Quantitative Assessment of Myocardial Blood Flow—Clinical and Research Applications Thomas H. Schindler, MD,* Alessandra Quercioli, MD,† Ines Valenta, MD,* Giuseppe Ambrosio, MD,‡ Richard L. Wahl, MD,* and Vasken Dilsizian, MD§ Myocardial perfusion imaging with SPECT/CT or with PET/CT is a mainstay in clinical practice for the diagnostic assessment of downstream, flow-limiting effects of epicardial lesions during hyperemic flows and for risk stratification of patients with known or suspected coronary artery disease (CAD). In patients with multivessel CAD, the relative distribution of radiotracer uptake in the left ventricular myocardium during stress and rest accurately identifies flow-limiting epicardial lesions or the most advanced, so called culprit, lesion. Often, less severe obstructive CAD lesions may go undetected or underdiagnosed. The concurrent ability of PET/CT with radiotracer kinetic modeling to determine myocardial blood flow (MBF) in absolute terms (mL/ g/min) at rest and during vasomotor stress allows the computation of regional myocardial flow reserve (MFR) as an adjunct to the visual interpretation of myocardial perfusion studies. Adding the noninvasive evaluation and quantification of MBF and MFR by PET imaging to the visual analysis of myocardial perfusion may (1) identify subclinical CAD, (2) better characterize the extent and severity of CAD burden, and (3) assess “balanced” decreases of MBF in all 3 major coronary artery vascular territories. Recent investigations have demonstrated that PETdetermined reductions in hyperemic MBF or MFR in patients with subclinical or clinically manifest CAD are predictive of increased relative risk of future cardiovascular events and clinical outcome. Quantifying MFR with PET enables the identification and characterization of coronary vasodilator dysfunction as functional precursor of the CAD process, which offers the unique opportunity to monitor its response to lifestyle or risk factor modification by preventive medical care. Whether an improvement or even normalization of hyperemic MBF or the MFR in subclinical or in clinically manifest CAD confers an improved long-term cardiovascular outcome remains untested. Nonetheless, given the recent growth in the clinical utilization of myocardial perfusion PET, image-guided and personalized preventive care of vascular health may become a reality in the near future. Semin Nucl Med 44:274-293 C 2014 Elsevier Inc. All rights reserved.

Introduction

W

ith the advent of 64- and 128-slice CT or dual-source CT, contrast CT coronary angiography is increasingly

applied for the detection of epicardial coronary artery disease (CAD).1 Conversely, invasive coronary angiography still remains the “gold standard” for evaluation of the luminal diameter of the epicardial artery and, thus, the severity and

*Division of Nuclear Medicine, Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD. †Division of Cardiology, Department of Specialties in Medicine, University Hospitals of Geneva, Geneva, Switzerland. ‡Division of Cardiology, School of Medicine, University of Perugia, Perugia, Italy. §Department of Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD. Financial support: Departmental fund from Johns Hopkins University, Baltimore, Maryland, USA, and research Grant no. 3200B0-122237 from the Swiss National Science Foundation, Switzerland (SNF; Dr Schindler), with contributions of the Clinical Research Center, University Hospital, and Faculty of Medicine, Geneva, and the Louis-Jeantet Foundation; Swiss Heart Foundation; and Gustave and Simone Prévot fund (Dr Schindler). Address reprint requests to Thomas H. Schindler, MD, Division of Nuclear Medicine, Cardiovascular Nuclear Medicine, Department of Radiology and Radiological Science SOM, Johns Hopkins University, JHOC 3225, 601 N Caroline St, Baltimore, MD 21287. E-mail: [email protected]

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http://dx.doi.org/10.1053/j.semnuclmed.2014.04.002 0001-2998/& 2014 Elsevier Inc. All rights reserved.

Myocardial flow reserve and CAD

275

extent of obstructive CAD.2 Previous pioneer investigations by Gould et al3-5 have outlined that resting coronary flow virtually remains normal unless the epicardial luminal diameter is decreased by 90%. In fact, a compensatory vasodilation of the downstream coronary arteriolar vessel may account for this, striving to balance an increase in epicardial vascular resistance induced by an obstructive CAD lesion. As hyperemic blood flow increases during pharmacologic vasodilation, an inverse relationship may exist between increasing severity of epicardial coronary artery lesions with Z50% luminal obstruction and the reduction of stress-induced regional myocardial blood flow (MBF), myocardial flow reserve (MFR), and stress-induced regional myocardial perfusion defect.6-9 Conversely, an increase in epicardial vascular resistance during hyperemic flows due to an advanced, flow-limiting lesion can also be paralleled by collateral flow supply and a relatively preserved MFR, which may confound the reported inverse relationship between the severity of epicardial obstruction and corresponding MFR.10 In clinical routine, therefore, there is no simple relationship between the severity of CAD lesions and hyperemic flow increases,6-9,11-14 and a marked variability in the individual patient may exist.6,8,15 The clinical decision-making process regarding coronary interventional procedures to restore coronary flow is commonly based on the findings of stress-induced myocardial ischemia. The concurrent quantification of the regional MFR with PET and tracer kinetic modeling extends the scope of conventional myocardial perfusion imaging from detection of advanced, obstructive epicardial CAD to the characterization of CAD burden in multivessel disease and to early stages of atherosclerosis or microvascular dysfunction.10,16 This review aims to summarize the contributions of PET and hybrid PET/CT systems in the diagnosis of subclinical or clinically manifest CAD, its diagnostic and prognostic implications, its potential influence on clinical decision-making process, and for monitoring responses to preventative measures of risk factor and lifestyle modification as well as medical and interventional therapy.

Methodological Aspects of PET Flow Quantification PET assessment of regional MBF in mL/g/min is accomplished following 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 within the left ventricular (LV) myocardium (Table 1).10,17-19 Tracer kinetic models (1-3 compartments) and operational equations are then used to compensate 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),20 and spillover of radioactivity between the LV blood pool and myocardium21 to yield global and regional MBFs in mL/g/min at rest and during vasomotor stress and corresponding MFR as the ratio of hyperemic and rest MBF (Fig. 1).22,23 In addition, the relative distribution of the radiotracer in the myocardium at rest and during vasomotor stress is evaluated visually or semiquantitatively (as percentage uptake relative to a reference region) from the final static image of the myocardium, derived from the last (eg, 900 seconds) frame of the PET image series.10,24 The quantification of MBF has been validated for 13 N-ammonia and 15O-water against independent microsphere blood flow measurements in animals over a flow range of 0.5-5.0 mL/g/min.25-28 In addition, comparative evaluation of PET flow measurements with 13N-ammonia and 15O-water in humans provide comparable MBF values over a wide range of flows.29,30 15O-water images of the myocardium exhibit low count density, which is related to its short physical and biological half-life in the myocardium (Table 1). The latter prohibits the visual and semiquantitative evaluation of 15 O-water regional myocardial perfusion from the static images. Unlike the static 15O-water images, 13N-ammonia myocardial perfusion images yield high-contrast resolution.10,22 The combination of the high first-pass myocardial extraction fraction of 13N-ammonia (near 80%), trapping of 13 N-ammonia in the myocardial cells as 13N-glutamine (adenosine triphosphate–dependent process with long biological half-life),31,32 and the relatively long physical half-life (9.8 minutes) of the 13N radiotracer may account for the high contrast resolution. These properties of 13N-ammonia confer statistically high count images of the myocardium by PET, which permits visual and semiquantitative evaluation of myocardial perfusion abnormalities on stress and rest images. Adding the assessment of regional MBFs and MFR with 13Nammonia PET and tracer-kinetic models allows a comprehensive identification and assessment of subclinical and clinically manifest CAD.10,16,17 In clinical practice, 13N-ammonia and 82 rubidium are commonly used for PET myocardial perfusion imaging.33 Some of the advantages of 82rubidium over 13Nammonia include its ultrashort 75-second 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

Table 1 PET Tracers of Myocardial Blood Flow Tracer

Half-Life

Extraction-Fraction (%)*

Method

Mechanism

O-15-water N-13-ammonia

2.4 minutes 9.8 minutes

E95% E80%

Cyclotron Cyclotron

Rubidium-82

75 seconds

E60%

Generator

Freely diffusible and metabolically inert Soluble, microspherelike, and metabolically trapped Soluble, microspherelike

*Extraction fractions are listed for baseline MBF (E1 mL/g/min).

276

Figure 1 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/s) and in the myocardium (counts/pixel/s) 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 (mL/g/min). The blue line indicates the arterial radiotracer input function, and the red line the myocardial tissue response. (Adapted with permission from Schindler et al.10)

5-week shelf life.10,34-37 However, the relatively lower first-pass extraction of 82rubidium and the more prominent nonlinear myocardial uptake with increasing blood flow, termed “roll-off phenomenon,” result in a relatively lower myocardial contrast resolution PET images when compared with 13N-ammonia. In clinical practice, however, the diagnostic accuracy of 82rubidium for the detection of CAD has been shown to be similar to that of 13N-ammonia.10,38 In recent years, 2 F-18-labeled perfusion tracers—18Flabeled p-fluorobenzyl triphenyl phosphonium cation and 18 F-BMS-747158-02 (2-tert-butyl-4-chloro-5-[4-(2-(18F)fluoroethoxymethyl)-benzyloxy]-2H-pyridazin-3-one) (also known as flurpiridaz)—have been developed for clinical application.39,40 Flurpiridaz is an analogue of the insecticide pyridine, which binds to the mitochondrial complex I of the electron transport chain with a very high affinity.39 The tracer is effectively and rapidly taken up in cardiomyocytes followed by a very slow washout.41 The uptake ratios of the heart and lungs, liver, or blood appear to be more than 3 times higher than those of 13N-ammonia in a pig model.40 In addition, the radiotracer has a first-pass extraction fraction higher than 90%, which is maintained at very high flow rates.42 These favorable physical and physiological properties of flurpiridaz produce high–diagnostic quality PET myocardial perfusion images.43,44 Beyond visual interpretation of images, the feasibility of MBF quantification with flurpiridaz PET was recently validated using radioactive microspheres as a reference in a pig model.40 The quantitative assessment of MBF with flurpiridaz showed an excellent, linear correlation (r ¼ 0.88) and agreement (mean difference ¼ 0.10) with that measured using radioactive microspheres over a wide flow range (0.2-3 mL/min/g) under rest and adenosine stress.40 The relatively long half-life of 18F of E110 minutes in concert with good image quality, stable

T.H. Schindler et al. kinetics, and high extraction over wide flow range in experimental and human studies may propel the use of flurpiridaz in clinical practice.40,45,46 In particular, the 110-minute half-life of F-18 expands the application of the radiotracer to patients who are referred for treadmill exercise myocardial perfusion studies and affords its distribution as a single dose on a daily basis. Hence, flurpiridaz has the potential for more widespread clinical use in patients referred to either exercise or pharmacologic stress myocardial perfusion PET, and in centers with and without an onsite cyclotron. Owing to their shorter half-lives, 82 rubidium and 13N-ammonia PET myocardial perfusion studies are limited to patients undergoing pharmacologic stress studies. Given that flurpiridaz performs well in phases 2-3 clinical studies, it may lead to a widespread clinical use of the assessment of myocardial perfusion and flow quantification in the detection of subclinical and clinically manifest CAD.

Clinical Application of Myocardial Perfusion Imaging The conventional comparative evaluation of relative myocardial distribution of the radiotracer in the left ventricle during exercise or pharmacologic vasodilation and at rest enables the identification of stress-induced myocardial perfusion defects and, thus, the presence of advanced obstructive coronary lesions. Similar to SPECT,47,48 assessment of stress-induced scintigraphic myocardial perfusion defects by PET has been established as an important diagnostic and prognostic tool for the evaluation of patients with suspected or known CAD.49-51 However, in contrast to SPECT imaging, soft tissue attenuation correction with PET imaging is reliable and accurate. This accurate attenuation correction combined with the higher spatial resolution may explain a 10% higher diagnostic accuracy of PET when compared with that of conventional SPECT imaging for the identification of obstructive CAD.52-55 Further advantages of PET over SPECT imaging apply not only to the high spatial and depth-independent resolution but also to the ability to quantify the radiotracer uptake in the myocardial tissue and to determine rapid alterations of radiotracer activity concentrations in the arterial blood and myocardium owing to a high temporal resolution in seconds (Fig. 1). The latter advantages of PET imaging, in concert with tracer kinetic compartment models, afford the noninvasive assessment of MBF in absolute terms.10,17,34 In clinical routine, stress myocardial perfusion studies with SPECT or PET, are evaluated visually and in “relative” terms. In other words, myocardial regions with the highest myocardial radiotracer uptake are assumed to be supplied by normal or nonobstructive epicardial coronary arteries. Conversely, myocardial regions with decreased radiotracer uptake during stress are interpreted as being supplied by hemodynamically obstructive epicardial CAD lesions. A stress-induced regional myocardial perfusion defect on SPECT or PET images commonly identifies the most advanced or severe “culprit lesion” in multivessel CAD. However, flow-limiting effects of the remaining epicardial lesions with stenosis diameter more than or equal to 50%, may go undetected by visual or semiquantitative

Myocardial flow reserve and CAD evaluation. This limitation may also apply to balanced reductions in myocardial perfusion in all 3 major coronary territories with myocardial ischemia due to severe 3-vessel CAD or left main disease. In principle, these disadvantages with visual or semiquantitative evaluation of regional myocardial perfusion defects may be resolved by MBF quantification with PET.10,16,17,56 Using quantitative tracer kinetic modeling, PET allows the quantification of regional MBF in mL/g/min in the visually normal and abnormal regions. Measuring the MBF during vasomotor stress and at rest allows the calculation of the regional MFR, which extends the scope of conventional myocardial perfusion imaging from the identification of more advanced and obstructive CAD lesions to (1) subclinical CAD, (2) an improved characterization of the extent and severity of CAD burden in multivessel disease, and (3) the unraveling of “balanced” reduction in MBF owing to 3-vessel or main stem CAD (Table 2).10,16

Identification of Subclinical CAD

277 relative reduction of radiotracer uptake (perfusion defect) underlying an advanced focal CAD lesion. However, in patients with multivessel CAD, the assigned normal reference region on relative radiotracer uptake images may be in fact abnormal as well, but relative to the remaining vascular territories, it is the least hypoperfused myocardial region.15,61-63 Under such circumstances, the concurrent assessment of hyperemic MBF and MFR with PET may unmask not only the most advanced or “culprit” lesion but also the flow-limiting effects of remaining CAD lesions of less severity in normal reference regions on semiquantitative perfusion assessment (Fig. 2). Therefore, the combined assessment of “relative” myocardial perfusion and “absolute” MBF allows not only identification of “culprit” epicardial lesion but also the downstream or flow-limiting effects of morphologically intermediate or sequential CAD lesions or both in the remaining myocardial territories.10,16

Identification of “Balanced” Decreases of Hyperemic MBFs

Early stages of subclinical CAD or microvascular dysfunction or both cannot be identified with conventional myocardial perfusion SPECT.10 Individuals with subclinical stages of CAD may present either a mild heterogeneity in relative myocardial radiotracer uptake or homogeneously impaired hyperemic MBF during pharmacologically induced hyperemic flow increases.56-58 However, such early stages of CAD-related functional or structural alterations or both in the coronary arterial wall have been demonstrated to be at increased longterm risk for cardiovascular events.59,60 Therefore, assessing hyperemic MBFs or MFR with PET can signify early functional abnormalities of the coronary circulation, which have been widely recognized as a functional precursor of the CAD process, carrying important diagnostic and prognostic information.10,16,19,59

Balanced reductions in hyperemic MBF in all vascular territories due to severe 3-vessel CAD or left main disease cannot necessarily be identified by conventional myocardial perfusion imaging when the radiotracer uptake of the left ventricle is homogenously reduced. This means that, in the presence of balanced reductions in hyperemic flows in the LV myocardium, regional perfusion defect may go undetected. The assessment of hyperemic MBF and MFR with PET may unravel balanced reductions in hyperemic flows of the LV myocardium in all 3 major coronary artery territories.17,63 However, for the proof of diffuse myocardial ischemia, the latter should be confirmed by a peak stress transient cavity dilation of the left ventricle during maximal vasomotor stress on gated PET images.64

Improved Characterization of CAD Burden

Diagnostic Accuracy of PET for Identifying Obstructive CAD

As previously discussed, a reduction in regional radiotracer uptake on standard SPECT or PET myocardial perfusion imaging during pharmacologically induced hyperemic flows is related to flow-limiting effects of an advanced or severe focal CAD lesion. The visual and semiquantitative evaluation of regional radiotracer uptake is in “relative” terms. The myocardial region with the highest radiotracer uptake is considered as the “normal reference region” as compared with stress-induced Table 2 Clinical Use of PET-Determined MFR 1. Identification and characterization of subclinical CAD 2. Characterization of the extent and severity of CAD burden in multivessel disease 3. Unraveling of “balanced” reduction in myocardial blood flow owing to 3-vessel or main stem CAD* *Effects of diffuse myocardial ischemia may be confirmed by a peak stress transient cavity dilation of the left ventricle during maximal vasomotor stress on gated PET images.

The clinical utility of 13N-ammonia or 82rubidium PET for identifying obstructive CAD is well established (Table 3). Regional myocardial perfusion is usually assessed at rest and during pharmacologically induced hyperemic flow increases. The average sensitivity and specificity of myocardial perfusion PET for detecting more than 50% luminal narrowing on coronary angiography are reported to be 91% and 89%, respectively.65 The higher sensitivities and specificities achieved with PET when compared with SPECT myocardial perfusion imaging can be related to the high spatial and contrast resolution of photon attenuation–free PET images and with the superior properties of PET perfusion tracers.10,35,36 As PET perfusion images are free of photon attenuation–related artifacts, PET is specifically suited for the detection of CAD in women with breast attenuation artifact, men with diaphragmatic attenuation artifact, and subjects with large body habitus.38,66 The higher diagnostic accuracy of PET

T.H. Schindler et al.

278

Figure 2 13N-ammonia PET in the evaluation of multivessel CAD. (A) Myocardial perfusion study with 13N-ammonia PET/ CT 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) Regional myocardial blood flow quantification (MBF) and myocardial flow reserve (MFR) calculation with 13N-ammonia PET/CT and tracer kinetic modeling. The summarized quantitative data suggest a marked impairment of the MFR not only in the left anterior descending (LAD) territory but also in the right coronary artery (RCA) and left circumflex (LCX) vascular territories (regional MFR o2.0). (C) Invasive 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%-60% lesions in the RCA (right panel). Corresponding regional MFRs are indicated for each vascular territory. (Adapted with permission from Schindler et al.10) (Color version of figure is available online.)

for detecting flow-limiting coronary artery lesions was recently reproduced when CT attenuation, rather than conventional rotating rod sources of germanium-68 (Ge-68)/gallium-68 (Ga-68) or cesium-137 (Cs-137),

was applied to acquire a transmission scan for attenuation correction. In a special population study consisting of women and obese individuals, the average sensitivity and specificity of 82rubidium PET acquired with an integrated

Table 3 Detection of Flow Limiting Coronary Artery Lesions by PET Reference

Radiotracer

Prior MI (%)

Sensitivity (%)

Specificity (%)

Marwick et al (1992) Grover-McKay et al (1992) Stewart et al (1991) Go et al (1990) Demer et al (1989) Tamaki et al (1988) Gould et al (1986) Schelbert et al (1982)

82

49 13 42 47 34 75 Not reported 0

90 (63/70) 100 (16/16) 83 (50/60) 93 (142/152) 83 (126/152) 98 (47/48) 95 (21/22) 97 (31/32)

100 (4/4) 73 (11/15) 86 (18/21) 78 (39/50) 95 (39/41) 100 (3/3) 100 (9/9) 100 (11/11)

92

92

Total

Rubidium Rubidium 82 Rubidium 82 Rubidium 82 Rubidium, 13N-ammonia 13 N-ammonia 82 Rubidium, 13N-ammonia 13 N-ammonia 82

Myocardial flow reserve and CAD PET/CT system for detecting more than or equal to 70% luminal narrowing on coronary angiography were 93% and 83%, respectively, with a diagnostic accuracy of 87%.38 More recently, regadenoson, a selective adenosine A2A receptor agonist as vasodilator stress agent, was approved for SPECT myocardial perfusion imaging.67 The use of regadenoson to induce hyperemic flow increases proved to be noninferior to using adenosine for diagnosing stress-induced reversible perfusion defects in patients undergoing 99mTc and 201Tl SPECT.68-70 However, some of the advantages of regadenoson over adenosine and dipyridamole include its rapid onset of maximal hyperemia (o1 minute), short duration of action, and ease of use (fixed-dose bolus administration).71 In the clinical setting, these advantages of regadenoson translate to a shorter stress protocol and more rapid patient throughput, particularly when applied with short-acting radiotracers such as 82rubidium.36,49,72 In addition, regadenoson may be used safely in patients with asthma, chronic obstructive pulmonary disease, and end-stage kidney and liver disease.73 The diagnostic performance of regadenoson 82rubidium PET perfusion imaging to detect obstructive CAD was investigated more recently.72 In 134 patients without known CAD, regadenoson 82rubidium-PET had a high sensitivity of 92% in detecting obstructive CAD, with a normalcy rate of 97% and a specificity of 77%. Regadenoson in conjunction with 82rubidium-PET enables a rapid assessment of stress-rest myocardial perfusion imaging, while maintaining a high diagnostic accuracy for the detection of obstructive CAD.

Advantages of Quantitative Assessment of MBF and Flow Reserve The visual or semiquantitative assessment of stress-induced regional myocardial perfusion defects commonly signifies the “culprit lesion” in patients with multivessel CAD, whereas hemodynamically less significant epicardial lesions may go undetected.10,16 Such a drawback may be overcome by quantifying MBF at rest and during stress and the corresponding MFR with PET or PET/CT imaging. The ability of PET myocardial perfusion imaging to concurrently assess regional MBFs may allow the identification of all epicardial lesions in patients with multivessel CAD (Fig. 2).10,63,74,75 Several investigations76-79 have aimed to identify the optimal threshold values of hyperemic MBFs or MFR to identify epicardial lesions. However, defining such threshold values of hyperemic MBF or MFR depends on the PET methodology, radiotracer applied for the assessment of MBF, and the definition of morphologically significant epicardial lesions.10,16,74 For example, Hajjiri et al77 investigated the diagnostic performance of hyperemic MBF, MFR, and the relative radiotracer content (mCi/mL) for detecting coronary stenosis more than or equal to 70% among patients with suspected or known CAD with 13Nammonia PET. A cut-point analysis for sensitivity,

279 specificity, and accuracy demonstrated the optimal MBF criteria for CAD, when a hyperemic MBF threshold value of less than 1.85 mL/g/min and the best relative tracer content as low as 70% maximum was applied. In addition, an abnormal MFR was defined as less than 2.0. Applying these 13 N-ammonia PET perfusion and flow parameters, the receiver operating characteristic analysis in the evaluation of the diagnostic accuracy of CAD lesions 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. More recently, Fiechter et al76 applied a predefined MFR threshold of less than or equal to 2.0 for predicting CAD lesions with a luminal narrowing of equal to 50% or more. Employing this predefined threshold of MFR resulted in a sensitivity, specificity, and diagnostic accuracy of 96%, 80%, and 92% for detecting epicardial lesions. When applying another radiotracer, such as 15Owater, a threshold of pharmacologically induced hyperemic MBFs of less than 2.5 mL/g/min was demonstrated to be most accurate in the identification of epicardial lesions of stenosis with more than 50% diameter.78 In a more extended investigation conducted by Kajander et al,79 104 patients with moderate (30%-70%) pretest likelihood of CAD underwent 15O-water PET perfusion imaging. The use of a hyperemic MBF threshold less than 2.5 mL/g/min for the detection of CAD, resulted in a sensitivity, specificity, and diagnostic accuracy of 95%, 91%, and 92%, respectively, which are comparable to those values as determined with 13N-ammonia PET using a MFR threshold of less than 2.0 for CAD identification.76 However, it is important to keep in mind that hyperemic MBFs during pharmacologic vasodilation also reflect coronary microvascular dysfunction in patients with or without focal CAD lesions on coronary angiography. The latter becomes particularly relevant in patients with multiple cardiovascular risk factors.10,16,74,75,80,81 Overall, the concurrent assessment of PET-determined regional hyperemic MBFs and MFR with conventional myocardial perfusion imaging may certainly increase the sensitivity in the identification of each flow-limiting epicardial lesion in multivessel CAD, while a lower specificity due to microvascular dysfunction must be taken into account.82,83 The relatively low specificity of an abnormal finding on MFR6,8,75,84 was recently confirmed in patients with high-risk CAD on angiography but with normal or small to medium stress-induced myocardial perfusion defects.15 In such patients, the sensitivity, specificity, positive predictive value, and negative predictive value of abnormal MFR (r1.93) for CAD detection were 86%, 46%, 15%, and 97%, respectively. Although the very high negative predictive value is helpful for excluding the presence of high-risk CAD on angiography, an abnormal MFR cannot reliably distinguish obstructive epicardial lesion from nonobstructive, diffuse atherosclerosis or microvascular dysfunction.15 Therefore, current use and interpretation of hyperemic MBFs and MFR with PET need to be placed in the proper clinical context with underlying coronary anatomy and cardiovascular risk factors (Fig. 3).10,16

280

Flow Parameters for Characterizing Coronary Circulatory Function Measurements of MBF with PET at rest and its responses to different forms of vasomotor stress afford the noninvasive identification and characterization of coronary circulatory function in the normal and diseased vascular states.19,53,80 The most commonly applied approach for the evaluation of coronary circulatory function is the pharmacologically induced hyperemic MBF increase.19,24,85 Vascular smooth muscle–relaxing substances, such as dipyridamole and adenosine, adenosine triphosphate, or adenosine receptor agonists, lower the resistance to flow at the site of the coronary arteriolar resistance vessels and thereby cause maximal or submaximal hyperemic increases in MBF. The hyperemic flow is deemed to be an indicator of a predominantly endothelium-independent flow response owing to the relaxation of the vascular smooth muscle cells of the arteriolar vessels during pharmacologic vasodilation. However, shear sensitive components of the coronary endothelium contribute through flow-mediated coronary vasodilation to the overall hyperemic flow increase during pharmacologic vasodilation. This has been evidenced by the inhibitory effect of intravenous infusion of NG-nitro-Larginine methyl ester on the endothelial nitric oxide (NO) synthase, which resulted in a decrease in adenosineinduced MBF by 21%-25% as measured with PET.86,87 As pharmacologically induced hyperemic MBF increases reflect smooth muscle cell function of the coronary arteriolar vessels and up to 21%-25% flow-mediated and thus endothelium-related vasodilatory effects, it is also frequently reported as the “total integrated coronary circulatory function.”19,85 Another possibility to assess coronary circulatory function is a sympathetic stimulation with so-called cold pressor testing (CPT), which provides more specific information on coronary

Figure 3 Integration of PET perfusion images and MFR. 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 toward revascularization or preventive medical therapy is shown. (Adapted with permission from Schindler et al.10)

T.H. Schindler et al. endothelial function.80,88 CPT with immersion of a hand into ice water causes a sympathetically mediated increase in heart rate and blood pressure and thus an increase in myocardial workload. Increases in myocardial workload and myocardial oxygen demand during CPT induce a vasodilation of the coronary arteriolar resistance vessels through the presumed release of endogenous adenosine as the metabolic vasodilator. This decrease in coronary vascular resistance then leads to an increase in coronary inflow, which in turn leads to a flowmediated and endothelium-dependent dilation of the upstream coronary artery segments (Fig. 4). Consequently, an increase in myocardial workload is normally accompanied by commensurate flow-mediated coronary vasodilation and an increase in MBF, as determined by PET. On the contrary, the CPT-induced increase in coronary inflow may not confer a flow-mediated vasodilation of the upstream vessel segments in the presence of an abnormal functioning of the coronary endothelium. At the same time, the sympathetically mediated vasoconstrictor effects of the vascular smooth muscle cells prevail, and cannot be offset by normal flow-related and endothelium-dependent coronary vasodilation. The CPTrelated MBFs are then attenuated, absent, or even paradoxically decreased, which signifies coronary endothelial dysfunction (Fig. 5). More recently, a decrease in longitudinal myocardial perfusion or MBFs during pharmacologically stimulated hyperemic flows has been described first in patients with diffuse CAD57 and, following also with quantitative MBF measurements in individuals with coronary risk factors.56,89,90 This longitudinal decrease in hyperemic flows from the base to the apex of the heart has been related to CAD vessel stiffness or functional abnormalities of the epicardial conduit vessel or both. Based on the HagenPoiseuille equation,91-93 intracoronary resistance relates to the velocity of the blood flow and inversely to the fourth power of the vessel diameter.91 A normal function of the coronary vascular endothelium ascertains that increases in flow velocity during exercise or pharmacologic vasodilation are associated with a flow-mediated dilation of the coronary circulation that compensates the velocityinduced increase in coronary resistance, so that the resistance is maintained low.94,95 However, structural or functional abnormalities or both of the vascular state during the early development of CAD are commonly paralleled by an impairment of flow-mediated epicardial vasodilation. This results in a paradoxical increase in coronary resistance during hyperemic flow increases with a proximal-to-distal decline in intracoronary pressure along the epicardial artery,91 which most likely accounts for a longitudinal base-to-apex relative decline in myocardial flow as several recent clinical investigations with PET suggest.56,57,89,90,96 The assessment of a longitudinal decrease in hyperemic MBF with PET could provide insights into functional or structural abnormalities, or both, of CAD in its early and clinically manifest stages.56-58,89,90 Although this concept may be intuitively correct, it awaits further validation through comparative studies between PET measurements of regional MBF and

Myocardial flow reserve and CAD

281

Figure 4 Angiographic visualization of a normal flow-mediated and thus endothelium-dependent vasodilation of the epicardial artery during sympathetic stimulation with cold pressor testing (CPT). (A) Normal coronary angiogram of the left coronary tree in the right-anterior-oblique view of a healthy individual without coronary risk factors (left panel). Corresponding angiogram during sympathetic stimulation with CPT (right panel). (B) Quantitative angiographic assessment of the proximal-middle LAD segment at rest (mean diameter ¼ 2.0 mm) (left panel) and during CPT (mean diameter ¼ 2.5 mm) (right panel). (Adapted with permission from Schindler et al.88)

invasive angiographic investigations of coronary blood flow and intracoronary pressure gradients.

PET Assessment of Coronary Circulatory Function and Clinical Implications The noninvasive assessment of coronary circulatory function with PET measurements of MBF at rest and its responses to different forms of vasomotor stress has added to our understanding of CAD pathophysiology, both in the development and progression of CAD.19,80,85 A normal function of the vascular endothelium plays a central and integrative role in the regulation and modulation of the vasomotor reactivity, metabolism of the vascular wall, and hemostasis. Thus, it confers numerous antiatherosclerotic and antithrombotic effects, predominantly mediated by a coronary flowstimulated production and release of NO. Although endothelial-derived NO is the predominant vasoactive mediator, inducing a NO-mediated relaxation of the vascular

smooth muscle cells with subsequent vasodilation, others such as prostacyclin and endothelium-derived hyperpolarizing factor contribute to it and may play a pivotal role in the coronary microcirculation.10,80 Risk factors for CAD, such as smoking, hypercholesterolemia, hypertension, hyperglycemia, insulin resistance, obesity, menopausal state, or a family history of premature atherosclerotic disease have been associated with an attenuation or loss of endothelium-dependent vasodilation.10,16,56,80,81 While the mechanisms underlying endothelium-dependent vasomotor dysfunction in individuals with risk factors are likely to be multifactorial, increases in vascular production of reactive oxygen species (ROS) derived from the superoxide producing endothelial enzymes, such as NAD(P)H oxidase, xanthine oxidase, and uncoupled NO synthase, have been put forth as the main cause for reductions in the bioavailability of endothelium-derived NO.97-99 Apart from this, increased amounts of ROS in the vascular endothelium and subintimal space not only diminish the bioavailability of endothelial-derived NO associated with impaired endothelium-mediated vasodilator function, but they may also induce the activation of a whole array of inflammatory genes such as nuclear factor-κB, activator protein-1, or the

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Figure 5 Angiographic visualization of an abnormal vasoconstrictor response of the epicardial artery during CPT, indicative of coronary endothelial dysfunction. (A) Normal coronary angiogram of the left coronary artery tree in the left-anterioroblique view in a chronic smoker at rest (left panel). Corresponding coronary angiogram during CPT (right panel). (B) Quantitative angiographic assessment of the proximal-mid LAD segment at rest (mean diameter ¼ 1.89 mm) (left panel) and during CPT (mean diameter ¼ 1.57 mm) (right panel). (Adapted with permission from Schindler et al.88)

peroxisome proliferator-activated receptors to further contribute to impaired coronary circulatory function in more advanced stages of CAD.97,100 In particular, abnormalities in vascular endothelial function are also associated with the loss of a potent antithrombotic endothelial surface.101 This increase in thrombogenicity is likely to mediate an increased risk for atherothrombotic events and its sequelae.102 Abnormalities in vascular endothelial function or commonly socalled endothelial activation, reflecting an initial injury of the vascular wall associated with inflammation, proliferation, or apoptosis, and the expression of vascular cellular adhesion molecules may initiate and accelerate the CAD process. Further, this “endothelial activation” is considered to play a pivotal role in the manifestation of acute coronary syndromes, characterized by coronary plaque vulnerability and paradoxical vasoconstriction paralleled by endothelial dysfunction, which is likely to contribute to plaque rupture and increased thrombogenicity due to loss of a potent antithrombotic endothelial surface.101,103 Abnormalities in coronary circulatory function may, at least in part, represent the vulnerability of plaques, which may explain the independent

predictive value of an impairment of coronary circulatory function for future cardiovascular events.59,102,104 Emerging data suggest incremental prognostic value of hyperemic MBF and MFR in patients with suspected or known CAD relative to myocardial perfusion assessment with PET.49,58,105 In fact, there may be a substantial number of patients with subclinical CAD and normal myocardial perfusion SPECT or PET studies. In these patients, the concurrent assessment of impaired hyperemic MBF increases and MFR with PET, indicative for early functional stages of developing CAD, could emerge as an important tool to identify those at an increased risk for cardiovascular events. For example, in 120 patients with normal or mildly diseased epicardial coronary arteries, invasive angiographic investigations have demonstrated an inverse relationship between reductions in hyperemic coronary flow increases (owing to intracoronary papaverine stimulation), and MFR was associated with an increase risk of future cardiovascular events.104 Similarly, an impairment of PET-measured endothelium-related MBF responses to sympathetic stimulation with CPT and its MFR were associated with a higher risk for

Myocardial flow reserve and CAD

Figure 6 PET-determined coronary endothelial vasoreactivity and prognosis. Kaplan-Meier analyses in patients with cardiovascular risk factors and normal coronary angiograms undergoing assessment of myocardial blood flow (MBF) response to cold pressor test (CPT) with positron emission tomography (PET). Attenuation of PET-measured and endothelium-related MBF responses to sympathetic stimulation with cold pressor testing are associated with a higher risk for cardiac events (during long-term follow-up) as compared with those with normal flow increases: normal (%ΔMBF Z40%), impaired (%ΔMBF 40% and o40%), and decreased (%ΔMBF r0%). (Adapted with permission from Schindler et al.10) (Color version of figure is available online.)

cardiac events as compared with those with normal flow stimulation.59 It is noteworthy that the incidence of cardiovascular events increased with the extent of abnormal flow response to CPT (Fig. 6). Such observations may suggest coronary endothelial dysfunction as an integrating index of the overall stress burden imposed by various coronary risk factors on the arterial wall, which favors the initiation and progression of CAD and its cardiovascular outcome.10,80,88,106 The following PET flow studies investigated the prognostic value of impaired hyperemic MBFs in patients

283 without and with obstructive CAD. Herzog et al60 demonstrated that when the findings of stress 13N-ammonia perfusion PET and MFR studies were normal, it signified a “warranty” period of event-free survival of approximately 3 years as compared with those with an abnormally reduced MFR. It is of further interest to note that even when PET flow studies identified a stress-induced regional myocardial perfusion defect as indicative of an obstructive CAD lesion, an abnormally reduced MFR provided incremental information to the conventional stress 13N-ammonia perfusion PET study for predicting adverse outcome. In a more extended clinical investigation, Ziadi et al107 evaluated the prognostic value of MFR using 82rubidium-PET in patients assessed for ischemia (Fig. 7). In this study, 704 consecutive patients were prospectively enrolled, whereas 677 (96%) completed follow-up of median of 387 days. Patients were divided into 4 groups: group 1, normal results on summed stress score (SSS) (o4) and normal results on MFR studies (Z2); group 2, normal results on SSS and MFR o2; group 3, SSS Z4 and MFR Z2; group 4, SSS Z4 and MFR o2. For prognostic evaluation, the primary outcome was defined as the prevalence of hard cardiac events: myocardial infarction and cardiac death, whereas for the secondary outcome the prevalence of major adverse cardiac events (MACE) such as cardiac death, myocardial infarction, late revascularization (percutaneous coronary intervention or coronary artery bypass graft) and cardiac hospitalization (eg, acute coronary syndrome and heart failure) were noted. For those with a normal results on SSS and impaired MFR compared with those with a preserved MFR, there was higher incidence of hard events (2% vs 1.3%, P ¼ 0.029) and a higher incidence of MACE (9% vs 3.8%, P ¼ 0.003) (Fig. 7). Among patients with an abnormal SSS, those with MFR o2 compared with those with a preserved MFR had a higher incidence of hard events (11.4% vs 1.1%, P ¼ 0.05) and a higher incidence of MACE (24% vs 9%,

Figure 7 Prognostic value of PET-determined myocardial flow reserve (MFR). Within subgroups of summed stress score (SSS) for different levels of MFR, at any level of SSS, the prevalence of major cardiac events (MACE) is higher in patients with the lowest MFR (o1.5) and statistically significant different compared with MFR Z2 among patients with ischemia. * P ¼ 0.028 for SSS Z4-7 and MFR o1.5 vs MFR Z2. **P ¼ 0.002 for SSS Z8 and MFR o1.5 vs MFR Z2. (Adapted with permission from Ziadi et al.107) (Color version of figure is available online.)

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284 P o 0.001). All cardiac deaths occurred in patients with an abnormal MFR (1 [1%] in group II; 11 [6.5%] in group IV). All patients who experienced cardiac death had a severely impaired MFR (MFR o1.5). Patients with impaired 82rubidium-PET–determined MFR had a higher incidence of hard cardiac events and MACE at approximately 1-year followup. In particular, in the multivariable model analysis, the MFR was an independent predictor of hard events and MACE over the SSS. Overall, the study demonstrated the added and independent prognostic value of MFR using 82 rubidium-PET beyond the relative myocardial perfusion imaging in a large cohort of patients referred for assessment of ischemia. Murthy et al108 reported similar observations. A total of 2783 consecutive patients with known or suspected CAD referred for rest or stress 82rubidium-PET myocardial perfusion imaging and assessment of MFR were followed up over a median of 1.4 years to evaluate the risk of cardiac death. Overall, 3-year cardiac mortality was 8.0%. Compared with the highest tertile of MFR (values 42), the lowest tertile (values o1.5) was associated with a 16-fold increased risk, whereas the intermediate tertile was associated with a 5.7-fold increased risk for cardiac death. Among patients whose clinical risk factors, LV ejection fraction, and stress imaging findings placed them at intermediate risk of cardiac death (1%-3% per year), 35% were reclassified as having either high risk (43% cardiac mortality per year) or low risk (o1% cardiac mortality per year). These findings may stress that incorporation of coronary vasodilator function assessment into stress testing by quantification of MFR may improve risk stratification not only in the long term but also in the short term in patients with known or suspected CAD.107,109 Similar observations of an incremental predictive value of MFR for cardiac death were also reported for specific risk populations such as patients with diabetes mellitus,110 chronic kidney disease,111 ischemic or idiopathic cardiomyopathy.112,113

Mechanistic Insight of Coronary Circulatory Function in Obesity In the last decade, the noninvasive assessment of coronary circulatory function with PET has provided important mechanistic insight underlying the development and progression of the CAD process. For example, the assessment of coronary circulatory function with PET demonstrated that increased body weight, paralleled by an increase in plasma markers of the insulin-resistance syndrome and chronic inflammation, is independently associated with abnormal coronary circulatory function.105 This functional abnormality of the coronary circulation in individuals with increasing body weight advanced from a dysfunctional coronary endothelium in overweight patients (body mass index [BMI]: 25-29.9 kg/ m2), as determined by the MBF response to CPT, to an impairment of the vascular smooth muscle cell relaxation of the coronary arteriolar vessels in obese patients (BMI Z 30 kg/ m2), as measured by a hyperemic flow response to dipyridamole stimulation (Fig. 8). Similar observations were reported in individuals with increasing severity of insulin resistance and clinically manifest type 2 diabetes mellitus.114 These observations support the consideration that initial stages of the vascular injury may involve only the endothelium,99,105,106,115-117 whereas more advanced and severe stages of cardiovascular risk factors, conferring increases in oxidative stress burden, may also lead to an impairment in smooth muscle cell vasodilator function.105,118 Notably, the previously observed independent predictive value of obesity for an abnormal functioning of the coronary circulation105,119 suggests that direct mediators released from the adipose tissue, so called adipocytokines such as leptin, adiponectin, and local mediators such as the endocannabinoids (ECs), may be involved in the regulation of coronary vasomotor function and thus in the initiation and development of CAD.105,120-122 ECs such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are

Figure 8 Relationship between increasing body weight and coronary circulatory (dys)function. (A) The dipyridamolestimulated MBF tended to be lower in overweight individuals than in controls, while it was lowest in obesity. (B) Change of endothelium-related MBF during CPT (ΔMBF) for the 3 study groups. As it can be observed, there is a progressive decrease of the endothelium-related MBF response to CPT from controls to overweight and obese individuals. (Adapted with permission from Schindler et al.105) (Color version of figure is available online.)

Myocardial flow reserve and CAD endogenous bioactive lipid mediators derived from arachidonic acid, which are physiologically synthesized and released on demand from the brain, peripheral organs, and adipose tissue and exert their biological effects via interaction with specific G protein–coupled cannabinoid receptors type 1 (CB1) and type 2 (CB2).120 Experimental evidence outlines that increases in adipose-derived ECs exert proatherosclerotic effects by signaling via CB1 or non-CB receptors or both in the arterial wall. Such an activation of CB1 or non-CB receptors or both appears to result in increases in oxidative stress, vascular smooth muscle cell proliferation, and recruitment of monocytes and neutrophils into the vascular wall.120,123 It is interesting to note that increases in EC 2-AG, but not in AEA, were found to be associated with atherosclerotic disease in hypercholesterolemic mice.123 On the contrary, it appears that stimulation of CB2 receptors may mediate antiinflammatory and antiatherosclerotic effects.120,124 In light of this controversy, PET flow assessment in concert with

285 measurements of plasma ECs contributed unmasks deleterious effects of elevated ECs concentrations on the function of the coronary circulation in obese but otherwise healthy individuals. As it was observed, increases in AEA and 2-AG plasma levels were inversely correlated with impaired endotheliumrelated MBF responses to CPT and hyperemic MBFs in obesity, respectively (Fig. 9). As an impairment of coronary circulatory function has been widely realized as the functional precursor of the CAD process and future cardiovascular events,10,59,60,107 the observed associations between increases in EC plasma levels and coronary circulatory dysfunction may suggest increases in AEA and 2-AG plasma levels as a potential novel and endogenous risk factor in the initiation and development of CAD in obesity. Other adipocytokines such as adiponectin and leptin, as well as metabolically triggered systemic inflammation, may also alter coronary circulatory function.125-127 Although adiponectin has been widely recognized to beneficially influence NO-mediated, endothelium-dependent

Figure 9 Inverse association between increases in endocannabinoid plasma levels and coronary circulatory function. Inverse association between change of endothelium-related myocardial blood flow (MBF) during cold pressor testing (CPT) in obesity and (A) anandamide (AEA) levels and (B) 2-arachidonoylglycerol (2-AG) plasma levels, respectively. Corresponding association between hyperemic MBFs and (C) AEA and (D) 2-AG. (Adapted with permission from Quercioli et al.122) (Color version of figure is available online.)

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286 vasomotor function,125 the role of leptin in the modulation of coronary circulatory function in obesity is controversial and continues to be debated.105,121 Notably, obesity and morbid obesity have been put forth to reflect 2 different disease entities with differences in adipocytokine profile, lipid and glucose metabolism, and systemic inflammation rather than a disease continuum.126,128 In view of this, PET flow studies examined the presence of coronary circulatory dysfunction in these 2 different disease entities of obese and morbidly obese individuals and evaluated whether these would differ in severity with different profiles of ECs, leptin, and high-sensitivity C-reactive protein (hsCRP) plasma levels.121 As expected, coronary circulatory function progressively declined from that in normal weight controls to that in overweight and obese individuals, whereas it did not differ significantly between those who were obese and morbidly obese.121 Thus, despite a marked increase in body weight from obesity to morbid obesity, somehow surprisingly, there was no further progressive worsening of coronary circulatory function. It is noteworthy that increases in EC plasma levels of AEA and 2-AG were inversely associated with an impairment of endothelium-related MBF responses to

CPT in obesity, whereas this association was not observed anymore in morbidly obese individuals (Fig. 10). This contrasts with the elevations in leptin and hsCRP plasma levels, which were positively correlated with endotheliumrelated MBF responses in morbidly obese individuals, whereas there was no such association in the obesity group (Fig. 10). The latter positive associations between increases in leptin and hsCRP plasma levels and coronary endothelial function may suggest some beneficial effects on the function of the coronary endothelium against adverse effects of body weight in morbid obesity. Visceral adipose tissue is characterized by an infiltration of macrophages, which have been demonstrated as a major source of inflammatory cytokines such as tumor necrosis factor-alpha, interleukin-6, and interleukin-10 in obesity.128 Increase in interleukin-10 has been reported to confer a protection to endothelium-dependent vasomotion by reducing oxidative stress burden within the arterial wall in an experimental model.129 Furthermore, some clinical evidence suggests a potential vascular protective role of interleukin-10.130,131 For example, if interleukin-10 plasma

Figure 10 Relationships among AEA, leptin, inflammation, and coronary endothelial function. Associations among (A) anandamide (AEA), leptin, and high-sensitivity C-reactive protein (CRP) plasma levels and change of endotheliumrelated myocardial blood flow (ΔMBF) during cold pressor testing (CPT) in the obese group and (B) correspondingly in the morbid obesity group. SEE ¼ standard error of the estimate. (Adapted with permission from Quercioli et al.121) (Color version of figure is available online.)

Myocardial flow reserve and CAD levels were increased in patients with CAD who had elevated hsCRP concentrations, there was impairment of acetylcholinestimulated forearm blood flow response.130 This observation of a preserved endothelium-dependent vasomotor function of the peripheral circulation in the presence of inflammatorytriggered increases in interleukin-10 plasma levels in patients with CAD130 might provide a mechanistic link between a better clinical outcome after acute coronary syndromes and reduced risk increased risk associated with elevated hsCRP plasma levels.131 Regarding the adipocytokine leptin, it has been implicated to directly alter coronary vasomotor function in obesity.132 For example, the administration of leptin may stimulate increases in oxidative stress in in vitro–cultured human endothelial cells.133 These increases in oxidative stress in the vascular endothelium may interact with NO to form peroxynitrite and thereby decrease the bioavailability of NO, which again is associated with an impairment of endothelium-dependent vasodilation.132 This contrasts with the findings in leptin-deficient mice, in which the administration of leptin normalized endotheliumdependent vasodilation by receptor-mediated endothelial release of NO.134 PET flow investigations provided unique in vivo insights to the effects of increased leptin plasma levels in obese and morbidly obese individuals.,105,121,122 As it was observed, in the obese individuals, increased leptin plasma levels were significantly associated with relatively higher endothelium-mediated MBF increases to CPT, which might reflect a beneficial effect of leptin or leptin-related but still undetermined factors or both on the coronary vascular endothelium to counterbalance the adverse effects of increases in body weight on coronary vasomotor function. In support of these observations, leptin has been demonstrated to stimulate both endothelium-dependent and endothelium-independent

287 vasorelaxation.135,136 In addition, intracoronary infusion of leptin in humans with angiographically normal coronary arteries may also directly lead to a coronary vasodilation of the conduit and arteriolar vessels.137 It is equally possible that the beneficial effects of leptin plasma levels may operate preferentially in morbidly obese individuals with a 7-fold increase of its concentration to counteract the adverse effects of obesity on coronary circulatory dysfunction (Fig. 10).121 However, contrasting associations of altered coronary endothelial function with increases in AEA, leptin, and hsCRP levels identify and characterize obesity and morbid obesity as different disease entities, rather than a simple continuation of increases in body weight, affecting coronary circulatory function.121,138 More recently, the effects of surgical bypass-induced weight loss in morbidly obese individuals (BMI Z 40 kg/m2) without other traditional cardiovascular risk factors on coronary circulatory dysfunction were also studied.139 In addition, it was assessed how a weight loss–related improvement in coronary circulatory dysfunction was related to alterations in body weight, EC, and adiponectin, and leptin plasma levels in initially morbidly obese individuals. After a median follow-up period of 22 months, gastric bypass intervention had decreased BMI from a median of 44.8 to 30.8 kg/m2. Gastric bypass– induced weight loss in morbidly obese individuals, paralleled by changes in lipid profile, a decrease in plasma markers of the insulin resistance syndrome, and chronic inflammation, widely restored not only endothelium-related MBF responses to CPT but also hyperemic flow reserve (Fig. 11). It is of particular interest that a decrease in EC plasma levels of AEA, induced by the weight loss, was associated with a normalization of coronary endothelial function. The described association between the decline in EC plasma levels and improvement in endothelium-related MBF responses to CPT (Fig. 12) provides further evidence of adverse effects of elevated EC

Figure 11 Effects of gastric bypass–induced weight loss on coronary circulatory function. Myocardial blood flows (MBF) during vasomotor stress in controls (CON) and morbidly obese (MOB) individuals. (A) Change in MBF to cold pressor testing from rest and (B) in hyperemic MBF in CON and in MOB individuals at baseline and at the follow-up. (Adapted with permission from Quercioli et al.139)

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Figure 12 Relationship between the decrease in AEA plasma levels and coronary circulatory function after gastric bypass–induced weight loss. Association of the differences in Δlog AEA and endotheliumrelated ΔMBF with CPT between baseline and follow-up. (Adapted with permission from Quercioli et al.139)

plasma levels on obesity-related coronary vasculopathy.121,122 Gastric bypass–induced weight loss in morbidly obese individuals did also lead to a marked increase in adiponectin plasma levels, which correlated significantly with the normalization in hyperemic flow increases (Fig. 13). Thus, weight loss-induced increases in adiponectin plasma levels were associated with relatively higher increases in hyperemic flows. This association strongly puts forth a beneficial effect of adiponectin in concert with weight loss–related decrease in insulin resistance and inflammation, and increases in HDL plasma levels or adiponectin or both but still undetermined factors on the vasodilator capacity of the coronary circulation.125

Figure 13 Relationship between the increase in adiponectin plasma levels and coronary circulatory function after gastric bypass–induced weight loss. Association between the differences in Δlog adiponectin and in hyperemic MBF between baseline and follow-up. (Adapted with permission from Quercioli et al.139)

T.H. Schindler et al. Somehow surprisingly, the weight loss-induced decline in leptin plasma levels was not correlated with the observed improvement in coronary circulatory function at follow-up. Such observation may suggest that a beneficial effect of leptin plasma levels on endothelium-related MBF responses to CPT may act predominantly in obese or in morbidly obese individuals with a 7-fold increase of its concentration to counterbalance the adverse effects of obesity on coronary circulatory dysfunction as described previously.121 Taken together, these in vivo investigations with PET flow measurements signify that, apart from the insulin-resistance syndrome and chronic inflammation, an endogenous (dys)balance between ECs, adiponectin, and leptin may represent an important determinant of coronary circulatory dysfunction in obesity.81 This again may underline an evolving concept that medical therapy strategies aiming to decrease EC plasma concentrations in obese individuals, perhaps using newgeneration CB1 antagonists with lesser central side effects, or to increase adiponectin or leptin or both may reverse or even normalize coronary endothelial dysfunction, leading to an improved cardiovascular outcome, which, however, awaits clinical confirmation.

Monitoring Therapy With PET PET measurements of MBF may be used to monitor the effects of pharmacologic interventions or lifestyle modification on coronary circulatory function in patients with and without manifest CAD.10,81 For example, PET flow studies have been used to denote an improvement in endothelial dysfunction in patients with cardiovascular risk with a regular exercise program, preventive medical care, antioxidant supplementation with vitamin C, and euglycemic control with antidiabetic medication.140-144 In patients with untreated essential hypertension, angiotensin II receptor blocker (ARB) improved endothelium-related MBF increases to sympathetic stimulation with CPT.145 Such improvement in coronary endothelial function was related to ARB-induced elevation of superoxide dismutase. These observations denote specific antioxidative effects of ARB inhibition, possibly mediated by inhibition of the endothelial NADPH oxidase activation associated with a decrease in ROS or increases in antioxidative superoxide dismutase concentrations, underlying the beneficial effect on coronary endothelial function in these hypertensive patients. More recently, the effects of glucose-lowering treatment with glyburide or metformin or both on coronary artery calcification (CAC), increased carotid intima-media thickness (IMT), and coronary circulatory function over a mean follow-up period of 14 months in 22 patients with type 2 diabetes were also investigated.146 In addition, possible associations between improvement in coronary circulatory function and the rate of progression of structural alterations of the arterial wall were analyzed. At follow-up, plasma glucose concentrations had significantly decreased to 160 ⫾ 44 mg/dL from initial 205 ⫾ 72 mg/dL after glucose-lowering treatment. The glucoselowering effect in type 2 diabetes mellitus beneficially affected structural alterations of the vascular arterial wall and coronary

Myocardial flow reserve and CAD circulatory function. The observed decrease in plasma glucose levels after a 1-year follow-up correlated with a lower progression of CAC and carotid IMT (r ¼ 0.48, P r 0.036 and r ¼ 0.46, P r 0.055, respectively) and with an improvement in endothelium-related MBF responses to CPT and to adenosine (r ¼ 0.46, P r 0.038 and r ¼ 0.36, P r 0.056, respectively).146 Thus, the more plasma glucose levels decreased the slower was the progression of CAC and carotid IMT, whereas flow response to CPT increased. These findings suggest direct adverse effect of elevated plasma glucose levels on diabetes-related structural alterations of the vascular wall and, as also observed previously,144 on coronary endothelial function, all of which can be beneficially affected by glucoselowering treatment with glyburide or metformin or both. Notably, the extent in improvement in coronary endothelial function and slowed progression in CAC correlated significantly (Fig. 14). Even after adjusting for metabolic parameters by multivariate analysis, the increases in flow responses to CPT after glucose-lowering treatment remained a statistically significant independent predictor of a slowed progression of CAC in these patients with type 2 diabetes.146 This observation is unique to demonstrate that an improvement in coronary endothelial function in type 2 diabetes mellitus may confer, at least in part, direct preventive effects on the progression of diabetic vasculopathy, in addition to that derived from glucose-lowering treatment. Another example to monitor the effects of preventive medical care on coronary circulatory function is the use of hormone replacement therapy in postmenopausal women.147-149 PET flow measurements also contributed to unravel beneficial effects of hormone replacement therapy in postmenopausal women with medically treated cardiovascular risk factors.147 Hormone replacement therapy using estrogen alone or in conjunction with progesterone

Figure 14 Relationship between improvement in coronary endothelial dysfunction and slowed CAD progression in response to glucoselowering therapy in type 2 diabetes mellitus after 1-year follow-up. Association between the differences in ΔMBF with CPT and in ΔlogCCS (coronary calcium score) between baseline and follow-up (negative values on the x-ordinate are indicative for a progression of coronary artery calcification). (Adapted with permission from Schindler et al.146) (Color version of figure is available online.)

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Figure 15 Hormone replacement and PET-determined coronary endothelial vasoreactivity in postmenopausal women. Effect of hormone replacement therapy (HRT) on coronary endothelial dysfunction in postmenopausal women with medically treated cardiovascular risk factors. The endothelium-related change in ΔMBF from rest to CPT at baseline (Base) and follow-up (FU) among different groups are shown. In postmenopausal women with HRT at baseline and follow-up, the ΔMBF response to CPT was generally maintained, whereas in the women without HRT, there was a significant decrease in ΔMBF to CPT. Interestingly, the ΔMBF to CPT in postmenopausal women who had discontinued HRT during follow-up was even worse than in those women who had never been on HRT, suggesting perhaps a “rebound” phenomenon on coronary endothelial (dys) function. (Adapted with permission from Schindler et al.147,10) (Color version of figure is available online.)

in postmenopausal women, in addition to standard preventive medical care of traditional cardiovascular risk factors, added to preserve endothelium-dependent MBF response to CPT (Fig. 15). Improvements or even normalization of coronary circulatory dysfunction in patients with subclinical or clinically manifest CAD are likely to reflect a reduction in the coronary risk and improvement in longterm cardiovascular outcome.10,16,17 For this reason, improvement of functional abnormalities of the coronary circulation by a variety of interventions, such as angiotensinconverting enzyme inhibitors, beta-hydroxymethylglutarylcoenzyme A reductase inhibitors, euglycemic controls in diabetes, and physical exercise, have emerged as a primary therapeutic goal in the prevention of the atherosclerotic process.80,140,144 Although the latter consideration may be seen as intuitively correct, it still remains to be demonstrated that an improvement in coronary circulatory dysfunction or its MFR, for example, by statin or ACE inhibitor therapy, is indeed directly related to the well-known beneficial effects of primary and secondary preventive medical intervention in the prognosis of patients with atherosclerotic heart disease.

Conclusion Combining cardiac PET, short-lived MBF tracers, and tracer kinetic models enables the noninvasive assessment of not only myocardial perfusion but also of regional MBF in mL/g/min at

290 rest and during vasomotor stress and of the corresponding MFR, which affords a reliable and comprehensive assessment of the CAD burden in individuals with cardiovascular risk. Although cardiac PET perfusion imaging has evolved as a reliable noninvasive imaging modality for the detection of CAD in clinical routine, the assessment of the coronary vasodilator capacity to different forms of vasomotor stress offers important “in vivo” insight into the complex nature of mechanisms underlying functional alterations of the coronary circulation. Cardiac PET imaging therefore contributes to unraveling the pathophysiology of the early development of CAD. Such “in vivo” imaging with PET may denote important associations between cardiovascular risk factors and coronary circulatory function that may complement or even contrast experimental studies that investigate direct cause-effect relationships. By identifying and characterizing the coronary vasodilator capacity, PET may signify early functional or structural abnormalities or both of the coronary artery circulation before its progression to clinically manifest CAD. Likewise, 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, on regional and global coronary function. The aim of imageguided personalized medicine may hold promise with PET technology in the near future.

Acknowledgments Some sections of the manuscript are similar to sections of an extensive review of cardiac PET by Schindler et al.10

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Quantitative assessment of myocardial blood flow--clinical and research applications.

Myocardial perfusion imaging with SPECT/CT or with PET/CT is a mainstay in clinical practice for the diagnostic assessment of downstream, flow-limitin...
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