Myocardial Metabolic Imaging in the Clinical Setting

Register or Login to View PDF Permissions
Permissions× For commercial reprint enquiries please contact Springer Healthcare:

For permissions and non-commercial reprint enquiries, please visit to start a request.

For author reprints, please email
Average (ratings)
No ratings
Your rating


Glucose and free fatty acids are a major energy source in the myocardium. Metabolic imaging with single photon emission tomography (SPECT) and positron emission tomography (PET) have been widely used for the evaluation of the pathophysiology of coronary artery disease (CAD) and heart failure. 18F fluorodeoxyglucose (FDG) is a glucose analogue that is used to measure myocardial glucose utilisation. The myocardial uptake of a modified branched fatty acid, 15-(p-[iodine-123] iodophenyl)-3-(R,S) methylpentadecanoic acid (BMIPP), reflects the activation of fatty-acid metabolism by co-enzyme A (CoA) and indirectly reflects cellular adenosine triphosphate (ATP) production. The turnover rate of the tricarboxylic acid (TCA) cycle reflects the rate of overall myocardial oxidative metabolism. 11C acetate is readily metabolised to CO2 almost exclusively through the TCA cycle. These three major agents have been most commonly used for probing myocardial energy metabolism in vivo. Such metabolic imaging has been used for assessing myocardial viability on the basis of persistent glucose utilisation in ischaemic but viable myocardium. BMIPP and FDG have been identified for locating a recent history of myocardial ischaemia. Furthermore, metabolic imaging is promising for the assessment of the pathophysiology of heart failure and the treatment effect of various drugs, as well as mechanical treatments. In this article we will provide an overview of the application of myocardial metabolic imaging in a clinical setting.

Disclosure:The authors have no conflicts of interest to declare.



Correspondence Details:Nagara Tamaki, Department of Nuclear Medicine, Hokkaido University Graduate School of Medicine, North 15, West 17, Sapporo, 060-8638, Japan.

Copyright Statement:

The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

The heart requires a high rate of oxygen uptake to maintain mechanical function in order to provide sufficient energy to balance the requirement of the mechanical function. Oxygen consumption increases in almost direct ratio to the increased workload; when the oxygen supply is inadequate for the demand, reversible or irreversible metabolic changes may occur. Such an imbalance is most often observed in coronary artery disease (CAD), where oxygen supply is limited due to severe stenosis or occlusion of major coronary arteries. Energy is also required to keep in the membrane the potential to regulate ion concentration in the cells.

Glucose and free fatty acids are major energy sources in the myocardium and each energy source requires enzymatic conversion before its breakdown. The term substrate can be used to describe a ‘fuel for the heart’. The uptake of various substrates by the heart is partially dependent on the arterial concentration of the fuel. In the fasting state, where plasma free fatty acids are high, free fatty acid uptake in the myocardium is also high due to the suppression of glucose oxidation. On the other hand, when glucose and/or insulin levels are high, such as in the post-prandial condition, glucose oxidation increases with suppression of fatty-acid utilisation. The myocardium converts chemical energy into mechanical energy.1 Energy substrate metabolism is a potential target of such novel therapies to improve the function of the failing heart because metabolism and function in the heart are inextricably linked.2

Metabolic Imaging

Metabolic imaging with single photon emission tomography (SPECT) and positron emission tomography (PET) have been widely used for the evaluation of pathophysiology of CAD and heart failure (see Figure 1).1,3–518F fluorodeoxyglucose (FDG) is a glucose analogue (one hydroxyl group is replaced by an 18F) and is used to measure myocardial glucose utilisation. 18F FDG enters the myocyte in proportion to glucose. After phosphorylation, unlike glucose, 18F FDG-6-phosphate becomes metabolically trapped by the myocyte (see Figures 1 and 2). Therefore, 18F FDG myocardial uptake reflects the rate of exogenous glucose utilisation.

Myocardial 11C palmitate kinetics reflects the uptake and metabolism of long-chain fatty acids. After 11C palmitate is etherified to acyl-co-enzyme A (acyl-CoA), a fraction proceeds via the carnitine shuttle into the mitochondria. Subsequently, β-oxidation categorises the long-chain fatty acids into two-carbon fragments that are oxidised via the tricarboxylic acid (TCA) cycle and released from the myocardium as 11C carbon dioxide (CO2) (see Figure 1).6 A straight-chain fatty acid, 15-(p-[iodine-123] iodophenyl) pentadecanoic acid (IPPA), is rapidly excreted from the myocardium as iodine-123 benzoic acid (see Figure 3).5 A modified branched fatty acid, 15-(p-[iodine-123] iodophenyl)-3-(R,S) methyl-pentadecanoic acid (BMIPP), is a methyl branched-chain fatty acid. BMIPP uptake in the myocardium reflects the activation of fatty-acid metabolism by CoA and indirectly reflects cellular adenosine triphosphate (ATP) production (see Figure 3).7,8

The turnover rate of the TCA cycle reflects the rate of overall myocardial oxidative metabolism.11C acetate is readily metabolised to CO2 almost exclusively through the TCA cycle.4,9 Acetate is converted to acetyl–CoA in the mitochondria and then enters the TCA cycle. Almost all of the acetate (80–90%) extracted by the myocardium is oxidised.12 The clearance of 11C from the myocardium reflects 11CO2 production from oxidative metabolism and also myocardial oxygen consumption (MVO2).4,9

Combined with an assessment of cardiac function (such as echocardiography or magnetic resonance imaging [MRI]), 11C acetate PET can be applied as a non-invasive approach to study myocardial energetics and efficiency, as can be seen in the following equation:
WMI = SVI x SBP x HR/k
where WMI = work metabolic index, SVI = stroke volume index determined by echocardiography or MRI, SBP = systolic blood pressure, HR = heart rate, k = mono-exponential (kmono) rate constant for 11C clearance from the myocardium after 11C acetate administration.10

Clinical Applications
Viability Assessment

It is of great value to identify dysfunctional but reversible ischaemic myocardium from scar tissue for decision-making in a therapeutic regime that includes revascularisation, medication or heart transplant. Hibernating myocardium (viable myocardium) is defined as a left ventricular (LV) dysfunction that is reversible after restoration of myocardial blood flow. Increased glucose metabolism has long been identified as a hallmark of reversible ischaemic myocardium.4,11 This may be a protective mechanism in which the myocardium reduces its oxygen requirements to ensure myocyte survival but as a consequence must reduce myocardial function. PET simply identifies such ischaemic but viable myocardium as an area with reduced perfusion with relatively preserved FDG uptake (see Figure 4). This dysfunctional but viable myocardium may have potential for recovery if perfusion can be adequately restored.

Conversely, a matched reduction in perfusion and glucose metabolism represents scar-tissue formation.4,11 This assessment of myocardial viability is also important for risk assessment of patients with heart failure. Those with a significant amount of ischaemic viable myocardium were in a relatively high-risk group for future cardiac events following conservative treatment compared with those with no or little ischaemic myocardium.12 However, early revascularisation may reduce the future cardiac event rate in these patients.12 Thus, patients with cardiac dysfunction and a significant amount of ischaemic myocardium should receive aggressive treatment, such as revascularisation, in order to recover LV function and also reduce future cardiac events.

Preserved oxidative metabolism is also required for LV functional recovery after revascularisation.13 The oxidative metabolism in hibernating myocardium estimated by 11C-acetate PET was lower than in remote myocardium.14 In addition, oxidative metabolic response to low-dose dobutamine in viable segments was significantly higher than in scar tissue without overlap.15 The recovery of function in myocardium defined as viable by FDG PET may differ from that defined by dobutamine stress echocardiography (DSE).

Furthermore, the lack of contractile reserve even in the preserved glucose metabolism was related to a reduction in metabolic response, indicating a close relationship between the contractive reserve and the oxidative metabolic response under low-dose dobutamine.16 The oxidative metabolism in dysfunctional myocardium is associated with regional myocardial blood flow. The metabolic response to inotropic agents can enhance the detection of viable myocardium.

Detection of Early Ischaemic Myocardial Damage

A metabolic switch from fatty acid to glucose should be considered when preserving myocardial viability, and likely represents an early adaptive response to ischaemia. More interestingly, delayed recovery of the metabolic response after recovery from ischaemia as an imprint of prior ischaemic events, as shown by a reduction of BMIPP uptake, is known as ischaemic memory.7,17–19

Recent data suggest BMIPP SPECT may be useful in acute coronary syndrome to detect myocardial damage. In a study of patients with myocardial infarction (MI), BMIPP defects were frequently greater than perfusion defects.20 When both perfusion and BMIPP imaging were administered for patients with acute chest pain syndrome without evidence of MI to contrast the coronary angiography (CAG) findings, CAD patients frequently had BMIPP defects even in the areas of normal perfusion at rest. Therefore, most CAD patients showed either perfusion- or BMIPP-matched reduction or BMIPP reduction with preserved myocardial perfusion.21,22 This study indicates that aerobic fatty-acid metabolism deterioration may persist shortly after blood flow is restored. In other words, the history of ischaemia may be identified in the areas of persistent metabolic alteration, the so-called ‘ischaemic memory’, indicating early myocardial damage (see Figure 5).7,17–19,21,22 Thus, BMIPP or related tracers may provide a means to detect higher-risk patients in the emergency department. Recently, BMIPP imaging performed within 30 hours after exercise was compared with exercise 201thallium (201Tl) SPECT in the US. This well-controlled study showed a good correlation between the resting BMIPP defects with exercise-induced perfusion defects, confirming the value of ischaemic memory imaging using BMIPP.19

FDG can be used for the detection of ischaemia as an area of metabolic alteration.23,24 Ischaemic myocardium may be identified as an area of increased FDG uptake when FDG was injected during the peak of the strenuous activity.23 Dual-isotope SPECT imaging was performed when both FDG and technetium-99m (Tc-99m) sestamibi was injected at peak exercise to demonstrate higher diagnostic accuracy of ischaemia by FDG than sestamibi.23 In addition, a persistent increase in FDG uptake was often observed at 24 hours after exercise-induced ischaemia, indicating persistent metabolic alteration following recovery after ischaemia.24 However, further study is warranted to determine how long the metabolic alteration persists and whether a reduction of BMIPP or an increase in FDG may be better suited to identifying such metabolic alterations in patients with ischaemic heart disease.

Assessment of Heart Failure

Alterations in myocardial substrate metabolism are associated with the pathogenesis of contractile dysfunction. In addition, metabolic imaging can provide useful clinical information for therapeutic response to treatment evaluation. In a metabolic study in patients with idiopathic dilated cardiomyopathy (DCM), myocardial fatty-acid utilisation is suppressed, while myocardial glucose utilisation is elevated.25 In the failing myocardium, substrate metabolism may change to a foetal-like state with elevated glucose metabolism and reduced fatty-acid metabolism.25,26

Another important use of metabolic imaging in heart failure is to assess the treatment effect of various pharmacological or mechanical interventions. β-adrenergic receptor blockers (β-AR) improve survival in patients with heart failure. Although β-AR blockade therapy is widely available, the mechanisms of benefit of β-AR blockade therapy are not fully understood in patients with heart failure. In a study of oxidative metabolism with β-AR blockade therapy, patients treated with metoprolol had a significant decrease in kmono and an improvement in LV efficiency.31 These improvements in myocardial energetics suggest β-AR blockers have energy-sparing effects.

Cardiac resynchronisation therapy (CRT) simultaneously stimulates both ventricles and can optimise contractile synchrony. CRT improved LV function without increasing oxidative metabolism, thus LV efficiency improved. The septal oxidative metabolism increased, as did the septal/lateral wall kmono ratio.32

Long-term CRT also improved LV efficiency and also restored unhomogenous metabolic distribution.33 These data indicate that CRT has favourable energy-sparing effects on the myocardium and changes metabolic distribution. The repeated apnoea–arousal cycles that characterise obstructive sleep apnea induce altered loading conditions, hypoxia and sympathetic nervous system activation. These alterations may increase metabolic demand. Continuous positive airway pressure (CPAP) therapy has been shown to improve LV function. In the study of patients with heart failure and obstructive sleep apnoea, six weeks of nocturnal CPAP treatment tended to reduce oxidative metabolism and improved LV efficiency.34 This indicates an energy-sparing effect. The cardiac energetic effects may contribute to the clinical benefits observed with CPAP therapy.


Myocardial metabolic imaging and fatty acid, glucose and oxidative imaging have considerably advanced and can now be applied to cardiac patients in a clinical setting. Fatty-acid imaging has been shown to have clinical utility in the detection of a previous ischaemic episode or the early stage of myocardial damage. On the other hand, FDG glucose metabolism is useful in distinguishing between viable myocardium and scar tissue. This can help to determine options for therapy in patients with severe LV dysfunction. Oxidative metabolic imaging provides useful information to estimate in a new therapeutic approach whether the new therapy has favourable effects on myocardial energetics. Using myocardial metabolic imaging provides useful information for risk stratification in patients with CAD and heart failure. Metabolic imaging has positive applications in the evaluation of novel therapies.


  1. Yoshinaga K, Chow BJ, deKemp RA, et al., Application of cardiac molecular imaging using positron emission tomography in evaluation of drug and therapeutics for cardiovascular disorders, Curr Pharm Des, 2005;11:903–32.
    Crossref | PubMed
  2. Taegtmeyer H, Energy metabolism of the heart: from basic concepts to clinical applications, Curr Probl Cardiol, 1994;19: 59–113.
  3. Taegtmeyer H, Cardiac metabolism as a target for the treatment of heart failure, Circulation, 2004;110:894–6.
    Crossref | PubMed
  4. Beanlands R, Ruddy TD, Maddahi J, Myocardial viability. In:Wahl RL (ed.), Positron emission tomography, Philadelphia: Lippincott Williams and Wilkins, 2002:334–50.
  5. Herreo P, Gropler RJ, Imaging of myocardial metabolism, J Nucl Cardiol, 2005;12:345–58.
    Crossref | PubMed
  6. Ukkonen H, Beanlands R, Oxidative metabolism and cardiac efficiency. In:Wahl RL (ed.), Principles and practice of positron emission tomography, Philadelphia: Lippincott Williams and Wilkins, 2002:351–67.
  7. Tamaki N, Morita K, Kuge Y, Tsukamoto E, The role of fatty acids in cardiac imaging, J Nucl Med, 2000;41:1525–34.
  8. Tamaki N, Kawamoto M, Takahashi N, et al., Assessment of myocardial fatty acid metabolism with positron emission tomography at rest and during dobutamine infusion in patients with coronary artery disease, Am Heart J, 1993;125:702–10.
    Crossref | PubMed
  9. Armbrecht JJ, Buxton DB, Brunken RC, et al., Regional myocardial oxygen consumption determined noninvasively in humans with [1-11C]acetate and dynamic positron tomography, Circulation, 1989;80:863–72.
    Crossref | PubMed
  10. Buxton DB, Schwaiger M, Nguyen A, et al., Radiolabeled acetate as a tracer of myocardial tricarboxylic acid cycle flux, Circ Res, 1988;63:628–34.
    Crossref | PubMed
  11. Bax JJ, van der Wall EE, Harbinson M, Radionuclide techniques for the assessment of myocardial viability and hibernation, Heart, 2004;90(Suppl. 5):v26–33.
    Crossref | PubMed
  12. Allman KC, Shaw LJ, Hachamovitch R, Udelson JE, Myocardial viability testing and impact of revascularization on prognosis in patients with coronary artery disease and lfet ventricular dysfunction; a meta-analysis, J Am Coll Cardiol, 2002;39:1151–8.
    Crossref | PubMed
  13. Gropler RJ, Geltman EM, Sampathkumaran K, et al., Functional recovery after coronary revascularization for chronic coronary artery disease is dependent on maintenance of oxidative metabolism, J Am Coll Cardiol, 1992;20:569–77.
    Crossref | PubMed
  14. Gropler RJ, Siegel BA, Sampathkumaran K, et al., Dependence of recovery of contractile function on maintenance of oxidative metabolism after myocardial infarction, J Am Coll Cardiol, 1992;19:989–97.
    Crossref | PubMed
  15. Hata T, Nohara R, Fujita M, et al., Noninvasive assessment of myocardial viability by positron emission tomography with 11C acetate in patients with old myocardial infarction. Usefulness of low-dose dobutamine infusion, Circulation, 1996;94:1834–41.
    Crossref | PubMed
  16. Yoshinaga K, Katoh C, Beanlands RS, et al., Reduced oxidative metabolic response in dysfunctional myocardium with preserved glucose metabolism but with impaired contractile reserve, J Nucl Med, 2004;45:1885–91.
  17. Tamaki N, Kawamoto M, Yonekura Y, et al., Regional metabolic abnormality in relation to perfusion and wall motion in patients with myocardial infarction: assessment with emission tomography using an iodinated branched fatty acid analog, J Nucl Med, 1992;33:659–67.
  18. Kawai Y, Tsukamoto E, Nozaki Y, et al., Significance of reduced uptake of iodinated fatty acid analogue for the evaluation of patients with acute chest pain, J Am Coll Cardiol, 2001;38:1888–94.
    Crossref | PubMed
  19. Dilsizian V, Bateman TM, Bergmann SR, et al., Metabolic imaging with beta-methyl-p-[(123)I]-iodophenylpentadecanoic acid identifies ischemic memory after demand ischemia, Circulation, 2005;112:2169–74.
    Crossref | PubMed
  20. Franken PR, De Geeter F, Dendale P, et al., Abnormal free fatty acid uptake in subacute myocardial infarction after coronary thrombolysis: correlation with wall motion and inotropic reserve, J Nucl Med, 1994;35:1758–65.
  21. Tamaki N, Morita K, Kawai Y, The Japanese experience with metabolic imaging in the clinical setting, J Nucl Cardiol, 2007;14:S145–52.
    Crossref | PubMed
  22. Chikamori T, Yamashina A, Hida S, Nishimura T, Diagnostic and prognostic value of BMIPP imaging, J Nucl Cardiol, 2007;14:111–25.
    Crossref | PubMed
  23. He ZX, Shi RF, Wu YJ, et al., Direct imaging of exerciseinduced myocardial ischemia with fluorine-18-labeled deoxyglucose and Tc-99m-sestamibi in coronary artery disease, Circulation, 2003;108:1208–13.
    Crossref | PubMed
  24. Dou KF, Yang MF, Yang YJ, et al., Myocardial 18F-FDG uptake after exercise induced myocardial ischemia in patients with coronary artery disease, J Nucl Med, 2008;49:1986–91.
    Crossref | PubMed
  25. Davila-Roman VG, Vedala G, Herrero P, et al., Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy, J Am Coll Cardiol, 2002;40:271–7.
    Crossref | PubMed
  26. Rosenblatt-Velin N, Montessuit C, Papageorgiou I, et al., Postinfarction heart failure in rats is associated with upregulation of GLUT-1 and downregulation of genes of fatty acid metabolism, Cardiovasc Res, 2001;52:407–16.
    Crossref | PubMed
  27. Nowak B, Sinha AM, Schaefer WM, et al., Cardiac resynchronization therapy homogenizes myocardial glucose metabolism and perfusion in dilated cardiomyopathy and left bundle branch block, J Am Coll Cardiol, 2003;41:1523–8.
    Crossref | PubMed
  28. Thompson K, Saab G, Birnie D, et al., Is septal glucose metabolism altered in patients with left bundle branch block and ischemic cardiomyopathy?, J Nucl Med, 2006;47: 1763–8.
  29. Lindner O, Vogt J, Baller D, et al., Global and regional myocardial oxygen consumption and blood flow in severe cardioyopathy with left bundle branck block, Eur J Heart Fail, 2005;7:225–30.
    Crossref | PubMed
  30. Wu YW, Naya M, Tsukamoto T, et al., Heterogenous reduction of myocardial oxidative metabolism in patients with ischemic and dilated cardiomyopathy using C-11 acetate, Circulation J, 2008;72:786–92.
    Crossref | PubMed
  31. Beanlands RS, Nahmias C, Gordon E, et al., The effects of beta(1)-blockade on oxidative metabolism and the metabolic cost of ventricular work in patients with left ventricular dysfunction: A double-blind, placebocontrolled, positron-emission tomography study, Circulation, 2000;102:2070–75.
    Crossref | PubMed
  32. Ukkonen H, Beanlands RS, Burwash IG, et al., Effect of cardiac resynchronization on myocardial efficiency and regional oxidative metabolism, Circulation, 2003;107:28–31.
    Crossref | PubMed
  33. Lindner O, Sorensen J, Vogt J, et al., Cardiac efficiency and oxygen consumption measured with 11C-acetate PET after long-term cardiac resynchronization therapy, J Nucl Med, 2006;47:378–83.
  34. Yoshinaga K, Burwash I, Leech J, et al., The effects of contiunous positive airway pressure on myocardial energetics in patients with heart failure and obstructive sleep apnea, J Am Coll Cardiol, 2007;49:450–58.
    Crossref | PubMed