Cardiac PET imaging
As part of the circulatory system, the heart consists of four chambers: Venous blood returning from the body flows into the right atrium (RA) through the superior and inferior vena cava (from the upper and lower part of the body, respectively), and then passes to the right ventricle (RV), which pumps the blood into the lung. From lung the blood returns to the left atrium (LA), and then into the left ventricle (LV), which pumps the blood to the body via the aorta.
Each heart beat pumps about 85-105 mL blood (stroke volume, SV), while the total volume of the filled LV is about 120-140 mL (end diastolic volume, EDV); thus about 35-55 mL blood remains in the LV (end systolic volume, ESV). Ejection fraction (EF) is defined as EF=SV/EDV, and is usually ∼0.6-0.7. RV volumes are similar than these LV volumes. Cardiac output (CO) is SV × heart rate (HR), about 4-8 L/min at rest, and up to 30 L/min during exercise. Cardiac index (CI) relates CO to body surface area (BSA): CI=CO/BSA; CI at rest is normally 2.6-4.2 L/(min×m2). Maximal oxygen uptake (VO2max) is directly related to the CO and red blood cell mass. The left ventricular and atrial volumes can be accurately and reproducibly assessed with MRI or CT (Järvinen et al., 2018).
The heart wall consists of three layers, endocardium, myocardium, and epicardium. Endocardium is in contact with the blood inside the atria and ventricles. Myocardium is consists of the contractile muscle, and is very thick in the ventricles. The right and left halves of the heart are divided by septum.
About 2/3 of the myocardial volume is made up by myocytes. Myocardial extracellular volume (ECV) in LV is 20-30% in healthy subjects, and similar in normal appearing myocardial tissue in infarct patients; ECV of normal appearing myocardium increases with age (Kellman et al., 2012; Ugander et al., 2012). Myocardial regions with oedema have ECV in range 30-40% and infarcted regions in range 35-50% (Garg et al., 2017). Myocytes in RV are smaller than in LV, and the collagen content of RV is higher.
Interstitial space of myocardium is composed of extracellular matrix (ECM) proteins, and coronary vasculature and cardiac nerves are located there. ECM contains large numbers of fibroblasts, that are the main producers of the ECM constituents. There are also other cell types, such as antibody-producing plasma cells. Myocardial collagen content or volume fraction may increase several fold in systemic hypertension, aortic valve stenosis, and chronic heart failure.
Fat content in myocardium (triglyceride droplets within cardiomyocytes) is low, ∼1% in lean subjects and ∼2% in obese subjects (Kankaanpää et al., 2006).
Myocardium has high density of capillaries, ∼1 capillary per muscle cell. They constitute about 3.3% of the myocardial volume (Bassingthwaighte et al., 1974).
Myocardial muscle cells have high oxidative capacity, with oxygen extraction fraction (OEF) of about 0.75 already at rest. Mitochondria take up about 20-30% of the cell volume. The heart consumes about 10% of the total oxygen uptake of the body. O2 extraction is 60% at rest. Capillary density is much higher than in skeletal muscle. LV myocardium does most of the work and gets most of the blood flow, but per mass perfusion in LV muscle, 0.8-1.0 mL/(min*g), is only ∼20% higher than in RV muscle.
Fatty acids, lactate, and ketone bodies are the usual substrates for ATP production in the myocardium, but glucose, pyruvate, and amino acids are consumed during ischemia and anoxia. Glutamine and glutamate may be especially important substrates during anoxia. In normal conditions, extraction of fatty acids is 40-70%, and extraction of glucose is 2-5%. Insulin resistance in cardiac muscle is typical in CAD and congestive heart failure (CHF), but not an inherent consequence of whole body insulin resistance (Bøtker et al., 2000).
Ischemic heart disease is one of the leading causes of death, although the acute management of myocardial infarction has improved. Adverse cardiac remodelling and syndrome of delayed heart failure increase morbidity in patients that have survived the acute infarction.
Atherosclerosis is a chronic vascular disease where the arterial walls become thick and stiff because of accumulation of white blood cells (foam cells), proliferation of smooth muscle cells, and subendothelial retention of cholesterol and triglycerides. Narrowing of arteries, usually due to the atherosclerosis, is called coronary artery disease (CAD) when it affects the heart. CAD is the main pathophysiological mechanism behind stress-induced myocardial ischemia.
Vascular inflammation plays a critical role in the early atherosclerosis, and its progression to infarction (Teague et al., 2017). The lipid core of the plaque is covered by matrix proteins, but if the cap is degraded (ruptured), the lipids and apoptotic cells are exposed to the immune system, leading to thrombosis. Melanocortins can attenuate plaque inflammation (Rinne et al., 2014). Narrowing of the arteries leads to gradually reduced blood flow and ischemia. Necrotic or ischemic myocytes can be replaced by connective tissue (fibrosis). Vascular calcification occurs in atherosclerosis as cardiac fibroblasts convert to an osteogenic cell type, leading to generation of hydroxyapatite crystals in the vessel (Pillai et al., 2017). Vascular calcification process is similar to the bone formation, and can even be assessed using [18F]fluoride PET (Basu et al., 2012; Scherer & Psaltis, 2016). Coronary artery calcium score (CACS) can be determined using CT (Agatston et al., 1990).
Hypertension can damage the arteries, leading to CAD. Myocardium (mal)adapts to the chronically increased work load by left ventricular remodelling: alteration of the size and shape via limited hypertrophic growth, progressive loss of contractile proteins, defective excitation-contractile coupling, decreased responsiveness to β-adrenergic stimulation, and fibrosis. Pulmonary hypertension (Harms et al., 2013) leads to increased workload for the right ventricle. Ventricular remodelling can be assessed as a change in LV volume and mass, and ejection fraction, using ECG, CT, MRI, and PET. Systemic and myocardial Renin-angiotensin system is upregulated in various cardiac diseases (Lautamäki et al., 2014) and blocking RAS benefits patients with systolic LV dysfunction. ACE inhibitors, ARBs, and aldosterone agonists reduce clinical symptoms and at least delay the LV remodelling. Repair processes following acute myocardial infarction include angiogenesis, inflammation, and ECM remodelling, which, if persistent, may lead to delayed heart failure including progressive ventricular dilatation and dysfunction.
Exercise testing is used for the provocation and identification of myocardial ischemia, in order to detect CAD in patients with chest pain or other symptoms, and to assess cardiovascular risk (Fletcher et al., 2013). Exercise stress is increasingly used in combination with myocardial perfusion imaging (MPI). Large proportion of patients are unable to exercise, or exercise may be difficult to carry out during MPI; stress induced by pharmacological vasodilator (usually adenosine or dipyridamole) provides an alternative for diagnosis and risk assessment of CAD. Dipyridamole causes more uniform respiratory pattern than adenosine, resulting in better success rate in respiratory gating in cardiac PET (Lassen et al., 2017). MPI PET during rest and stress allows quantification of coronary flow reserve (CFR). Radiation exposure from PET MPI is substantially lower than from cardiac SPECT (Desiderio et al., 2018). Advancements in cardiovascular magnetic resonance (CMR) technology enable quantitative CFR assessment with MRI (Engblom et al., 2017). High CACS and noncalcified plaque volumes are associated with decreased CFR (Assante et al., 2017; Driessen et al., 2018). Exercise-induced increase in blood pressure and heart rate have prognostic value, independent of MPI or other clinical variables. Vasodilator-induced increase in heart rate, but not blood pressure, also has prognostic value (Witbrodt et al., 2017).
Myocardial perfusion imaging (MPI) with PET can utilize tracers radiowater, N-13-ammonia, Rb-82, or [18F]flurpiridaz (Saraste and Knuuti, 2017). Additionally, [68Ga]DOTA has been validated as myocardial perfusion tracer in animal studies. Quantitative perfusion (myocardial blood flow, MBF) imaging with PET allows detection of multi-vessel disease and permits also assessment of coronary flow reserve (CFR). CFR is reduced in CAD) and in dilated and hypertrophic cardiomyopathy with poor prognosis. MPI with PET can also be used to assess coronary endothelial function when combined with cold pressor testing (CPT) which causes sympathetic stimulation and endothelium-dependent vasodilation (Schindler et al., 2004; Tuffier et al., 2016). Oxygen consumption has been measured using [15O]O2, or indirectly using [1-11C]acetate (Knaapen et al., 2007).
Work metabolic index (WMI) represents myocardial efficiency, and it can be calculated by combining PET-derived cardiac oxygen consumption and angiography-derived stroke volume (Beanlands et al., 1993; Laine et al., 1999; Bengel et al., 2000; Ukkonen et al., 2009; Hansson et al., 2017). First-pass analysis and indicator-dilution method can be applied to [1-11C]acetate PET to derive also estimate of stroke volume, from heart rate and CO, and thus WMI from a single PET scan (Sörensen et al., 2003; Hansson et al., 2018). Cardiac output is calculated from Stewart-Hamilton formula as
, where blood curve CB(t) can be measured from ROI placed on either right or left cavity, and the AUC includes only the first-pass phase of the curve (Sörensen et al., 2003; Harms et al., 2018). Forward stroke volume (FSV) can be estimated using either [1-11C]acetate or [15O]H2 (Knaapen et al., 2008; Harms et al., 2015; Nordström et al., 2017; Bouallègue et al., 2018). [1-11C]acetate can also be used to measure myocardial mass and volume (Harms et al., 2016).
Glucose consumption has been quantified using [18F]FDG. Right ventricular volume and ejection fraction can be assessed with moderate precision from gated [18F]FDG images (Wang et al., 2013; Saygin et al., 2017). Pulmonary hypertension leads to increased [18F]FDG uptake in the right ventricle and reduced uptake in the left ventricle (Kluge et al., 2005; Wang et al., 2013; Yang et al., 2014; Frille et al., 2016; Saygin et al., 2017).
These methods are applicable to rodents as well (Cicone et al., 2017).
Cardiac remodelling is associated with alterations in myocardial metabolism, including oxidative metabolism, which can be assessed using [1-11C]acetate PET (Ohte et al., 2009). Myocardial dysfunction is related to down-regulation of cardiac postsynaptic β-AR density, which has been observed in remote non-infarcted region with [11C]CGP12177 PET (Ohte et al., 2012). Cardiac remodelling can be studied in pigs with a chronic post-infarction model of heart failure (Tarkia et al., 2015; Ballo et al., 2018).
Increased integrin αvβ3 expression is potential biomarker of tissue repair processes (Grönman et al., 2017). After myocardial infarction, its expression is upregulated during angiogenesis. Increased uptake of αvβ3 tracer [18F]fluciclatide in patients with myocardial infarction is associated with better regional recovery (Jenkins et al., 2017).
Myocardial strain is a principle for quantification of LV function with speckle-tracking echocardiography. Strain describes local shortening, thickening, and lengthening of the myocardium (Smiseth et al., 2016). Combined measurement of oxidative metabolism with PET and myocardial strain can provide information on regional efficiency of cardiac work (Ballo et al., 2018).
If white blood cells are accumulated into the atherosclerotic plaques or sites of inflammation, it can be observed using many of the usual PET tracers targeted for imaging inflammation and infection (Kircher and Lapa, 2017; Saraste and Knuuti, 2017).
TSPO ligands are being studied for plaque imaging; [18F]FEMPA uptake is increased in plaques with high macrophage content, but no difference between atherosclerotic and healthy mice could be detected (Hellberg et al., 2017). Somatostatin receptor subtype 2 (SSTR2) is highly expressed in activated macrophages, and specific SSTR2 tracer [68Ga]DOTATATE has given both promising and disappointing results in imaging high-risk plaques (Tarkin et al., 2017; Wan et al., 2017). Chemokine receptors, such as CXCR4 and CCR5 which are upregulated on white blood cells, have been targeted with specific PET tracers. 18F-labelled folate is taken up by macrophages in plaques, and folate uptake in myocardial muscle is lower than that of [18F]FDG (Silvola et al., 2018).
Sarcoidosis is a systemic inflammatory granulomatous disease, which usually involves lymph nodes and lungs, but can affect the heart (Birnie et al., 2017). Sarcoidosis, infection, and cardiotoxic agents can lead to myocarditis, characterized by necrotic lesions and fibrosis. Cardiac sarcoidosis (and myocarditis) can cause ventricular tachycardia and sudden cardiac death. [18F]FDG is useful but not optimal tracer for the diagnosis, treatment follow-up, and prognosis of cardiac sarcoidosis (Lee et al., 2017; Weinberg et al., 2017; Chareonthaitawee et al., 2017). Successful imaging with [18F]FDG requires prolonged fasting, as it reduces glucose consumption of myocytes, revealing uptake into the patchy regions with active macrophages. Measurement of myocardial heterogeneity of [18F]FDG uptake improves the detection of cardiac sarcoidosis (Schildt et al., 2017). The liver should not be used as reference region, because steroid therapy increases hepatic [18F]FDG uptake; blood activity derived from ROI placed on ascending aorta should be used instead (Furuya et al., 2018).
[18F]FLT was found to detect cardiac sarcoidosis as well as [18F]FDG (Norikane et al., 2017). Somatostatin receptor imaging may be useful in acute phase of sarcoidosis, but less so in the chronic phase, because fibrotic tissue has less somatostatin receptor expression (Slart et al, 2017).
Fibrotic tissue has higher extracellular volume (ECV) and water content than normal myocardial tissue. ECV can be measured with MRI and PET, using tracers that are confined to the extracellular space, for example [64Cu]DOTA and [68Ga]DOTA.
Cardiac amyloidosis (CA) is caused by deposition of “amyloid” in the heart, leading to hypertrophy, diastolic dysfunction, and heart failure. Cardiac amyloid is not the same as amyloid β that is the main component of senile plaques in the brains of Alzheimer’s disease patients. In AL amyloidosis the cardiac amyloid is derived from the light chains of immunoglobulin that are overproduced by malignant proliferation of plasma cells. In TTR amyloidosis the amyloid is derived from transthyretin, which may occur as a senile form, or as a result of one of numerous gene mutations (Soman & Masri, 2018). Cardiac MRI can detect both AL-CA and TTR-CA. [18F]fluoride PET may be able to detect only TTR-CA (Gallegos & Miller, 2018). Despite the different origins and contents of the protein deposits, CA is also being investigated as a potential target for β-amyloid PET (Antoni et al., 2013; Kero et al., 2016).
Myocardial infarction induced apoptosis can be detected using PET tracers that are specific for the apoptotic processes and cell death. In murine model of myocardial infarction, [68Ga]annexin A5 was able to show the effect of treatment with parathyroid hormone (Lehner et al., 2014).
[11C]HED is a catecholamine analogue, and it is actively transported into presynaptic sympathetic nerve terminals by the norepinephrine transporters (NETs). [11C]HED has been used to assess the status of cardiac sympathetic innervation. [11C]HED is not stored in presynaptic vesicles or released from them like noradrenaline, and therefore the release of [11C]HED cannot directly be used as a measure of cardiac sympathetic activity, although it seems to be somewhat indicative of noradrenaline release (Grassi & Esler, 1999). [18F]fluorodopamine is taken up into sympathetic nerves, converted by β-hydroxylase into [18F]fluoronoradrenaline, stored in the transmitter vesicles and released like noradrenaline; therefore the washout rate of activity from tissue is quantitatively related to the sympathetic activity (Grassi & Esler, 1999). [18F]LMI1195 is a new promising PET tracer (Saraste and Knuuti, 2017; Kobayashi et al., 2017), and since it is released from storage vesicles, it has potential for assessing sympathetic activity.
Angiotensin II AT1 receptors
PET tracers for AT1R have been developed, but currently used mainly in imaging kidney disease animal models, but there is possibility, and demand, for application in human heart studies (Higuchi et al., 2010; Fukushima et al, 2012; Lautamäki et al., 2014).
Adenosine receptors play an important role in cardiovascular physiology, and may be a target for new therapies (Geldenhuys et al., 2017). A2A receptors in cardiac muscle have been studied using [11C]TMSX.
- Circulatory system
- Myocardial blood flow using radiowater
- Adenosine receptors
- Inflammation and infection
- Natriuretic peptides
- Chronic kidney disease (CKD)
- Instructions by tracer
Aikawa E (ed.): Cardiovascular Imaging: Arterial and Aortic Valve Inflammation and Calcification. Springer, 2015. doi: 10.1007/978-3-319-09268-3.
Bassingthwaighte JB. The myocardial cell. In: Cardiology: Fundamentals and Practice (Brandenburg RO, Fuster V, Giuliani ER, McGood, eds.). Year Book Medical Publishers, 1987, pp. 113-148.
Bol A, Michel C, Melin J, Wijns W. Requisites to modelling of tracer kinetics in the heart using positron emission tomography. In: C Beckers et al (eds.), Positron Emission Tomography in Clinical Research and Clinical Diagnosis: Tracer Modelling and Radioreceptors, 1989, 249-262.
Budinger TF, Yano Y, Huesman RH, Derenzo SE, Moyer BR, Mathis CA, Ganz E, Knittel B. Positron emission tomography of the heart. Physiologist 1983; 26(1): 31-34. PMID: 6601810.
Chen X, Werner RA, Javadi MS, Maya Y, Decker M, Lapa C, Herrmann K, Higuchi T. Radionuclide imaging of neurohormonal system of the heart. Theranostics 2015; 5(6): 545-558. doi: 10.7150/thno.10900.
Cicone F, Viertl D, Quintela Pousa AM, Denoël T, Gnesin S, Scopinaro F, Vozenin M-C, Prior JO. Cardiac radionuclide imaging in rodents: a review of methods, results, and factors at play. Front Med. 2017; 4:35. doi: 10.3389/fmed.2017.00035.
Eisen H (ed.): Heart Failure - A Comprehensive Guide to Pathophysiology and Clinical Care. Springer, 2017. doi: 10.1007/978-1-4471-4219-5.
Escaned J, Davies J (eds.): Physiological Assessment of Coronary Stenosis and the Microcirculation. Springer, 2017. doi: 10.1007/978-1-4471-5245-3.
Goldberger JJ, Ng J (eds.): Practical Signal and Image Processing in Clinical Cardiology. Springer, 2010. doi: 10.1007/978-1-84882-515-4.
Kajander S, Joutsiniemi E, Saraste M, Pietilä M, Ukkonen H, Saraste A, Sipilä HT, Teräs M, Mäki M, Airaksinen J, Hartiala J, Knuuti J. Cardiac positron emission tomography/computed tomography imaging accurately detects anatomically and functionally significant coronary artery disease. Circulation 2010; 122(6): 603-613. doi: 10.1161/CIRCULATIONAHA.109.915009.
Kirscher M, Lapa C. Novel noninvasive nuclear medicine imaging techniques for cardiac inflammation. Curr Cardiovasc Imaging Rep. 2017; 10: 6. doi: 10.1007/s12410-017-9400-x.
Knuuti MJ, Nuutila P, Ruotsalainen U, Teräs M, Saraste M, Härkönen R, Ahonen A, Wegelius U, Haapanen A, Bergman J, Haaparanta M, Voipio-Pulkki L-M. The value of quantitative analysis of glucose utilization in detection of myocardial viability by PET. J Nucl Med. 1993; 34: 2068-2075. PMID: 8254389.
Liu Y-H, Sinusas AJ (eds.): Hybrid Imaging in Cardiovascular Medicine. CRC Press, 2018. ISBN 978-1-4665-9537-8.
Manabe O, Naya M, Tamaki N. Feasibility of PET for the management of coronary artery disease: comparison between CFR and FFR. J Cardiol. 2017; 70: 135-140. doi: 10.1016/j.jjcc.2017.03.002.
Nicholls SJ, Crowe T (eds.): Imaging Coronary Atherosclerosis. Humana Press, Springer, 2014. doi: 10.1007/978-1-4939-0572-0.
Pappano AJ, Withrow GW: Cardiovascular physiology, 10th ed. Elsevier, 2013. ISBN: 978-0-323-08697-4
Quarteroni A (ed.): Modeling the Heart and the Circulatory System. Springer, 2015. doi: 10.1007/978-3-319-05230-4.
Saraste A, Knuuti J. PET imaging in heart failure: the role of new tracers. Heart Fail Rev. 2017; 22: 501-511. doi: 10.1007/s10741-017-9620-9.
Schindler TH, George RT, Lima JAC (eds.): Molecular and Multimodality Imaging in Cardiovascular Disease. Springer, 2015. doi: 10.1007/978-3-319-19611-4.
Schwaiger M (ed.): Cardiac Positron Emission Tomography. Kluwer Academic Publishers, 1996. doi: 10.1007/978-1-4613-1233-8.
Sengupta PP, Kramer CM, Narula J, Dilsizian V. The potential of clinical phenotyping of heart failure with imaging biomarkers for guiding therapies: a focused update. JACC Cardiovasc Imaging 2017; 10(9): 1056-1071. doi: 10.1016/j.jcmg.2017.07.001.
Tarkin JM, Joshi FR, Rudd JH. PET imaging of inflammation in atherosclerosis. Nat Rev Cardiol. 2014; 11(8): 443-457. doi: 10.1038/nrcardio.2014.80.
van der Wall EE, Blanksma PK, Niemeyer MG, Paans AMJ (eds.): Cardiac Positron Emission Tomography - Viability, Perfusion, Receptors and Cardiomyopathy. Springer, 1995. doi: 10.1007/978-94-011-0023-6.
Weber KT. Cardiac interstitium in health and disease: the fibrillar collagen network. J Am Coll Cardiol. 1989; 13: 1637-1652. doi: 10.1016/0735-1097(89)90360-4.
Wu JC, Bengel FM, Gambhir SS. Cardiovascular molecular imaging. Radiology 2007; 244(2): 337-355. doi: 10.1148/radiol.2442060136.
Zamorano JL, Bax J, Knuuti J, Sechtem U, Lancellotti P, Badano L (eds.): The ESC Textbook of Cardiovascular Imaging, 2nd ed, Oxford University Press, 2015. ISBN 978-0-19-870334-1.
Updated at: 2019-05-04
Created at: 2016-05-14
Written by: Vesa Oikonen