Myocardial Viability Imaging: An Attractive Idea Without the Clinical Outcomes to Back It Up

Guest Bloggers: 

Alvin S. Chen, MD

Thomas H. Hauser, MD, MPH, MMSc

Heart failure is increasingly common and presents a major clinical and public health challenge.  Coronary artery disease is the leading cause of heart failure in the United States, causing myocardial injury leading to reduced systolic function and ultimately heart failure.1  It was first demonstrated in the 1970s that dysfunctional myocardium in the setting of coronary artery disease could be coaxed back to life using an infusion of epinephrine.2  This dysfunctional myocardium that could regain function was termed viable myocardium.  Subsequent studies have shown that coronary revascularization provides more durable improvements in systolic function and superior clinical outcomes. 
 Advancements in cardiac imaging and understanding of underlying pathophysiology have demonstrated that dysfunctional myocardium exists on a spectrum of myocardial stunning, hibernation and necrosis/infarction. Myocardial stunning, occurring with acute ischemia with no ultrastructural changes of the cardiac myocyte, recovers in minutes to days after revascularization while myocardial hibernation, occurring with chronic ischemia, requires weeks to months for recovery of systolic function due to extensive ultrastructural changes of the cardiac myocyte and disassembly of the contractile apparatus. Identifying patients with stunned or hibernating myocardium, as opposed to truly irreversible myocardial necrosis is of utmost importance as patients with significant amounts of viable myocardium may see marked improvement or even normalization of their ejection fraction following successful revascularization.  Patients who are typically evaluated for myocardial viability have significant systolic dysfunction, known or suspected coronary artery disease, candidates for revascularization, and no definite angina (which would provide a separate indication for revascularization). 
Nuclear imaging is frequently used for the assessment of myocardial viability. SPECT imaging at rest with either Thallium-201 or a Technetium-99m agent is commonly used for this indication.  While these radiotracers are typically used for perfusion imaging, cellular uptake requires active metabolic processes that indicate viability.3  PET imaging using a glucose analog (fluorine-18 labeled deoxyglucose; FDG) has particular advantages in addition to the improved spatial resolution of PET compared to SPECT.  Ischemic myocardium favors glucose metabolism and specific patient preparation, most commonly done with oral or intravenous glucose loading typically with supplemental insulin administration, reliably shifts cardiac myocyte metabolism to glucose utilization (as opposed to free fatty acids, which are the major alternative to glucose as an energy substrate).4   The presence of glucose metabolism implies viability and studies have shown that FDG-PET imaging is the most sensitive technique for the detection of viable myocardium.5  Pairing the glucose metabolism images with perfusion images, obtained using either PET or SPECT tracers, allows additional classification. FDG uptake with decreased perfusion (“PET mismatch”) represents viable myocardium, whereas a concordant decrease in FDG uptake and perfusion (“PET match”) represents necrotic myocardium.
There are two main lines of observational data that support the hypothesis that revascularization of viable myocardium is beneficial.  The first is outcomes after surgical revascularization in patients with significant systolic dysfunction.  This patient population presumably has a significant amount of viable myocardium, although with these observational trials specific viability imaging was not performed.  A meta-analysis of 7 observational studies in this patient population found a 30-50% increase in three year survival but high operative mortality in these high risk patients, suggesting that revascularization of viable myocardium is beneficial.6
The second line of observational data in support of revascularization of viable myocardium are an abundance of studies that have shown that myocardial viability imaging can identify specific myocardial segments that are likely to recover after revascularization.  Most of these studies were able to demonstrate an improvement in systolic function that was related to the presence of viable myocardium, but were underpowered to identify any mortality benefit.  A subsequent meta-analysis that of 24 viability studies that showed an improvement in mortality with revascularization in those with viable myocardium but not in those without.7  In this analysis involving 3,088 patients with an average baseline ejection fraction of 32 ± 8%, revascularization was associated with a 79.6% reduction in annual mortality compared to medical treatment in patients with myocardial viability (Figure). In patients without viability, there was no significant difference in mortality though there was a trend toward higher mortality in the revascularization arm. 

These promising observational results subsequently led to randomized clinical trials to better define the mortality benefit of revascularization in those with viable myocardium.  Three randomized, controlled trials have been published to date that have examined the utility of viability imaging prior to revascularization (Table).8-10  Unfortunately, all have shown no mortality benefit.  Why is this?  Observational studies often have confounding factors and biases that are removed in the context of a randomized, controlled trial.  In this case, we suspect that selection bias is the major factor in the difference between the observational and randomized, controlled data.  In clinical practice, cardiac surgeons and interventional cardiologists can readily identify high risk patients who are at likely to have bad outcomes.  In an observational study, these high risk patients are frequently consigned to medical therapy instead of revascularization while randomization removes this bias.  Anecdotally, viability studies are seldom ordered in low risk patients who are good candidates for revascularization, while they are much more commonly ordered in high risk patients to help determine if revascularization is worthwhile.  The utility of viability imaging in this context has not yet been evaluated, but the randomized trial data does not suggest that this strategy leads to favorable outcomes. 
Figure 1

Data from Allman et al.7 

Table 1
Trial N Study Design Results Commentary
The Heart Failure Revascularization Trial (Cleland et al)10 138 Study subjects with LVEF <35%, CAD, and significant viability by any standard imaging technique were randomized to revascularization or medical therapy. There was no difference in mortality between the two groups (mortality rate at 1 year 38% in the revascularization group and 37% in the medical therapy group, p=0.63). The trial was significantly underpowered, enrolling only a small fraction of the planned goal of 800.  This was due to competing enrollment with the STICH trial.
PARR-2 (Beanlands et al)8 430 Study subjects with LVEF ≤35% and CAD were randomized to FDG-PET viability imaging.  Those with significant viability were recommended to undergo revascularization. There was no difference in the composite endpoint of cardiac death, MI, or hospitalization for a cardiac cause at 1 year (30% in the FDG-PET group and 36% in the standard therapy group, p=0.16) A significant number of study subjects underwent treatment that was not consistent with viability testing. A secondary analysis restricted to only those that had treatment consistent with viability imaging had favorable results.
STICH Viability Substudy (Bonow et al)9 601 Study subjects with LVEF <35%, CAD, and suitable coronary anatomy were  randomized to surgical revascularization or medical therapy.  Those in the viability substudy underwent viability imaging (either SPECT or dobutamine echocardiography) prior to randomization. After 5 years of follow-up, the death rate for those with viable myocardium was 37% and 51% for those without (p=0.003), but the difference was not significant after adjustment for baseline factors.  There was no significant relationship between viability and treatment assignment with respect to mortality. Only about half of the STICH trial patients were in the viability substudy due to difficulty with enrollment in the trial.
CAD = coronary artery disease; FDG = F-18-fluorodeoxyglucose;
LVEF = left ventricular ejection fraction; MI = myocardial infarction;
PET = positron emission tomography

1.           Virani SS, Alonso A, Aparicio HJ, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Cheng S, Delling FN, Elkind MSV, Evenson KR, Ferguson JF, Gupta DK, Khan SS, Kissela BM, Knutson KL, Lee CD, Lewis TT, Liu J, Loop MS, Lutsey PL, Ma J, Mackey J, Martin SS, Matchar DB, Mussolino ME, Navaneethan SD, Perak AM, Roth GA, Samad Z, Satou GM, Schroeder EB, Shah SH, Shay CM, Stokes A, VanWagner LB, Wang NY, Tsao CW. Heart disease and stroke statistics-2021 update: A report from the american heart association. Circulation. 2021;143:e254-e743
2.           Horn HR, Teichholz LE, Cohn PF, Herman MV, Gorlin R. Augmentation of left ventricular contraction pattern in coronary artery disease by an inotropic catecholamine. The epinephrine ventriculogram. Circulation. 1974;49:1063-1071
3.           Udelson JE, Coleman PS, Metherall J, Pandian NG, Gomez AR, Griffith JL, Shea NL, Oates E, Konstam MA. Predicting recovery of severe regional ventricular dysfunction. Comparison of resting scintigraphy with 201tl and 99mtc-sestamibi. Circulation. 1994;89:2552-2561
4.           Dilsizian V, Bacharach SL, Beanlands RS, Bergmann SR, Delbeke D, Dorbala S, Gropler RJ, Knuuti J, Schelbert HR, Travin MI. Asnc imaging guidelines/snmmi procedure standard for positron emission tomography (pet) nuclear cardiology procedures. J Nucl Cardiol. 2016;23:1187-1226
5.           Schinkel AF, Bax JJ, Poldermans D, Elhendy A, Ferrari R, Rahimtoola SH. Hibernating myocardium: Diagnosis and patient outcomes. Curr Probl Cardiol. 2007;32:375-410
6.           Baker DW, Jones R, Hodges J, Massie BM, Konstam MA, Rose EA. Management of heart failure. Iii. The role of revascularization in the treatment of patients with moderate or severe left ventricular systolic dysfunction. JAMA. 1994;272:1528-1534
7.           Allman KC, Shaw LJ, Hachamovitch R, Udelson JE. Myocardial viability testing and impact of revascularization on prognosis in patients with coronary artery disease and left ventricular dysfunction: A meta-analysis. J Am Coll Cardiol. 2002;39:1151-1158
8.           Beanlands RS, Nichol G, Huszti E, Humen D, Racine N, Freeman M, Gulenchyn KY, Garrard L, deKemp R, Guo A, Ruddy TD, Benard F, Lamy A, Iwanochko RM. F-18-fluorodeoxyglucose positron emission tomography imaging-assisted management of patients with severe left ventricular dysfunction and suspected coronary disease: A randomized, controlled trial (parr-2). J Am Coll Cardiol. 2007;50:2002-2012
9.           Bonow RO, Maurer G, Lee KL, Holly TA, Binkley PF, Desvigne-Nickens P, Drozdz J, Farsky PS, Feldman AM, Doenst T, Michler RE, Berman DS, Nicolau JC, Pellikka PA, Wrobel K, Alotti N, Asch FM, Favaloro LE, She L, Velazquez EJ, Jones RH, Panza JA. Myocardial viability and survival in ischemic left ventricular dysfunction. N Engl J Med. 2011;364:1617-1625
10.         Cleland JG, Freemantle N. Revascularization for patients with heart failure. Inconsistencies between theory and practice. Eur J Heart Fail. 2011;13:694-697

Author Biographies:
Alvin Chen is a general cardiology fellow at Beth Israel Deaconess Medical Center in Boston, MA. Dr. Chen's areas of interest include multi-modality cardiac imaging (echo, nuclear, CT and MRI) , valvular heart disease and preventative cardiology.
Thomas Hauser is Director of Nuclear Cardiology at Beth Israel Deaconess Medical Center and Assistant Professor of Medicine at Harvard Medical School, both in Boston, MA.  He is a volunteer on ASNC's Social Media Committee.  Dr. Hauser's has previously published work on the use of nuclear imaging, CMR, and cardiac CT in cardiovascular disease.