Myocardial Viability: From PARR-2 to IMAGE HF - Current Evidence and Future Directions

Erthal, Fernanda; Wiefels, Christiane; Promislow, Steven; Kandolin, Riina; Stadnick, Ellamae; Mielniczuk, Lisa; Ruddy, Terrence; Small, Gary; Beanlands, Rob

doi:10.5935/2359-4802.20180068

Fernanda Erthal

University of Ottawa Heart Institute, Ontário - Canadá

Christiane Wiefels

University of Ottawa Heart Institute, Ontário - Canadá

Steven Promislow

University of Ottawa Heart Institute, Ontário - Canadá

Riina Kandolin

University of Ottawa Heart Institute, Ontário - Canadá

Ellamae Stadnick

University of Ottawa Heart Institute, Ontário - Canadá

Lisa Mielniczuk

University of Ottawa Heart Institute, Ontário - Canadá

Terrence Ruddy

University of Ottawa Heart Institute, Ontário - Canadá

Gary Small

University of Ottawa Heart Institute, Ontário - Canadá

Rob Beanlands

University of Ottawa Heart Institute, Ontário - Canadá

http://orcid.org/0000-0001-7857-8169

Author contributions

Acquisition of data: Erthal F, Wiefels C, Promislow S. Analysis and interpretation of the data: Erthal F, Wiefels C, Promislow S. Writing of the manuscript: Erthal F, Wiefels C, Promislow S, Kandolin R, Stadnick E. Critical revision of the manuscript for intellectual content: Erthal F, Wiefels C, Promislow S, Stadnick E, Mielniczuk L, Ruddy T, Small G, Beanlands R.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Figures (8)
Tables (3)

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Figure 1
"Images illustrating different combinations of FDG uptake and LGE transmurality. First column: FDG ≥ 50%/LGE nontransmural ('PET viable/MRI viable); second column: FDG < 50%/LGE transmural ('PET non-viable/MRI non-viable'); third column: FDG < 50%/LGE non-transmural ('PET non-viable/MRI viable'). White arrows indicate the respective area of ischaemically affected myocardium." – With permission from Rischpler et al, Eur Heart J Cardiovasc Imaging.³⁰30 Rischpler C, Langwieser N, Souvatzoglou M, Batrice A, van Marwick S, Snajberk J, et al. PET/MRI early after myocardial infarction: evaluation of viability with late gadolinium enhancement transmurality vs. 18F-FDG uptake. Eur Heart J Cardiovasc Imaging. 2015;16(6):661-9.

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Figure 2
"Regional wall motion abnormality and functional recovery in the long-term course. The wall motion abnormality early after AMI and at follow-up as well as the resulting functional recovery of the 95 dysfunctional segments were evaluated regarding different patterns of LGE transmurality and FDG uptake [LGE transmurality (A and D), FDG uptake (B and E), combination of LGE transmurality and FDG uptake (C and F)] "- With permission from Rischpler et al, Eur Heart J Cardiovasc Imaging.³⁰30 Rischpler C, Langwieser N, Souvatzoglou M, Batrice A, van Marwick S, Snajberk J, et al. PET/MRI early after myocardial infarction: evaluation of viability with late gadolinium enhancement transmurality vs. 18F-FDG uptake. Eur Heart J Cardiovasc Imaging. 2015;16(6):661-9.

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Figure 3
"Risk-adjusted, event-free survival curves for time-to-composite event for patients who adhered to PET imaging recommendations (FDG PET Adhere) versus standard care (STD) in patients randomized at sites participating in long-term follow-up. Hazard ratio = 0.73 (95% CI 0.54–0.99; p = 0.042). No at risk = number of patients who had not died, not had transplant, not dropped out, and not had events. Seven patients whose last follow-up date was within 10 days of 1,825 days (5 years) were included in the 5-year total. CI indicates confidence interval; FDG PET, F-18-fluorodeoxyglucose positron emission tomography; and STD, standard care". – With permission from Mc Ardle et al, Circ Cardiovasc Imaging.¹¹11 Mc Ardle B, Shukla T, Nichol G, deKemp RA, Bernick J, Guo A, et al; PARR 2 Investigators. Long-term follow-up of outcomes with F-18-fluorodeoxyglucose positron emission tomography imaging-assisted management of patients with severe left ventricular dysfunction secondary to coronary disease. Circ Cardiovasc Imaging. 2016;9(9). pii: e 004331.

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Figure 4
Interaction between mismatch on ¹⁸FDG PET (hibernating myocardium) and clinical outcome. A) Various levels of mismatch and its hazards ratios and 95% CI. For patients with mismatch > 7% there was improvement in the primary outcome (cardiac death, myocardial infarction and cardiac hospitalization at 1 year) (with permission from D’Egidio et al.⁷7 D'Egidio G, Nichol G, Williams KA, Guo A, Garrard L, deKemp R, et al; PARR-2 Investigators. Increasing benefit from revascularization is associated with increasing amounts of myocardial hibernation: a substudy of the PARR-2 trial. JACC Cardiovasc Imaging. 2009;2(9):1060-8.). B) Relationship between % of mismatch and adjusted HR for all cause of death in patients who received medical therapy or early revascularization. Greater amounts of hibernating myocardium related with increased risk of medical therapy (with permission from Ling et al.¹²12 Ling LF, Marwick TH, Flores DR, Jaber WA, Brunken RC, Cerqueira MD, et al. Identification of therapeutic benefit from revascularization in patients with left ventricular systolic dysfunction: inducible ischemia versus hibernating myocardium. Circ Cardiovasc Imaging. 2013;6(3):363-72.). C) Relationship between amount of mismatch and improvement in functional status after revascularization (with permission from Di Carli et al., Circulation¹⁰10 Di Carli MF, Asgarzadie F, Schelbert HR, Brunken RC, Laks H, Phelps ME, et al. Quantitative relation between myocardial viability and improvement in heart failure symptoms after revascularization in patients with ischemic cardiomyopathy. Circulation. 1995;92(12):3436-44.).

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Figure 5
Flow diagram illustrating a potential algorithm for use of viability imaging. – With permission from Mc Ardle et al., Can J Cardiol⁵²52 Mc Ardle BA, Beanlands RS. Myocardial viability: whom, what, why, which, and how? Can J Cardiol 2013;29(3):399-402.

CABG: coronary artery bypass grafting; CAD: coronary artery disease; CRT: cardiac resynchronization therapy; EF: ejection fraction; ICD: implantable cardiac defibrillator; LV: left ventricle; MRI: magnetic resonance imaging; NYHA: New York Heart Association; PCI: percutaneous coronary intervention; SPECT: single-photon emission computed tomography. †Denotes the required indications for 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging in Ontario.

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Figure 6
(A) 13N perfusion PET and 18FDG metabolism PET in short axis (SAO), horizontal long axis (HLA) and vertical long axis (VLA) showing extensive area of mismatch in the mid to distal anterior wall and apex (white arrow). (B) Polar map with quantitative analysis of the scar amount (7%) on the top (match defect) and hibernating myocardium (22%) on the bottom (mismatch). “Given the significant amount of hibernating myocardium, it was recommended that the patient proceed with coronary artery bypass grafting.” (adapted from Weifels et al., with permission).73 (C) Cardiac MRI showing subendocardial scar involving > 75% of the myocardium from the basal to apical anteroseptal wall, mid to apical anterior wall and apex, suggesting no viability in the LAD territory in a patient with a history of previous anterior myocardial infarction and coronary angiogram showing occluded mid LAD. (D) Cardiac MRI of a patient with occluded proximal LAD with collaterals, 95% stenosis ostial LCx and occluded OM1 showing subendocardial scar from the basal to apical anterior wall, mid to apical anteroseptal wall, and basal to mid lateral wall involving < 50% myocardium, suggesting viability in the LAD and LCx territories. Given these findings, the patient went on to have CABG (LITA->LAD, left radial- >OM1, SVG->right PIV). He is clinically doing well one year post-CABG.

LAD: left anterior descending artery; LCx: left circumflex artery; OM1: first marginal artery; SAO: short axis.

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Figure 7
“The AIMI-HF (Alternative Imaging Modalities in Ischemic Heart Failure) trial algorithm”. “The primary endpoint is a composite of cardiac death, MI, resuscitated cardiac arrest, or cardiac rehospitalization.” – With permission from Mielniczuk et al., JACC Cardiovasc Imaging⁴³43 Mielniczuk LM, Toth GG, Xie JX, De Bruyne B, Shaw LJ, Beanlands RS. Can functional testing for ischemia and viability guide revascularization? JACC Cardiovasc Imaging. 2017;10(3):354-64.

CMR: cardiac magnetic resonance; LGE: late gadolinium enhancement; LVEF: left ventricular ejection fraction; SPECT: single-photon emission computed tomography; PET: positron emission tomography; R: randomization.

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Figure 8
NT-proBNP (A) and hs-cTnT (B) concentrations in "patients with and those without significant (> 10%) hibernation. Median (interquartile range) values of (A) serum NT-proBNP and (B) hs-cTnT levels are shown at the top of each corresponding bar." – Adapted with permission from Zelt et al., Can J Cardiol⁵⁸58 Zelt JG, Liu PP, Erthal F, deKemp RA, Wells G, O'Meara E, et al. N-terminal pro B-type natriuretic peptide and high-sensitivity cardiac troponin T levels are related to the extent of hibernating myocardium in patients with ischemic heart failure. Can J Cardiol. 2017;33(11):1478-88.

NT-proBNP (Log of serum N-terminal pro b-type natriuretic peptide), hs-cTnT (high-sensitivity cardiac troponin T).

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Table 1
Viable and non-viable myocardium

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Table 2
Comparison of the STICH Viability Substudy with PARR-2 - Adapted with permission from Mielniczuk et al., JACC Cardiovasc Imaging⁴³43 Mielniczuk LM, Toth GG, Xie JX, De Bruyne B, Shaw LJ, Beanlands RS. Can functional testing for ischemia and viability guide revascularization? JACC Cardiovasc Imaging. 2017;10(3):354-64.

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Table 3
Guidelines, Appropriate Use Criteria and Position Statements for the use of viability imaging in patients with ischemic heart failure. With permission from Wiefels et al., Curr Cardiovasc Imaging Rep.⁷³73 Wiefels C, Erthal F, de Kemp RA, et al. Radionuclide imaging in decision-making for coronary revascularization in stable ischemic heart disease. Curr Cardiovasc Imaging Rep. 2018. (in press).

Myocardium	Flow	Glucose metabolism/FDG	Function	Potential to recover
Non-Viable
Scar/Fibrosis	Reduced	Reduced	Reduced	Unlikely
Viable
Stunned	Preserved(has suffered an intermittent ischemic insult)⁶⁵65 Canty JM Jr, Fallavollita JA. Hibernating myocardium. J Nucl Cardiol. 2005;12(1):104-19.^,⁶⁶66 Camici PG, Dutka DP. Repetitive stunning, hibernation, and heart failure: contribution of PET to establishing a link. Am J Physiol Heart Circ Physiol. 2001;280(3):H929-36.	Variable [can be normal, increased or reduced (reverse mismatch)]⁶⁵65 Canty JM Jr, Fallavollita JA. Hibernating myocardium. J Nucl Cardiol. 2005;12(1):104-19.^–⁶⁹69 Dou KF, Xie BQ, Gao XJ, Li Y, Yang YJ, He ZX, et al. Use of resting myocardial 18F-FDG imaging in the detection of unstable angina. Nucl Med Commun. 2015;36(10):999-1006.^,67^–⁷¹71 Schwaiger M, Pirich C. Reverse flow-metabolism mismatch: what does it mean? J Nucl Med. 1999;40(9):1499-502.^,⁶⁷67 Abramson BL, Ruddy TD, deKemp RA, Laramee LA, Marquis JF, Beanlands RS. Stress perfusion/metabolism imaging: a pilot study for a potential new approach to the diagnosis of coronary disease in women. J Nucl Cardiol. 2000;7(3):205-12.^–⁷¹71 Schwaiger M, Pirich C. Reverse flow-metabolism mismatch: what does it mean? J Nucl Med. 1999;40(9):1499-502.	Reduced	Likely to recover if ischemic injury does not persist or become repetitive;⁴4 Ghosh N, Rimoldi OE, Beanlands RS, Camici PG. Assessment of myocardial ischaemia and viability: role of positron emission tomography. Eur Heart J. 2010;31(24):2984-95.^,¹⁴14 Lim SP, McArdle BA, Beanlands RS, Hessian RC. Myocardial viability: it is still alive. Semin Nucl Med. 2014;44(5):358-74. may benefit from revascularization
Hibernation	Reduced	Preserved (flow-metabolism mismatch)	Reduced	Likely to have part or full recovery if adequate revascularization can be achieved⁵5 Schinkel AF, Bax JJ, Poldermans D, Elhendy A, Ferrari R, Rahimtoola SH. Hibernating myocardium: diagnosis and patient outcomes. Curr Probl Cardiol. 2007;32(7):375-410.^,⁷²72 Fukuoka Y, Nakano A, Tama N, Hasegawa K, Ikeda H, Morishita T, et al. Impaired myocardial microcirculation in the flow-glucose metabolism mismatch regions in revascularized acute myocardial infarction. J Nucl Cardiol. 2017;24(5):1641-50.
Ischemia	Preserved at rest (impaired at stress)	Normal at rest, increased at stress⁶⁷67 Abramson BL, Ruddy TD, deKemp RA, Laramee LA, Marquis JF, Beanlands RS. Stress perfusion/metabolism imaging: a pilot study for a potential new approach to the diagnosis of coronary disease in women. J Nucl Cardiol. 2000;7(3):205-12.	Preserved	May benefit from revascularization

	STICH substudy	PARR-2
Patient population
Randomized?	Not the substudy	Yes
Mean age, years	60.7	63
Male sex	85	84
Previous CABG	3	19
Diabetes mellitus	39	39
Estimated GFR < 60 mL/min/1.73m²	7.5	34
Mean serum creatinine		108 µmol/L
Viability testing	SPECT or dobutamine echocardiography	PET
Prevalence of viability	81	22

Recommendation	Grade	Level	Organization
Nuclear imaging for assessment of myocardial viability for consideration of revascularization in patients with CAD and LV dysfunction who do not have angina	I	B	ACC/AHA/ASNC Radionuclide Imaging 2003⁴⁴44 Klocke FJ, Baird MG, Lorell BH, Bateman TM, Messer JV, Berman DS, et al; American College of Cardiology; American Heart Association Task Force on Practice Guidelines; American Society for Nuclear Cardiology. ACC/AHA/ASNC Guidelines for the Clinical Use of Cardiac Radionuclide Imaging-Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASNC Committee to Revise the 1995 Guidelines for the Clinical Use of Cardiac Radionuclide Imaging). Circulation. 2003;108(11):1404-18.
Cardiac PET and CMR should be used in the evaluation and prognostication of patients with ICM and LV dysfunction	I	B	CCS/CAR/CANM/CNCS/Can SCMR 2007⁴⁷47 Beanlands R, Chow B, Dick A, Friedrich MG, Gulenchyn KY, Kiess M, et al; Canadian Cardiovascular Society; Canadian Association of Radiologists; Canadian Association of Nuclear Medicine; Canadian Nuclear Cardiology Society; Canadian Society of Cardiac Magnetic Resonance. CCS/CAR/CANM/CNCS/CanSCMR joint position statement on advanced noninvasive cardiac imaging using positron emission tomography, magnetic resonance imaging and multidetector computed tomographic angiography in the diagnosis and evaluation of ischemic heart disease - executive summary. Can J Cardiol. 2007;23(2):107-19.
Noninvasive imaging to detect myocardial ischemia /viability in HF and CAD	IIa	C	ACCF/AHA CHF 2013⁴⁸48 Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, et al; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA Guideline for the Management of Heart Failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013;128(16):e240-327.
Viability assessment is reasonable before revascularization in HF patients with CAD	IIa	B	ACCF/AHA CHF 2013⁴⁸48 Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, et al; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA Guideline for the Management of Heart Failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013;128(16):e240-327.
Non-invasive stress imaging (CMR, echo, SPECT, PET) may be considered for the assessment of myocardial ischemia and viability in patients with HF and CAD (considered suitable for coronary revascularization) before the decision on revascularization.	IIb	B	ESC CHF 2016⁴⁴44 Klocke FJ, Baird MG, Lorell BH, Bateman TM, Messer JV, Berman DS, et al; American College of Cardiology; American Heart Association Task Force on Practice Guidelines; American Society for Nuclear Cardiology. ACC/AHA/ASNC Guidelines for the Clinical Use of Cardiac Radionuclide Imaging-Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASNC Committee to Revise the 1995 Guidelines for the Clinical Use of Cardiac Radionuclide Imaging). Circulation. 2003;108(11):1404-18.
Myocardial viability testing should be considered in patients with ischemic CM and reduced LV EF eligible for revascularization	Appropriate use score: 9		AACF/ASNC/ACR/ASE/ SCCT/SCMR/ SNM 2009⁴⁵45 Hendel RC, Berman DS, Di Carli MF, Heidenreich PA, Henkin RE, Pellikka PA, et al; American College of Cardiology Foundation Appropriate Use Criteria Task Force; American Society of Nuclear Cardiology; American College of Radiology; American Heart Association; American Society of Echocardiography; Society of Cardiovascular Computed Tomography; Society for Cardiovascular Magnetic Resonance; Society of Nuclear Medicine. ACCF/ASNC/ACR/AHA/ASE/SCCT/SCMR/SNM 2009 appropriate use criteria for cardiac radionuclide imaging: a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, the American Society of Nuclear Cardiology, the American College of Radiology, the American Heart Association, the American Society of Echocardiography, the Society of Cardiovascular Computed Tomography, the Society for Cardiovascular Magnetic Resonance, and the Society of Nuclear Medicine. Circulation. 2009;119(22):e561-87.

[1] Author contributions

Acquisition of data: Erthal F, Wiefels C, Promislow S. Analysis and interpretation of the data: Erthal F, Wiefels C, Promislow S. Writing of the manuscript: Erthal F, Wiefels C, Promislow S, Kandolin R, Stadnick E. Critical revision of the manuscript for intellectual content: Erthal F, Wiefels C, Promislow S, Stadnick E, Mielniczuk L, Ruddy T, Small G, Beanlands R.

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Myocardial Viability: From PARR-2 to IMAGE HF - Current Evidence and Future Directions

Abstract