Myocardial flow reserve (MFR) with positron emission tomography (PET)/computed tomography (CT): clinical impact in diagnosis and prognosis

General principles of PET imaging

PET imaging is based on the use of radiotracers that decay by positron emission. A positron, which is a positively charged electron, is emitted from the nuclei of unstable isotopes during radioactive decay. The ejected positron is successively slowed down by Coulomb interaction with numerous nearby electrons. Then, both the positron and an electron undergo a process known as positron annihilation and are converted into two coincident gamma-ray photons of 511 keV that travel at opposite directions with an angle close to 180 degrees apart from each other (1). Electronic detectors are placed on either side of the active volume and connected in a coincidence circuit. When many such events are detected, the activity distribution of the positron-emitting radionuclide within a volume of interest may be reconstructed. The electronic detection of these photons in coincidence constitutes the foundation of PET imaging (2).

PET vs. SPECT

Cardiac imaging using PET provides several technical advantages over the conventional SPECT and is described as follows: (I) accurate depth-independent attenuation correction (AC) decreases the number of false-positives and as a result, augments specificity. Besides, AC makes it possible absolute MBF quantification. (II) higher spatial resolution improves the detection of small perfusion defects, and thus, increases sensitivity. (III) superior temporal resolution (5–10 s) permits fast dynamic imaging of tracer kinetics and makes absolute quantification of myocardial perfusion possible. (IV) higher extraction fractions and shorter half-lives of the commonly used radiotracers (⁸²Rubidium or ¹³N-ammonia) in comparison with SPECT agents [technetium-99m (^99mTc)-sestamibi, thallium-201 (²⁰¹Tl)], would permit detection of lesser degrees of ischemia as well as faster assessment of myocardial perfusion, respectively. (V) Although stress perfusion abnormalities can be identified with conventional SPECT in the majority cases, the interpretation of PET perfusion images is less equivocal, possibly due to the better quality images. Furthermore, ECG-gated PET is able to assess left ventricular (LV) function at rest and during peak stress (as opposed to post stress with gated SPECT) (2-5).

Clinical PET perfusion tracers

MBF PET tracers that are current Food and Drug Administration (FDA) approved and Centers for Medicare and Medicaid services (CMS)-reimbursable PET MBF tracers are limited to ⁸²Rb and ¹³N-ammonia. While ¹⁵Oxygen-water (H₂¹⁵O)—a freely diffusible tracer—is also used clinically in Europe, it is not FDA approved in the United States (6) (see Table 1). There are also ¹⁸F-labeled MBF agents that are currently investigational and in clinical trials.

Table 1 Myocardial PET flow tracers
Full table

Nitrogen-13 Ammonia (¹³NH₃)

Its physical half live of 10 min. requires an onsite cyclotron and radiochemistry synthesis capability (7,8). The extraction fraction is approximately 80% in the resting state, but like other no diffusible tracers it decreases as MBF increases (Figure 1).

Figure 1 Tracer uptake rate K₁vs. FLOW from a one-tissue-compartment model of tracer kinetics. K₁ is equal to the product of FLOW times the unidirectional extraction fraction. In all tracers except ¹⁵O-water, the tracer extraction is reduced when perfusion is increased leading to underestimation of perfusion if only tracer uptake is used.

In patients with severe impairment of the left ventricular ejection fraction (LVEF), chronic obstructive pulmonary disease (COPD) and smoking, the sequestration of ¹³NH₃ in the lungs can be abnormally increased (9).

Rubidium-82 (⁸²Rb)

⁸²Rb is produced from a strontium-82 (⁸²Sr)/⁸²Rb generator and it is widely available in the US, with increasing availability in Canada, and in several regions of Europe and Japan. It has a short physical half-life of 76 s. Furthermore, patient and staff radiation exposure is significantly reduced compared to conventional technetium-99m (^99mTc) SPECT because of the much shorter scan time and no waiting time to clear background radiation (2). ⁸²Rb is a monovalent cationic analogue of potassium and has similar biological activity to ²⁰¹Tl. Myocardial uptake of ⁸²Rb requires active transport via the sodium/potassium adenosine triphosphate transporter, which is dependent on coronary blood flow. There is accurate data available in the literature with ⁸²Rb MPI linked to outcomes (10-12).

Novel ¹⁸F-labeled agents for PET myocardial perfusion imaging

¹⁸F-tagged agents can take the full advantage of PET superior spatial resolution. Flurpiridaz is an inhibitor of mitochondrial complex I (MC-1), with a physical half-life of 110 minutes, has a high first-pass extraction with less roll-off. Flurpiridaz has demonstrated an excellent relationship to flow in animal models (and in humans has shown a very good diagnostic accuracy for the detection of significant CAD (13,14). Regarding its potential for quantification of absolute MBF, in an experimental study, measurement of the standardized uptake value (SUV) obtained at 5 to 10 minutes after ¹⁸F-flurpiridaz IV injection showed a linear correlation with adenosine hyperemia MBF as quantified by radiolabeled microspheres. This tracer is currently in phase III clinical trials.

Why MBF quantification with PET/CT?

Although other modern imaging techniques are currently being investigated, PET remains the most accurate noninvasive modality for MBF quantification and the modality to which others are compared. Its accuracy has been extensively validated in experimental animals and humans, and the reproducibility of this technique is well established (15-17). However, multiple factors have limited widespread clinical application including availability of scanners, increased cost, and reimbursement issues.

Quantification of MBF using PET has been broadly applied in research for many years. Nowadays, PET measurements of MBF and MFR yield a paradigm shift in the evaluation and management of patients with CAD. In light of the recent shift in the management of CAD from an anatomical gold standard (i.e., coronary angiogram) to a functional one, PET MBF quantification may enable definition of the entire spectrum of vascular dysfunction: from endothelial dysfunction related cardiovascular risk factors or early atherosclerosis and non-coronary cardiac diseases; to advanced diffuse atherosclerotic disease. Various research studies have suggested an incremental prognostic value of MBF assessed with PET imaging in CAD and other cardiac conditions (18-22). As previously mentioned the use of hybrid imaging enables functional and anatomical data, namely, the unique opportunity to visualize and characterize the atherosclerotic burden, coronary stenosis and evaluate the functional consequences of a specific anatomic lesion in a single step (23) (Figure 2). It is important to mention that visualization of the coronary arteries requires administration of an intravenous iodinated contrast agent. PET MBF quantification can also serve as a guide to monitor a number of pharmacologic interventions.

Figure 2 Hybrid PET/CT allows non-invasive evaluation of the coronary anatomy and functional information in one setting. (A) CT angiography (step and-shoot mode) shows multi-vessel disease with massive coronary calcifications and severe stenosis in all major coronary arteries. (B) Hybrid display during adenosine stress demonstrates quite preserved perfusion in anterolateral wall but moderate reduction in septal wall (anterior view). In RCA related region the perfusion was the most severely reduced (posterior view) indicating culprit stenosis in this vessel. Perfusion was colour scaled so that red colour denotes to 3.5 mL/min/g. Resting perfusion was normal (not shown). Total radiation dose of the hybrid study was 11.3 mSv. Reproduced with permission of (21).

MFR can be done with the PET acquisition protocols that are currently utilized (i.e., List Mode Acquisition) without the need of adding time, radiation exposure to the patient and/or additional cost. In order to obtain accurate MBF values, image-derived time-activity curves of the flow tracer from arterial blood and myocardial tissue regions are used as inputs into a validated tracer kinetic model (Figure 3) (6). Automated image analysis tools have been used to facilitate relatively robust quantification of MBF and MFR, even accounting for variations across different modeling approaches (24-26).

Figure 3 Schematic diagram of Time-Activity curves of tracer radioactivity in Blood and in the myocardium. Flow quantification with PET requires IV injection of a PET perfusion tracer and dynamic acquisition of images. 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), and spillover of radioactivity between the left ventricular blood pool and myocardium. Time activity curves, in red in the blood and in light blue the pure tracer concentration after we correct for partial volume and spillover of blood in the myocardium.

Hybrid scanners with both coronary anatomical and hemodynamic measurement capabilities are advantageous alternatives with a high diagnostic accuracy, compared to dedicated PET scanners alone (27,28). CT-based attenuation correction and tissue boundary are more effective than traditional radionuclide transmission sources used in dedicated PET. Perfusion abnormalities can be based on the CT-derived anatomy without the use of frequently inaccurate standard assumptions about vascular distribution pattern (27). In addition, hybrid PET/CT allows routine evaluation of relative myocardial perfusion, LV performance at rest and during peak stress, quantification of perfusion and, depending on the CT scanner capabilities, the addition of calcium score estimation and non-invasive evaluation of the epicardial coronary arteries, thus enhancing test sensitivity for diagnosis of CAD. In order to translate PET flow quantification as a routine clinical tool, the method should be proved to be reproducible and validated in animal models and in humans; the tracer and technology should be available, easy to apply into clinical practice, and importantly, demonstrate an added value for diagnostic or prognostic application and/or impact on therapy decision and patient outcomes (29). Over the past 8 years, several observational research studies have been published in regards of the potential value of MFR in the clinical setting, particularly in patients with known or suspected CAD. Indeed the recently published ASNC PET guidelines (6) have incorporated and enumerate some clinical potential applications of this tool.

MBF PET parameters

Resting MBF is the absolute amount of blood flow that the myocardium receives per minute per gram of tissue under baseline conditions. It is affected by several factors, including age, gender, hemoglobin content, heart rate, blood pressure, drugs, myocardial contractility and cardiac work which can be estimated by the rate pressure product (RPP) (30). In normal individuals, average values of MBF at rest are 0.6 to 1.3 mL/min/g (average, 0.98±0.23 mL/min/g) (30,31). There is a linear association between resting MBF and age (32), which is partly explained by the trend for an association between age and RPP (33).

Hyperemic blood flow (or stress flow) represents the maximum blood flow that can be supplied to the heart during maximum vasodilatation of the coronary vascular bed. Usually, this is achieved by intravenous pharmacologic agents, such as vasodilators or inotropic agents (6). Factors that affect measurement of stress MBF include: caffeine and its derivatives, increased microvascular tone, anatomic remodeling of the microcirculation, submaximal coronary vasodilatation, increased extravascular resistance, coronary risk factors, autonomic nervous system dysfunction and systemic inflammation (34). PET MBF quantification is not possible with treadmill testing because the early time frames post-tracer injection cannot be acquired. Cold pressor test (CPT) and mental stress test have been applied in the research laboratory to induce hyperemic MBF. CPT provokes a mixed vascular response with adrenergically mediated vasoconstrictor and vasodilatory response, reflecting mostly endothelium-dependent vasodilatation.

Myocardial flow reserve (MFR) constitutes the ratio of MBF during maximal coronary vasodilatation to resting MBF and is therefore impacted by both rest and stress flow. MFR represents the relative reserve of the coronary circulation. The optimal cut-point between normal and abnormal has been somewhat empirical and there is some variability in the literature in part depending on the flow tracer applied and on different software, but at general it is accepted that MFR values can be interpreted as follows:

• MFR more than 2.3 indicates a favorable prognosis (assuming that there is no lower regional value).
• MFR less than 1.5 suggests significantly diminished flow reserve (in the absence of concomitant elevated resting blood flow), and is associated with elevated cardiac risk.

According to the recently published ASNC guidelines (6), MFR with PET appear most helpful in:

• Patients without known prior history of cardiac disease who present with symptoms suspicious for myocardial ischemia;
• Patients with known CAD, in whom more specific physiological assessment is desired;
• Identifying an increased suspicion for multivessel CAD;
• Situations with a disparity between visual perfusion abnormalities and apparently normal coronary angiography, in order to assess possible microvascular dysfunction;
• Heart transplant when there is a question of vasculopathy.

Role of MBF quantification to optimize detection of microvascular disease

Although the diagnosis of CAD has been traditionally focused on obstructive atherosclerosis of the epicardial arteries, in recent years significant focus has turned to abnormalities of function and structure that reside at the level of the microcirculation (small vessels; 300–400 µm)—so-called microvascular dysfunction. Evaluation of the coronary microcirculation in vivo relies on the measurement of parameters that are indices of its functional status, such as absolute MBF and MFR (34). In the absence of epicardial CAD, impaired MFR may reflect changes associated with cardiovascular risk factors (35-38), such as hypercholesterolemia, hypertension, diabetes mellitus (DM), and smoking, (all known to have a deleterious effect on the vessel wall). The WISE study (39) has shown that women with ischemic heart disease symptoms, but without significant coronary artery stenosis were at higher risk of cardiovascular events than women without any symptoms, most likely due to endothelial dysfunction. MFR determined using PET has also been used as a surrogate end point to assess efficacy of treatments aimed at halting or delaying the progression of the atherosclerotic process.

Role of MBF quantification in established coronary artery disease

Since the pioneering studies performed by Gould et al. in the late 70s (40,41), MFR has been proposed as an functional indicator of the severity of CAD. MBF at rest remains normal during the progression of coronary lesions until there is an 80–85% diameter stenosis, while hyperemic MBF measured after maximal vasodilatation begins to decrease progressively if the stenosis is more than about 40% (41). Uren et al. showed the relationship between coronary artery stenosis on angiography and MFR data obtained by H₂¹⁵O PET (42). Similar results were obtained with ¹³NH₃ (43). Di Carli et al. showed that intermediate severity coronary lesions exhibited a differential MFR that decreased with increasing stenosis severity (44).

A well-known limitation of relative MPI with both PET and SPECT is that this method often uncovers only coronary territories supplied by coronary arteries with the most severe stenosis, and therefore, it is relatively insensitive to accurately delineate the extent of obstructive angiographic CAD in patients with balanced ischemia due to multivessel CAD (45-47). These observations have served as the basis for the clinical use of quantitative MBF may help overcome these limitations and to improve identifications of obstructive CAD, particularly to exclude the presence of multivessel CAD. Parkash et al. (46) illustrated sensitivity of semi-quantitative and quantitative ⁸²Rb PET nearly on par (87% vs. 83%), but correct identification of disease in all three diseased vascular territories (≥70% stenosis in each territory) was significantly better with quantitative ⁸²Rb PET (46% vs. 92%). In a more recent study (47), we enrolled 120 patients with known or suspected CAD, and demonstrated that patients with 3-vessel CAD had a significantly lower MFR compared to patients without (Figure 4). Global MFR (<2.0) was concluded as an independent predictor of 3-vessel CAD, by results from a multivariable Cox analysis including summed stress score (SSS), MFR, and other significant risk factors. MFR had a diagnostic sensitivity of 88% for 3-vessel disease, whereas only 60% of these patients had other generally accepted risk factors, such as reduced ejection fraction, transient ischemic dilation, and ischemic ECG changes. Figures 5,6 illustrate case examples. In line with previous results, another study showed that a global preserved MFR (>2.0) provides a high negative predictive value of 97% to exclude the presence of 3-vessel CAD, regardless of relative perfusion results (48).

Figure 4 Unadjusted predicted probability (red line) and 95% Confidence Interval (blue lines) of severe 3 vessel CAD at various levels of ⁸²Rb PET MFR based on the analysis model. When MFR is preserved, the likelihood of multivessel CAD is low, whereas with reducing MFR the likelihood of 3-vessel CAD increases. MFR, myocardial flow reserve. Reproduced with permission of (47).

Figure 5 Clinical example in which flow quantification with PET may improve diagnosis of CAD. (A) Dypiridamole ⁸²Rb PET MPI static images demonstrate normal relative perfusion at rest and during peak stress; (B) 17-segment model polar maps of rest MBF (lower left; color display scale 0 to 1.5 mL/min/g), stress MBF (upper left; scale: 0–3.0 mL/min/g), MFR (upper right; scale: 0–3.0) and MFD (lower right; scale: 0–2.0) which demonstrate global impairments, absolute values displayed in the table below; (C) Coronary Angiogram reveals significant obstructive 3-vessel CAD, relative perfusion underestimated the presence of disease (arrows point out significant stenosis). HLA, horizontal long axis; SA, short axis; VLA, vertical long axis; MBF, myocardial blood flow; MFR, myocardial flow reserve; MFD, myocardial flow difference; LAD, left anterior descending artery; LCX, left circumflex; RCA, right coronary artery; RPLS, right posterolateral branch.

Figure 6 A 70-year-old male with hypertension, PVD, renal insufficiency, worsening angina with exertion. (A) dipyridamole ⁸²Rb PET MPI static images demonstrate moderate ischemia in the RCA territory (red arrows); (B) 17-segment model polar maps of rest flow (lower left; color display scale 0–1.5 mL/min/g), stress flow (upper left; scale: 0–3.0 mL/min/g), MFR (upper right; scale: 0–3.0) and MFD (lower right; scale: 0–2.0) with several global reduction in MFR; (C) coronary anatomy showed severe LM stenosis and critical ostial RCA with diffuse CAD in LAD and LCX (arrows point out significant stenosis). Relative MPI underestimated CAD in LM territory. HLA, horizontal long axis; SA, short axis, VLA, vertical long axis; MBF, myocardial blood flow; MFR, myocardial flow reserve; MFD, myocardial flow difference. Reproduced with permission of (47).

From the information provided it is apparent that MFR represents a sensitive parameter, but not necessarily specific for obstructive epicardial CAD. In several patients with overt CAD and reduced global, microvascular disease together with epicardial stenosis coexists, and thus the ability of separating these two when regional perfusion defects are missing, is difficult. As stated earlier, in this regard, the information provided by CT angiography (CTA) in hybrid scanners PET/CT can facilitate the diagnosis or exclusion of epicardial coronary stenosis (23,49-51). With exclusion of stenosis, functional information with decreased MFR will point to microvascular dysfunction and subclinical CAD.

Role of MBF quantification in non-CAD microvascular diseases

In patients with hypertrophic cardiomyopathy (HCM), symptoms and signs of myocardial ischemia are usually present. In the absence of significant coronary stenosis, this finding is indicative of diffuse microvascular dysfunction. It appears that besides reduced capillary density caused by hypertrophy, extravascular compressive forces contribute to endothelial dysfunction (52), and that inadequate hyperemic MBF response to demand in patients with HCM predisposes to myocardial ischemia. Cecchi et al. (21) showed that altered microvascular function is strongly associated with poor outcomes. In line with these observations, Olivotto et al. (20) suggested that the degree of microvascular dysfunction is a potent long term predictor of remodelling and systolic impairment, while a preserved vasodilator capacity was associated with a powerful protective effect.

Among patients with idiopathic dilated cardiomyopathy (IDCM), impaired MBF at rest and during hyperemia with reduced MFR have been demonstrated in PET research studies (19,53). Neglia et al. (18) reported that global impaired vasodilator capacity is an independent predictor of subsequent cardiac events and associated with an increased risk of death and further progression of CHF.

These findings have enhanced our understanding of the role of microvascular dysfunction in these cardiac conditions. However, it is not clear how PET flow measurements will be helpful to: (I) diagnose these conditions—keeping in mind that MFR is affected by many factors and thus may be rather nonspecific; (II) monitor disease progression; and (III) direct management decisions towards strategies that impact outcomes. Continued research is needed to clearly ascertain this clinical role of PET flow quantification (29).

Clinical added prognostic value of MBF quantification

Quantitative myocardial perfusion constitutes a valuable tool for risk stratification both in CAD states and in other clinical conditions, as previously described. MFR provides higher sensitivity to uncover the total burden of myocardial ischemia and overall vascular health that has shown to be reproducible data in several research studies.

In a prospective cohort study with 704 consecutive patients assessed for ischemia, we found that patients with abnormal MFR (<2.0) had a significantly higher cardiac event rate after one year of follow-up (54). MFR was the strongest predictor of MACE with the highest hazard ratio. Importantly, an abnormal MFR identified patients at increased risk of cardiac death even among those normal scans by semi-quantitative visual analysis (Figure 7). These results were extended by two other prognostic studies with slightly smaller enrolled populations, that is, n=275 and n=351, of patients referred for known or suspected CAD (55,56). The semi-quantitative measurements had a significant prognostic value in all three studies as well. Recently, a large study including 2,783 consecutive patients referred for known or suspected CAD, documented global MFR’s incremental value for prognostication over other recognized clinical risk factors, including LV systolic function and a semi-quantitative assessment of myocardial ischemia. Patients in the lowest tertile of MFR (<1.5) had a significantly worse prognosis with a 6-fold increase risk of death that was independent of other risk factors. On the other hand, patients in the highest tertile of MFR (>2.0) had a good prognosis despite of other risk factors resulting in correct reclassification of risk in a large group of patients, including 35% of intermediate risk patients (57).

Figure 7 MACE within subgroups of SSS for different levels of MFR. At any level of SSS, the prevalence of MACE is higher in patients with the lowest MFR (<1.5), and statistically significant different compared to MFR ≥2 among patients with overt ischemia. (*P=0.028 for SSS ≥4–7 and MFR <1.5 vs. MFR ≥2 and **P=0.002 for SSS ≥8 and MFR <1.5 vs. MFR ≥2). SSS, summed stress score; MACE, major adverse cardiac events; MFR, myocardial flow reserve. Reproduced with permission of (55).

The prognostic value of MFR can be also applicable to patients with DM and in patients with chronic renal dysfunction. For patients with DM, an abnormal MFR can predict higher rates of cardiac and all-cause mortality (58). Of note, diabetic patients without known CAD and with impaired MFR experienced a rate of cardiac death comparable to, and possibly higher than, that for nondiabetic patients with known CAD. Likewise, in patients with moderate to severe renal dysfunction (estimated glomerular filtration rate less than 60 mL/min/1.73 m²) clinically referred for PET MPI, impaired CFR less than 1.5 was associated with an adjusted 2.1-fold increase in the risk of cardiac death (P<0.01) (59).

Concluding remarks and future directions

Cardiac PET and PET/CT are rapidly evolving; MFR with PET represents a sensitive means by which to uncover the presence of CAD, particularly to delineate the extent of disease, also to estimate the functional importance of hemodynamically significant epicardial disease, and improve risk stratification of patients. In spite of the limited specificity of MFR, the capability to separate coexisting ischemic conditions can be quite challenging, and may be supported by the addition of CTA to the PET/CT session, thus, providing complementary useful information.

Estimation of flow quantification with PET and integration with traditional relative MPI is relative straightforward utilizing specific standardized protocols and highly reproducible software algorithms that consecutively, facilitate implementation of MFR in clinical routine. Compelling evidence in the literature supports that quantification of MBF with PET has the power to become a reliable non-invasive imaging tool assisting in diagnosis, treatment, and risk stratification of patients with known or suspected CAD and other specific non-ischemic conditions. Last but not least, large randomized controlled trials that evaluate treatment effect are needed to definitively elucidate the clinical significance of MFR on the final outcome in different patient populations.

Acknowledgements

None.

Footnote

Conflicts of Interest: The author has no conflicts of interest to declare.

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