Cardiac PET Imaging for the Detection and Monitoring of Coronary Artery Disease and Microvascular Health
Thomas H. Schindler, MD*,*,
Heinrich R. Schelbert, MD, PhD ,
Alessandra Quercioli, MD*,
Vasken Dilsizian, MD
* Nuclear Cardiology and Cardiac Imaging, Division of Cardiology, Department of Medicine, University Hospitals of Geneva, Geneva, Switzerland
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California
Department of Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, Maryland
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Abstract
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Positron emission tomography (PET) myocardial perfusion imaging in concert with tracer-kinetic modeling affords the assessment of regional myocardial blood flow (MBF) of the left ventricle in absolute terms (milliliters per gram per minute). Assessment of MBF both at rest and during various forms of vasomotor stress provides insight into early and subclinical abnormalities in coronary arterial vascular function and/or structure, noninvasively. The noninvasive evaluation and quantification of MBF and myocardial flow reserve (MFR) extend the scope of conventional myocardial perfusion imaging from detection of end-stage, advanced, and flow-limiting, epicardial coronary artery disease (CAD) to early stages of atherosclerosis or microvascular dysfunction. Recent studies have shown that impaired hyperemic MBF or MFR with PET, with or without accompanying CAD, is predictive of increased relative risk of death or progression of heart failure. Quantitative approaches that measure MBF with PET identify multivessel CAD and offer the opportunity to monitor responses to lifestyle and/or risk factor modification and to therapeutic interventions. Whether improvement or normalization of hyperemic MBF and/or the MFR will translate to improvement in long-term cardiovascular outcome remains clinically untested. In the meantime, absolute measures of MBF with PET can be used as a surrogate marker for coronary vascular health, and to monitor therapeutic interventions. Although the assessment of myocardial perfusion with PET has become an indispensable tool in cardiac research, it remains underutilized in clinical practice. Individualized, image-guided cardiovascular therapy may likely change this paradigm in the near future.
Key Words: cardiovascular disease prevention • coronary artery disease • coronary circulation • endothelium • microcirculation • myocardial blood flow • myocardial flow reserve • positron emission tomography
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Abbreviations and Acronyms
| | CAD = coronary artery disease | | CPT = cold pressor test(ing) | | CT = computed tomography | | MBF = myocardial blood flow | | MFR = myocardial flow reserve | | PET = positron emission tomography | | SPECT = single-photon emission computed tomography |
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Despite aggressive medical and interventional therapies, morbidity and mortality that is attributable to coronary artery disease (CAD) remains high (1). There is a striking increase in the prevalence of obesity and type 2 diabetes mellitus in the U.S., which poses a considerable public health concern (2). In particular, patients with type 2 diabetes mellitus exhibit accelerated progression of CAD, which may account for the increased morbidity and mortality in these patients (2). Another area of a cardiovascular health concern is the expected increase in the longevity of post-menopausal women. Unlike pre-menopausal women who benefit from endogenous atheroprotective estrogens, the cardiovascular risk profile in post-menopausal women becomes comparable to that of age-matched men, exhibiting higher total cholesterol, low-density lipoprotein cholesterol, triglycerides, and lower high-density lipoprotein levels as well as increases in body weight and arterial hypertension, all known to be proatherogenic (3). According to the Framingham Heart Study (4), individuals with a high cardiovascular risk profile, such as type 2 diabetes mellitus or multiple coronary risk factors, are at risk for future cardiovascular events, and are commonly referred for primary and secondary medical prevention of CAD (5–7). Individuals with an intermediate cardiovascular risk, however, may not necessarily be considered for preventive medical interventions and/or life style modifications.
Apart from standard myocardial perfusion imaging, noninvasive assessment of absolute myocardial blood flow (MBF) with positron emission tomography (PET), in milliliters per gram per minute (ml/g/min), opens opportunities for a comprehensive evaluation of asymptomatic and/or early stages of symptomatic CAD. Assessment of coronary vascular function with PET may further risk stratify individuals with an intermediate cardiovascular risk (8–10). For example, impaired MBF responses to vasomotor stress have been shown to independently predict the development of CAD (11–14). Other possible surrogate markers for subclinical CAD include measurements in carotid intima-media thickness determined by vascular ultrasound (15), or coronary artery calcification and/or coronary morphology by multidetector computed tomography (CT) (16,17). Assessment of functional abnormalities of the coronary vessels with PET may have an advantage over structural alterations of the arterial wall, as it may identify the earliest functional stage of the initiation and development of the coronary atherosclerotic process before structural alterations within the arterial wall may manifest (18). If CAD-related functional abnormalities of the coronary circulation precede morphologic changes of the vessels (8,9,19,20), then PET could emerge as a promising tool to better identify asymptomatic individuals with an intermediate or even low cardiovascular risk, who are likely to benefit from an early initiation or intensified medical preventive therapy (8,21).
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Methodological Considerations of PET Flow Quantification
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PET approaches for the assessment of regional MBF in ml/g/min entails the intravenous injection of a positron-emitting perfusion tracer, such as 13N-ammonia, 15O-water, or 82Rubidium, and dynamic acquisition of images of the radiotracer passing through the central circulatory system to its extraction and retention in the left ventricular myocardium (Table 1) (19,22,23). Tracer-kinetic models (1 to 3 compartments) and operational equations are then applied to correct for physical decay of the radioisotope, partial volume-related underestimation of the true myocardial tissue concentrations (by assuming a uniform myocardial wall thickness of 1 cm) (24), and spillover of radioactivity between the left ventricular blood pool and myocardium (25), to yield regional MBFs in absolute terms, ml/g/min (Figs. 1 and 2) (19,26). The relative distribution of the radiotracer in the myocardium can also be assessed visually or semiquantitatively (as percentage uptake relative to a reference region) from the final static image of the myocardium, obtained from the last (e.g., 900 s) frame of the PET image series (27).
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Figure 1 Serially Acquired Images of a Bolus Transit of 13N-Ammonia Through the Central Circulation
The serially acquired 10-s short-axis images denote the transit of the intravenously applied radiotracer bolus through the central circulation (from left to right and top to bottom). The initial 2 images illustrate the tracer activity mostly in the right ventricular cavity. Subsequently, the tracer bolus is dispersed into both lungs and returns into the left ventricular cavity, as shown in image 3. This is followed by a clearance of the tracer activity from the arterial blood pool into the myocardium (serial 10-s images). The late static image after 18 min (not shown), displays the tracer activity retained in the left ventricular myocardium after the radiotracer has widely disappeared from the blood pool.
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Figure 2 Arterial Radiotracer Input Function and Myocardial Tissue Response
From regions of interest assigned to the left ventricular blood pool and left ventricular myocardium on the serially acquired images, time activity curves are derived that denote the alterations in radiotracer activity (y-axis) in the arterial blood pool (counts/pixel/second) and in the myocardium (counts/pixel/second) as a function of time (x-axis). Through fitting of the time activity curves with the operational equation formulated from tracer-kinetic models, myocardial blood flows are obtained in absolute units (in ml/g/min). The green line indicates the arterial radiotracer input function, and the red line the myocardial tissue response.
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PET Myocardial Perfusion Tracers
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The quantification of MBF in absolute units has been validated for 13N-ammonia and 15O-water against independent microsphere blood flow measurements in animals over a flow range of 0.5 to 5.0 ml/g/min (28–32). In human subjects, 13N-ammonia and 15O-water provide similar absolute MBF information over a wide range of blood flows (33,34). However, 15O-water images of the myocardium are usually of lower count density, due to its short physical and biological half-life in the myocardium (Table 1), thereby limiting the visual or semiquantitative assessment of regional myocardial perfusion from the static images. Unlike 15O-water static images of the myocardium, 13N-ammonia yields high-contrast resolution myocardial perfusion images (8,26). The latter is due to the combination of the high first-pass myocardial extraction fraction of 13N-ammonia (near 80%), trapping of 13N-ammonia in the myocardial cells as 13N-glutamine (long biological half-life), and the relatively long physical half-life (9.8 min) of the 13N radiotracer. These properties of 13N-ammonia permit the acquisition of statistically high count images of the myocardium by PET with a high diagnostic quality for the visual and semiquantitative assessment of myocardial perfusion defects during stress and rest (Fig. 3) (35). The concurrent evaluation of regional MBFs at rest and during various forms of vasomotor stress with 13N-ammonia PET and tracer-kinetic models enables the identification and characterization of subclinical and early stages of the coronary atherosclerotic process (8,19,36–38).
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Figure 3 Normal PET Myocardial Perfusion Images (Short Axis) With Different Positron-Emitting Flow Tracers
Note the excellent and good image quality with 13N-ammonia and 82Rubidium (22), respectively, whereas the visual analysis of the static 15O-water (23) is limited due to the lower count density. Reproduced with permission from Yoshinaga et al. (22) and Adachi et al. (23). PET = positron emission tomography.
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In the clinical setting, 13N-ammonia and 82Rubidium are the only PET myocardial perfusion tracers that have received U.S. Food and Drug Administration approval. 82Rubidium for PET myocardial perfusion imaging is increasingly used in the clinical routine as it affords the advantages of an ultra-short 75-s physical half-life and its independency of an onsite cyclotron through the availability of a Strontium-82/Rubidium-82 generator system with a 4- to 5-week shelf life. However, its relatively lower first-pass extraction and the more prominent nonlinear myocardial uptake with increasing blood flow, termed "roll-off phenomenon," may lead to relatively lower myocardial contrast resolution images when compared with 13N-ammonia (Fig. 3). Despite the known limitations of flow-dependent extraction fraction of 82Rubidium for quantification of MBF, recent clinical investigations have reported promising results (39–41).
More recently, F-18–labeled perfusion tracer was introduced for myocardial perfusion imaging with PET (42,43). The radiotracer has a high first-pass extraction fraction of 94%, and is currently being evaluated in phase 1 and 2 clinical studies. The 110-min half-life of F-18 permits its distribution as a single-unit dose on a daily basis. Moreover, the longer half-life of F-18 allows the application of the perfusion agent during treadmill exercise, rather than with vasodilator stress alone, as is currently the case with 82Rubidium PET myocardial perfusion studies.
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Clinical Utility of Quantification of Myocardial Blood Flow with PET
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Assessment of stress-induced myocardial perfusion defects, with single-photon emission tomography (SPECT) or PET, have been firmly established as an important diagnostic and prognostic tool for the evaluation of patients with suspected CAD (44,45). However, there are distinct limitations with visual or semiquantitative assessment of regional myocardial perfusion defects that may be overcome by absolute quantification with PET. The noninvasive evaluation and quantification of MBF and myocardial flow reserve (MFR) extends the scope of conventional myocardial perfusion imaging from detection of end-stage, advanced and flow-limiting, epicardial CAD to early stages of atherosclerosis or microvascular dysfunction, as in: 1) the identification of subclinical CAD; 2) the improved characterization of the extent and severity of CAD burden; and 3) the identification of "balanced" reduction of MBF in all vascular territories.
Identification of subclinical CAD.
In symptomatic patients with known or suspected CAD, SPECT myocardial perfusion imaging is accurate for identifying flow-limiting epicardial coronary lesions (46,47). However, vascular disease at the microcirculatory level of the coronary circulation or early stages of subclinical CAD may remain undetected with the standard myocardial perfusion SPECT imaging (32). Patients with subclinical stages of CAD may exhibit either subtle heterogeneity in relative myocardial uptake of the radiotracer or homogenously impaired hyperemic blood flow of the left ventricular myocardium. These same individuals with early stages of CAD-related functional and/or structural alterations of the coronary arterial wall have been shown to be at increased long-term risk for cardiovascular events (12,13). By quantifying hyperemic MBF or MFR in absolute terms, PET can identify early functional abnormalities of the coronary circulation, which may be a precursor of the ensuing CAD process (8,13,48–50).
Improved characterization of CAD burden.
Decreased regional radiotracer uptake on standard SPECT or PET myocardial perfusion imaging during hyperemic flow are a consequence of flow-limiting epicardial coronary artery lesions. Visual or semiquantitative interpretation of regional radiotracer uptake is in relative terms, where the myocardial region with the highest radiotracer uptake is considered as the "normal reference region." However, in patients with multivessel CAD, the designated normal reference region may in fact be abnormal as well, but relative to the other vascular territories it is the least hypoperfused myocardial region (51–53). In such patients, the concurrent absolute MBF or MFR assessment with PET may uncover, not only the most hemodynamically significant culprit lesion, but also the true extent of ischemic burden in the left ventricular myocardium, in a multivessel territory, which includes the normal reference region (53,54). Thus, the combined assessment of "relative" and "absolute" myocardial perfusion imaging provides information, not only on flow-limiting isolated epicardial lesions, but also on the downstream functional consequences of anatomically intermediate and/or sequential coronary artery lesions, or continuous tapering of coronary artery vessel due to diffuse atherosclerosis (55–57).
Identification of "balanced" reduction of MBF in all vascular territories.
The assessment of only "relative" distribution of the radiotracer uptake in the left ventricular myocardium with standard myocardial perfusion imaging may also fail to identify "balanced" reduction of MBF in all vascular territories. In such patients, the relative distribution of myocardial perfusion may be homogenously reduced in the entire left ventricular myocardium without visually discernable regional defects that characterize CAD patients (52). Consequently, only about 10% of patients with severe 3-vessel CAD or significant stenosis of the left main coronary artery ( 50%) may be detected by stress-induced regional perfusion defects on SPECT images (51,58). The addition of gated SPECT functional data may improve the identification of patients with severe 3-vessel CAD or left main disease to 25% (59). A more direct assessment of absolute MBF of MFR with PET may unmask balanced ischemic burden of the left ventricular myocardium in all 3 major coronary artery vascular territories. The latter, however, should always be confirmed by a peak stress transient ischemic cavity dilation of the left ventricle during maximal vasomotor stress on gated PET images (60,61).
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Evaluation of Flow-Limiting Epicardial Lesions: Advantages of PET
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The high spatial and contrast resolution of the photon attenuation–free images of PET in concert with superior properties of 13N-ammonia or 82Rubidium as MBF tracers offers several advantages of PET over SPECT for detection of CAD. PET cameras identify paired photons (511 keV of energy each) produced by the positron annihilation effect (Fig. 4). The paired 511 keV travel in the opposite direction at a 180° angle from each other. Therefore, positron decay can be localized without collimation, as used for SPECT, but with the use of the principle of coincidence detection. As PET cameras do not necessitate collimators, these systems have a much higher sensitivity than do SPECT cameras, resulting in a higher spatial resolution in the range of 4 to 7 mm (62). The principle of coincidence detection in concert with the superior properties of MBF tracers such as 13N-ammonia with a better extraction fraction at higher flows has also led to an increase in contrast resolution (Table 1) (Fig. 3). Both the higher spatial and contrast resolution of PET perfusion studies may allow the identification of regional differences in radiotracer uptake during pharmacologically induced hyperemia (Fig. 5). These properties of PET perfusion imaging may explain, at least in part, the higher sensitivity in the identification of flow-limiting epicardial lesions as compared with SPECT imaging with 201Thallium or 99mTc-labeled perfusion tracers (19). The average sensitivity and specificity of myocardial perfusion PET or PET/CT scanners for detecting 50% or 70% luminal narrowing on coronary angiography is reported to be in the mean of 92% and 90%, respectively (63–65). The increase in specificity of PET perfusion imaging as compared with SPECT (66,67) can be related to the robust attenuation correction of the emission data using the transmission source (68Ge rotating rod source or CT) (Fig. 6).
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Figure 4 Principles of Coincidence Detection
A positron (β+) emitted from the atomic nucleus of 13N travels through a medium and loses energy and slows down until it interacts with an electron (e–). Since the e– and β+ are antiparticles, they undergo a process called "annihilation." The latter manifests in the generation of 2 photons traveling in opposite directions at a 180° angle from each other with an energy of 511 keV each. These photons are identified as coincidences in the detector ring of the PET camera. PET = positron emission tomography.
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Figure 5 13N-Ammonia PET/CT and Coronary Angiography in the Evaluation of CAD
(A) Stress and rest 13N-ammonia PET images of the heart in short-axis, vertical long-axis, and horizontal long-axis slices are shown from a 62-year-old type 2 diabetic patient. The stress images demonstrate a moderately decreased perfusion defect involving the lateral extending to the inferolateral region of the left ventricle, which is completely reversible on rest images. (B) Corresponding coronary angiography shows an occluded marginal branch of the left circumflex coronary artery (arrow), with diffuse 50% stenosis of the proximal left anterior descending coronary artery (arrow) and a 50% stenosis in the mid right coronary artery (not shown). CAD = coronary artery disease; CT = computed tomography; PET = positron emission tomography.
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Figure 6 Attenuation Correction of PET Emission Data Using CT
(A) Transaxial image from a PET/CT 13N-ammonia study without attenuation correction. Myocardial radiotracer distribution shows relatively higher 13N-ammonia uptake in the lateral wall with evidence of lung uptake. (B) The corresponding transmission attenuation map demonstrates the lung and tissue regions. (C) After the application of attenuation correction, the myocardial 13N-ammonia uptake demonstrates a more homogenous myocardial distribution with relatively higher uptake in the septum compared with the lateral wall and decreased background activity. Abbreviations as in Figure 5.
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Concordance and Discordance Between Coronary Artery Narrowing and Myocardial Perfusion Abnormality
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Quantitative coronary angiography (QCA) is commonly accepted as a "gold standard" for the assessment of the epicardial coronary artery diameter and luminal narrowing (68). When epicardial luminal narrowing exceeds 50%, it is commonly paralleled by a decrease in MBF reserve and manifestation of myocardial ischemia (69–72). It should be kept in mind, however, that despite the well-described inverse relationship between severity of coronary artery stenosis and MFR, a high degree of variability in the individual flow responses may exist, in particular when the coronary artery luminal narrowing is of intermediate severity (Fig. 7) (56,69,71). In the case of CT-determined luminal narrowing, stress-induced regional myocardial perfusion defects as determined with 201ThaIlium SPECT were seen in 33% of regions with 60% to 70% stenosis, 54% of regions with 70% to 80% stenosis, and 86% of regions with 80% stenosis (73). Beyond an adaptive vasodilation of the coronary arteriolar vessels to compensate increases in epicardial resistance due to significant epicardial narrowing of the arterial lumen (56,57), other possible explanations for the discordances in the literature include an overestimation of the severity of coronary artery stenosis by angiography and/or a lack of absolute regional MBF assessment with the perfusion data. Nonetheless, a relatively preserved regional hyperemic MBF or MFR may in fact prevent the manifestation of stress-induced myocardial ischemia even in the presence of intermediate to severe epicardial artery lesions. Thus, medical therapy that targets and improves the function of the coronary artery circulation or its vasodilator capacity, e.g., HMG-CoA reductase or angiotensin-converting enzyme inhibitors, may prevent or even regress clinically manifest myocardial ischemia in patients with CAD (74,75). This possibility is supported by the recent subanalysis of the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial (45). Medical treatment of cardiovascular risk factors in patients with SPECT-determined regional myocardial perfusion defects over a 1-year follow-up targeting the improvement of MBF reserve was associated with a significant reduction in ischemic burden and a favorable clinical outcome. Another factor that is likely to prevent the manifestation of stress-induced regional ischemia is the induction of collaterals by the hypoxic stimulus, which strive to balance reduced flow increases during times of increased metabolic demand in myocardial regions subtended by flow-limiting epicardial lesions (76).
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Figure 7 MBF and Coronary Vasodilator Reserve in Relation to Percentage Coronary Artery Diameter Stenosis
(A) At rest (green circles), there is no relationship between myocardial blood flow (MBF) and percentage coronary artery stenosis. During pharmacologic vasodilation (red circles), there is an inverse relationship between hyperemic MBFs and percentage coronary artery stenosis. (B) Similar to hyperemic MBFs, myocardial (or coronary) flow reserve (MFR = hyperemic MBF / resting MBF) shows a similar inverse relationship with percentage coronary artery stenosis (69). However, for coronary stenoses of intermediate severity, there was a relatively high variability in MFR. Notably, in individuals without epicardial coronary artery stenoses, reductions in hyperemic MBFs or the MFR due to microvascular disease may be comparable to those in myocardial regions subtended by epicardial lesions 50% diameter stenosis. (C) The observed relationship between MFR and percentage stenosis persists when the severity of coronary artery lesions are determined with quantitative coronary angiography (correlation coefficient r = 0.77, root mean square error = 0.37, p < 0.00001) (71). Panels A and B are reproduced with permission from Uren et al. (69); panel C is reproduced from Di Carli et al. (71).
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Assessment of Hyperemic MBF, MFR, and Relative Radiotracer Content
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The ability of PET to assess regional MBF at rest and during vasomotor stress, concurrently, affords absolute quantification of regional hyperemic MBFs and MFR, by which, apart from the "culprit lesion" causing the stress-induced regional myocardial perfusion defect, the hemodynamic significance of each epicardial lesion can be identified in all 3 vascular territories. The optimal threshold values of hyperemic MBFs or MFR to identify flow-limiting epicardial lesions, however, is dependent on the PET methodology and radiotracer applied for the MBF quantification (19,36,56). Among patients with known or suspected CAD undergoing pharmacologic vasodilation with 13N-ammonia PET, the diagnostic value of hyperemic MBF, MFR, and the relative radiotracer content (millicuries per milliliter) for detecting 70% flow-limiting epicardial lesions was the highest, when a hyperemic MBF threshold value of <1.85 ml/g/min was applied (67). The receiver-operator characteristic analysis of PET parameters in the evaluation of the diagnostic accuracy of CAD demonstrated the highest value of 0.90 for adenosine-stimulated absolute hyperemic MBF, 0.86 for MFR, and 0.69 for 13N-ammonia relative uptake (77,78). Similar findings were recently reported by other investigators (79,80). Using 15O-water, a threshold of pharmacologically induced hyperemic MBFs of 2.5 ml/g/min was shown to be most accurate in the identification of epicardial lesions of >50% diameter stenosis (79). Another investigation using quantitative 82Rubidium PET demonstrated a nonlinear decrease in hyperemic MBFs as the severity of coronary artery stenosis increased (80). It appeared that the MFR could differentiate epicardial lesions between 70% to 80% from those with 50% to 69% stenosis.
Hyperemic MBFs during pharmacologic vasodilation may also be diminished due to coronary microvascular dysfunction in patients with or without focal CAD lesions on coronary angiography but with multiple cardiovascular risk factors (49,81,82). Furthermore, a grey zone may exist in patients with epicardial lesions 50% and a MBF reserve between 2.0 and 2.5, where the significance of downstream consequences of a focal epicardial lesion may remain uncertain. Overall, adding PET-determined regional hyperemic MBFs and MFR to standard myocardial perfusion imaging certainly increases the sensitivity in the identification of each flow-limiting epicardial lesion in multivessel disease but at the expensive of a lower specificity (83,84). Whether this approach may play a role in the future for revascularization planning with percutaneous interventions or coronary artery bypass surgery, or both (so-called hybrid interventions) in patients with multivessel CAD remains uncertain and requires clinical validation. Current clinical application of myocardial perfusion imaging with PET is aimed at differentiating normal vasomotor stress response from hemodynamically significant coronary artery lesions (stress-induced regional perfusion defect) (Fig. 8) and subclinical CAD (Fig. 9). Among individuals with high cardiovascular risk who exhibit reduced hyperemic MBF and MFR on PET but without significant epicardial coronary artery luminal narrowing, preventive medical intervention and lifestyle modifications may apply. However, in view of the relatively low specificity of abnormal MBF reserve (69,85), current application and interpretation of MBF reserve with PET have to be placed in the proper clinical context with underlying coronary anatomy and cardiovascular risk factors (Fig. 9).
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Figure 8 13N-Ammonia PET in the Evaluation of CAD
(A) Myocardial perfusion study with 13N-ammonia PET during dipyridamole stimulation and at rest in a 61-year-old patient with arterial hypertension and type 2 diabetes mellitus. On stress images, there is a moderately decreased perfusion defect involving the mid-to-distal anterior, anteroseptal, and apical regions of the left ventricle, which becomes reversible on the rest images. Uptake is preserved in the lateral and inferior regions. (B) Stress and rest integrated PET/CT images of the left ventricular myocardium are shown (middle panel). Integrated PET/CT image allows an accurate coregistration of relatively low spatial resolution of the 13N-ammonia perfusion signal of PET with the high-resolution anatomic signal of the CT-contrast image. For direct comparison, 13N-ammonia PET perfusion images (right panel) and CT-contrast images with delineation of the left ventricular cavity and myocardial wall (left panel) are shown prior to integration. (C) Polar maps of 13N-ammonia PET during dipyridamole stimulation, at rest, and the difference between stress and rest are displayed in terms of absolute regional myocardial blood flow (MBF) (upper panel) and within the 3 major vascular territories (lower panel) are shown (Munich Heart Program software package, S. Nekolla). The summarized quantitative data (lower panel), suggests a distinct impairment of the MFR not only in the left anterior descending artery (LAD) territory, but also in the right coronary artery (RCA), and left circumflex artery (LCX) vascular territories (MFR <2.0). (D) Coronary angiography in this patient demonstrated a proximal occlusion of the LAD, 80% stenosis in the proximal segments of the LCX (left panel), and sequential 50% to 60% lesions in the RCA (right panel) (53). Abbreviations as in Figures 3 and 5.
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Figure 9 Algorithm for the Integration of PET Perfusion Images and MFR
Algorithm for the integration of PET myocardial perfusion imaging and absolute myocardial blood flow (MBF) and flow reserve (MFR) quantification in individuals with suspected or an intermediate risk for developing CAD for clinical decision making towards revascularization or preventive medical therapy is shown. Abbreviations as in Figures 3 and 5.
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Assessment of Subclinical Stages of CAD and Prognosis
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In patients exhibiting normal SPECT or PET myocardial perfusion studies by relative radiotracer content, the assessment of impaired hyperemic MBFs and MFR by absolute quantitative PET (49,81,86) may further identify individuals who are at increased risk for cardiovascular events (12,13,87). For example, in insulin-resistant individuals with normal stress-rest myocardial perfusion PET images, concurrent MBF quantification has uncovered abnormalities in endothelium-related MBF responses to cold pressor testing (CPT), whereas hyperemic flows during pharmacologic vasodilation were preserved (88). These observations support the contention that initial stages of the vascular injury may involve only the endothelium (89–91), whereas more advanced stages of coronary risk factor states, such as increases in oxidative stress burden, may lead to an impairment in smooth muscle cell vasodilator function (92). Indeed, coronary circulatory dysfunction in individuals with increasing body weight may progress from an impairment in endothelium-dependent coronary flow response to CPT, in the early stages of overweight, to an impairment of the predominantly endothelium-independent hyperemic flows during dipyridamole stimulation in the late stages of obesity (49). Similarly, in patients with insulin resistance, progressive worsening of functional abnormalities of endothelium-dependent vasomotion may occur with increasing severity of insulin resistance and carbohydrate intolerance, with attenuation of the total vasodilator capacity occurring in the later stages, in patients with clinical type 2 diabetes mellitus (70). An inverse relationship between MFR and plasma glucose levels has been shown in patients with type 2 diabetes mellitus, providing first evidence of direct adverse effect of raised plasma glucose concentration on diabetes-related coronary vasculopathy (88).
In individuals with increased cardiovascular risk, the assessment of MBF response to CPT may provide the earliest insight into coronary endothelial (dys)function as a precursor to progression of CAD and its prognostic consequence (8,18,50). In patients with normal coronary angiograms, but with cardiovascular risk factors, attenuation of PET-measured and endothelium-related MBF responses to sympathetic stimulation with CPT and its MFR were associated with a higher risk for cardiac events as compared with those with normal flow increases (12). Moreover, the incidence of cardiovascular events increased with the extent of abnormal flow response to CPT (Fig. 10). Others have shown that beyond reduced MFR, stress-induced myocardial perfusion defects is also an independent predictor of cardiovascular outcome (9). However, adding the MFR information to the stress 13N-ammonia perfusion PET data allowed further risk stratification, identifying a "warranty" period of event-free survival of 3 years when both stress myocardial perfusion and MFR data were normal. Contrarily, when both stress myocardial perfusion and MFR data were abnormal, impaired MFR provided incremental information to the stress 13N-ammonia perfusion PET data for predicting adverse outcomes. It is important to highlight the prognostic differences between stress myocardial perfusion SPECT or PET studies and PET-assessment of coronary circulatory dysfunction. Whereas the presence of stress-induced myocardial perfusion defects on SPECT or PET is predictive of cardiovascular events during a shorter follow-up period of time (e.g., 1 year), PET assessment of coronary circulatory dysfunction in patients without flow-limiting epicardial coronary artery lesions commonly predicted future cardiovascular events (e.g., after 2 to 3 years) (12,13,27,87,93,94). Consequently, the assessment of coronary circulatory dysfunction with PET may identify individuals with cardiac risk factors, who are at risk of developing CAD and its atherothrombotic sequelae.
Beyond its incremental value in individuals with CAD or subclinical stages of CAD, impairment in coronary circulatory function has also been shown to be predictive of future cardiovascular outcome in patients without underlying CAD, such as those with hypertrophic cardiomyopathy and idiopathic cardiomyopathy (10,95). Such clinical observations emphasize the importance of integrating coronary circulatory function as an index of the overall stress burden imposed by various coronary risk factors on the arterial wall (8,96).
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Reproducibility of MBFs During Vasomotor Stress
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If impaired coronary circulatory function is a predictor of future cardiovascular events, then medical interventions or lifestyle modifications, that improve or normalize the coronary circulatory function, would be expected to improve patient outcome. In view of this evolving concept, PET measurements of MBF responses to cold exposure and/or to pharmacologic vasodilation are being applied increasingly in the clinical setting in order to detect and monitor the effects of medical therapy and/or lifestyle modifications on coronary circulatory function (8,9,20,78). The use of serial PET myocardial blood flow studies to monitor progression or regression of coronary circulatory (dys)function necessitates establishing the reproducibility of repeated PET MBF measurement (8,97). The reproducibility of MBF to CPT and measurement error of MBF at rest and during various forms of vasomotor stress along with hemodynamic and biologic factors, that may contribute to the variability in these repeat MBF measurements, are shown in Table 2
(97–102). The reproducibility of hyperemic MBF increases during pharmacologic vasodilation and bicycle exercise using 13N-ammonia, 15O-labeled water or 82Rubidium with PET are reasonable and in the range of 4 to 15% (99,103–105). Also when CPT-related MBFs were measured with 15O-labeled water on a 1-day protocol, the MBFs appeared to be reproducible within 27% (106). In a more comprehensive investigation (97), the hemodynamic and endothelium-related MBF responses to CPT from rest ( MBF), as measured with 13N-ammonia and PET, were demonstrated to be not only highly reproducible in short-term (1-day protocol), but also in long-term (2- to 3-weeks protocol) within a range of 10% (Table 2). In this regard, the range of measurement errors, as indicated by the standard error of the estimate (SEE) from the Pearson correlation coefficient (r) of the least-square regression for the endothelium-related MBF to CPT determined with 13N-ammonia PET, was observed to be 0.09 ml/g/min for short-term and 0.17 ml/g/min for long-term repeat measurements (Table 2). According to these values of SEE, changes in MBF to CPT in serial medical intervention and/or lifestyle modification studies are likely to exceed this range of SEE (97). Applying the mean difference and the corresponding standard deviation (SD) of repeat MBF assessment in Table 2, one can derive the sample size of a study population that would be needed to sufficiently power a serial MBF PET study. For example, using the longitudinal mean difference and the corresponding SD of the MBF to CPT of 0.08 ± 0.05 ml/g/min in the short-term and of 0.19 ± 0.10 ml/g/min in the long-term, at a 5% significance level with a power of 87%, a sample size of 14 and 22 individuals would be needed for serial 13N-ammonia PET flow studies in order to identify possible intervention-related, statistically significant alterations in MBF responses to CPT (97). Another useful statistical parameter commonly referred to in the interpretation of reproducibility data is the repeatability coefficient as suggested by Bland and Altman (107), which denotes the agreement between repeat measurements. Conversely, the repeatability coefficient can also be used as an index for direct comparison of the precision of MBF measurements between PET flow studies that have utilized different radiotracers (97). For example, the repeatability coefficient for short- and long-term reproducibility measurements of MBF to CPT with 13N-ammonia PET were lower than those for hyperemic MBF increases reported previously (99,104,108).
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Table 2 MBF and Hemodynamics at Measurements 1 (m = 1) and 2 (m = 2) on the Same Day and Measurement 3 (m = 3) After 2 Weeks for All Study Participants (N = 20)
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Monitoring Therapy
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According to the Framingham Heart Study (4), individuals with a high cardiovascular risk profile, such as type 2 diabetes mellitus or multiple coronary risk factors, are at risk for future cardiovascular events, and are commonly referred for primary and secondary medical prevention of CAD (5–7). Individuals with an intermediate cardiovascular risk, however, may not necessarily be considered for preventive medical interventions and/or life style modifications. In this regard, assessment of coronary vascular or circulatory function with PET may further risk stratify these individuals with an intermediate cardiovascular risk (8–10). Other possible surrogate markers for subclinical CAD include measurements in carotid intima-media thickness determined by vascular ultrasound (15), or coronary artery calcification and/or coronary morphology by multidetector CT (16,17). Assessment of functional abnormalities of the coronary vessels with PET may have an advantage over structural alterations of the arterial wall, as it may identify the earliest functional stage of the initiation and development of the coronary atherosclerotic process before structural alterations within the arterial wall may manifest (18). If CAD-related functional abnormalities of the coronary circulation precede morphologic changes of the vessels (8,9,19,20), then PET could emerge as a promising tool to better identify asymptomatic individuals with an intermediate or even low cardiovascular risk, who are likely to benefit from an early initiation or intensified medical preventive therapy (8,21). Further, given the pivotal role of functional abnormalities of the coronary circulation in the development and progression of atherosclerosis, an improvement or even restoration of PET-determined coronary circulatory dysfunction in response to various forms of vasomotor stress by a variety of preventive medical interventions, such as angiotensin-converting enzyme inhibitors (75), beta-hydroxymethylglutaryl coenzyme A reductase inhibitors (109), hormone replacement therapy in post-menopausal women (48,89), insulin-sensitizing thiazolodinedione in insulin-resistant individuals (88), euglycemic control in diabetes, and physical exercise (110,111), has become a primary therapeutic strategy for prevention of the atherosclerotic process. Notably, some preliminary observations in the assessment of vascular function of the peripheral circulation may strongly suggest that a normalization of endothelium-dependent vascular function by preventive medical intervention may indeed lead to an improved cardiovascular outcome (112,113). Among patients presenting with acute coronary syndrome and treated with standard medical therapy, the group that normalized their endothelial function (assessed at the forearm) was paralleled by an event-free survival, but not in those patients who did not normalize their endothelial function (112). In post-menopausal hypertensive women, an improvement in brachial artery flow-mediated (endothelium-dependent) vasodilation after installation of aggressive antihypertensive therapy resulted in an improved clinical outcome (113). In view of these preliminary findings, PET assessment of MBF responses to vasomotor stress may prove as an unique tool to noninvasively identify and characterize coronary circulatory dysfunction, as functional precursor of CAD, and to monitor the success of effects of pharmacologic interventions or lifestyle modification on the functioning of the coronary circulation in asymptomatic cardiovascular risk individuals or in patients with clinically manifest CAD (8,114). Using PET measurements of MBF in response to CPT to evaluate coronary endothelial function, a divergent response after medical control of blood pressures with the angiotensin II receptor blocker olmesartan and with the calcium antagonist amlodipine was observed (116). Whereas angiotensin II receptor blocker improved coronary endothelial function, no such beneficial effect was observed for the calcium antagonist amlodipine. Most likely, specific antioxidative effects of angiotensin II receptor blocker accounted for the improvement in coronary endothelial function and, thereby, mediated vascular resistance against the development of CAD in these hypertensive patients. PET flow studies also contributed to unmask beneficial effects of hormone replacement therapy with medically treated cardiovascular risk factors (48). As it was observed, hormone replacement therapy with estrogen alone or in concert with a progesterone in post-menopausal women, in addition to standard preventive medical intervention of traditional cardiovascular risk factors, contributed to preserve the functional integrity of the coronary endothelium (Fig. 11). Conceptually, a normal function of the coronary circulation in cardiovascular risk individuals in fact should exert numerous vasoprotective effects against the development of CAD-related structural disease, predominantly mediated through the release of atheroprotective and endothelium-derived nitric oxide (8). If this holds true, then a normalization of coronary circulatory function in cardiovascular risk individuals should prevent the manifestation and/or progression of a CAD process. Indeed, as recent investigations suggest (115), an improvement of endothelium-related MBF responses to CPT in type 2 diabetes mellitus after 1-year follow-up in response to glucose lowering treatment with metformin and/or glyburide may mediate direct preventive effects on the progression of epicardial structural disease. Although these preliminary observations of PET flow studies strongly support the evolving concept that improvement in coronary circulatory function in asymptomatic cardiovascular risk individuals or in patients with clinically manifest CAD may lead to an improved clinical outcome, it remains to be tested in further prospective, large-scale clinical trials.
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Conclusions
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Assessment of stress-induced myocardial perfusion defects have been firmly established as an important diagnostic and prognostic tool for the evaluation of patients with suspected CAD. Cardiac PET in conjunction with tracer-kinetic modeling for 13N-ammonia, 15O-water, or 82Rubidium affords the assessment of regional MBF of the left ventricle in absolute units in ml/g/min, which adds a new dimension to the noninvasive evaluation of the CAD process. By assessing MBFs and the MFR noninvasively, PET may identify early functional and/or structural abnormalities of the coronary artery circulation before its progression to symptomatic CAD ensues. In particular, the identification and characterization of the vasodilator capacity and endothelial reactivity of the coronary circulation may guide decisions for medical therapy as well as monitor the effects of pharmacologic interventions, risk factor modification, or lifestyle changes. The aim of image-guided and personalized preventive vascular medicine may soon be attainable with PET technology.
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Footnotes
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Dr. Schindler is supported by grants from the Swiss National Science Foundation (SNF grant: 3200B0-122237), and the Department of Internal Medicine of the University Hospitals of Geneva; Dr. Quercioli is supported by Fellowship grants from the Novartis Research Foundation; and Professor Schelbert is supported by Research Grant HL 33177, from the National Heart, Lung and Blood Institute.
* Reprint requests and correspondence: Dr. Thomas H. Schindler, Department of Internal Medicine, Cardiovascular Center, 6th Floor, Nuclear Cardiology, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4, CH-1211 Geneva, Switzerland (Email: thomas.schindler{at}hcuge.ch).
Manuscript received February 11, 2010;
revised manuscript received April 21, 2010,
accepted April 26, 2010.
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H. Gewirtz
Cardiac PET: A Versatile, Quantitative Measurement Tool for Heart Failure Management
J. Am. Coll. Cardiol. Img.,
March 1, 2011;
4(3):
292 - 302.
[Abstract]
[Full Text]
[PDF]
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Abstract
Methodological Considerations of...
0%). Reproduced with permission from Schindler et al. (