

greater improvement in LVEF (43). Small numbers (82

driven by the discretion of the clinician caring for the

patients) and absence of important parameters of

patient (76). Notably, when the analysis included only

function, including ventricular volumes and stress-

those who adhered to the PET-guided recommenda-

induced ischemia, limited this pilot study.

tions, there was a significant benefit for FDG PET.

The PARR-2 study (76) was designed to assess the

Additionally, there was benefit for FDG PET in the

effectiveness of FDG-PET–assisted management in

group without recent coronary angiography. A sub-

patients with severe LV dysfunction and suspected

study of the PARR-2 trial confirmed the established

CAD compared with standard of care (Table 3). The

trend that patients with ischemic cardiomyopathy

study randomized 430 patients, with 218 patients

with

receiving PET-assisted care and 212 receiving stan-

mismatch have improved outcomes with revascular-

larger

amounts

of

perfusion-metabolism

dard therapy (76). The study did not demonstrate a

ization (77). In this study, if >7% of the LV demon-

significant reduction in cardiac events with FDG-PET–

strated

directed therapy compared with the standard of care

revascularization

(76). Nonetheless, there are important nuances that

endpoint of cardiac death, myocardial infarction, or

deserve mention. First, the standard-of-care arm

cardiac repeat hospital stay at 1 year. Lastly, renal

could include a non-PET viability test. Second, close

impairment was an independent prognosticator, as

to 25% of the FDG-PET study group were not managed

found in other studies (77,78).

viability,

there with

was regard

a

benefit

to

a

from

composite

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Revascularization in Severe LV Dysfunction

The Ottawa-FIVE substudy of the PARR-2 trial was a

A substudy of the STICH investigation sought to

post hoc analysis of the utility of PET-assisted man-

examine the role of myocardial viability in identifying

agement of patients with severe LV dysfunction and

patients who might have a survival benefit with CABG

suspected CAD (79). This substudy included patients

(82). In this nonrandomized substudy, the optional

in both the FDG-PET–directed therapy (group 1) and

viability tests included SPECT and dobutamine

standard therapy (group 2) arms who were recruited at

echocardiography (82). Notably, neither FDG-PET,

the University of Ottawa Heart Institute (79). The

which was established as the most sensitive test for

primary outcome was the composite endpoint of car-

viability (64) at the time of study enrollment, nor

diac death, myocardial infarction, or cardiac hospi-

CMR were options for viability testing. Of the 1,212

talization within 1 year, which was compared with the

patients enrolled into STICH, only 601 underwent

patients in the rest of the PARR-2 study with FDG-

viability testing. The assignment of presence or

PET–assisted therapy (group 3) and standard of care

absence of viability was classified by use of a binary

(group 4). Within the Ottawa-FIVE subgroup of

approach. In the SPECT imaging group, the presence

PARR-2, the cumulative proportion of patients expe-

of substantial viability was defined as those with 11 or

riencing the composite event was 19% in group 1 versus

more viable segments. For dobutamine echocardiog-

41% in group 2, which indicates a significant benefit of

raphy, this same threshold was met in those patients

the FDG-PET–assisted approach (79). Among the non–

with 5 or more viable segments (82). Other important

Ottawa-FIVE patients of the PARR-2 study, there was

parameters of ventricular function, including size,

no significant difference in the primary endpoint

shape, wall thickness, and cardiac mass, were not

based on an FDG-PET versus standard-of-therapy

used in the predictive model.

approach (79). This emphasizes the importance of

In the STICH viability substudy, of the 601 patients

institutional expertise when these imaging techniques

who underwent viability testing, 487 patients were

are used and applied to clinical practice.

found with and 114 without substantial viable

A subsequent nonrandomized observational study

myocardium. In both groups, there was a balanced

(80) from the Cleveland Clinic that included 648 pa-

distribution of those receiving OMT alone versus OMT

tients and used PET to assess inducible ischemia and

and CABG (82). At first glance, the investigation sug-

viability in patients with CAD and moderate to severe

gested that the presence of substantial myocardial

LV dysfunction was designed to evaluate the benefit

viability portended a survival benefit, with 63% sur-

of revascularization according to extent of viable

vival of patients with viability versus 49% survival of

myocardium. A series of interaction models were

patients without viability. After adjustment for

examined to determine the differential benefit of

baseline variables, this significance was lost. Addi-

revascularization versus medical therapy according to

tionally, there was no demonstrable relationship be-

presence of ischemia, hibernating myocardium, or

tween the viability information, treatment allocation,

scar. Interestingly, no interaction was found between

or patient outcome, and this was true regardless of

the use of early revascularization and proportions of

whether

either ischemic or scarred myocardium (80); how-

intention-to-treat analysis or according to the treat-

ever, there was a significant interaction with the

ment actually received. The results of this trial are

extent of hibernating myocardium, with a cutoff of

controversial and remain a source of vigorous debate.

>10% indicating benefit from a revascularization

There are some important limitations that must be

strategy (79). These findings highlight the complex

emphasized. First, the substudy was nonrandomized,

interplay of a heterogeneous myocardial substrate in

and <50% of patients enrolled in the study under-

the setting of significant LV dysfunction, as affirmed

went viability testing. Second, viability testing was

in published reports (19,40,80).

limited to SPECT or dobutamine echocardiography.

patients

were

grouped

according

to

STICH (Surgical Treatment for Ischemic Heart Fail-

Third, there was inherent bias regarding the decision

ure) was primarily designed to examine the outcomes

to pursue viability testing, and the protocols for

of patients with CAD and LV dysfunction randomized

SPECT imaging varied among the multiple enrollment

either to OMT alone or OMT plus CABG surgery (81). In

sites. Fourth, the presence of substantial viability was

this randomized clinical trial (Table 3), there was no

measured in a binary fashion, whereas the current

significant difference between OMT alone and OMT

published paradigm would contend that the concept

plus CABG with respect to the primary endpoint of

of viability encompasses a wider spectrum (19). Fifth,

death of any cause; however, patients assigned to

ancillary information that is integral to understand-

CABG had lower rates of cardiovascular death and of

ing cardiac function, such as ventricular geometry,

the composite endpoint of death of any cause or hos-

volumes, wall thickness, and EF, was not reported;

pitalization for cardiovascular causes (81).

there was no discussion regarding the association

Anavekar et al.

JACC VOL. 67, NO. 24, 2016 JUNE 21, 2016:2874–87

Revascularization in Severe LV Dysfunction

between SPECT tracer uptake and regional wall mo-

scarring, the benefit of high-risk procedural in-

tion; and the biphasic response in patients who un-

terventions is likely to be low. In reality, patients

derwent dobutamine echocardiography was not used

present with a mixture of abnormal myocardial sub-

as a criterion for viability. Moreover, clinicians were

strates, the balance of which is challenging to define

not blinded to the results of viability testing, which

with

has the potential to create an ethical dilemma

although revascularization is considered the gold

regarding the enrollment of patients with ischemic

standard

heart disease and viability on the basis of noninvasive

pathophysiological findings might benefit from a

testing into a randomized clinical trial.

more aggressive modification of neurohormonal and

a

single

imaging

treatment,

modality.

patients

Furthermore,

with

intermediate

electrical activation. With the aforementioned ca-

FUTURE DIRECTIONS

veats, we wait expectantly for the results of an

Myocardial viability testing in contemporary practice remains controversial. The promise of answers to important clinical questions hinged on the STICH investigation; however, several methodological issues, including the nonrandomized nature of the viability substudy and the potential for referral bias, limited this study. As it stands, the results of STICH can only truly be applied to a very small group of patients with severe LV dysfunction, a setting in which scar and deleterious remodeling could overwhelm whatever viable myocardium remains. A recently published review highlights some of the major current challenges of trial design (83). Eliciting patient consent for randomization and recruiting centers to participate and accept randomization in the setting of clinical equipoise are some of the greatest hurdles to overcome. A spectrum exists,

ongoing trial, AIMI-HF (Alternative Imaging Modalities in Ischemic Heart Failure) (84). This study aims to randomize patients with ischemic heart failure to SPECT imaging, CMR, or PET to assess ischemia or viability (84), and it is hoped it will shed light on some of the current controversies. So, is myocardial viability a viable concept in contemporary

clinical

practice?

Viability

testing

might: 1) help predict the response to revascularization in selected patients with CAD

and LV

dysfunction; 2) be a marker of prognosis; and 3) influence

response

to

medical

therapy.

Multi-

modality imaging could provide deeper insight into the spectrum of myocardial substrate, emphasizing not only the role of revascularization but also neurohormonal modulation and resynchronization therapy.

including stunned, hibernating, remodeled, and predominating

REPRINT REQUESTS AND CORRESPONDENCE: Dr.

abnormality is myocardial hibernation, revasculari-

Bernard J. Gersh, Division of Cardiovascular Diseases,

zation would offer clinical benefit. Conversely, when

Mayo Clinic, 200 First Street SW, Rochester, Minne-

the

sota 55905. E-mail: [email protected].

scarred

myocardium.

predominating

When

the

abnormality

is

myocardial

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KEY WORDS coronary artery bypass graft, coronary artery disease, myocardial hibernation, myocardial ischemia, myocardial stunning

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