Noninvasive PET Flow Reserve Imaging to Direct Optimal Therapies for Myocardial Ischemia
Nuclear cardiology imaging with SPECT or PET is used widely in North America for the diagnosis and management of patients with coronary artery disease. Conventional myocardial perfusion imaging (MPI) can identify areas of reversible ischemia as suitable targets for coronary artery revascularization by angioplasty or bypass surgery. However, the accuracy of this technique is limited in patients with advanced disease in multiple coronary arteries, where there is no normal reference territory against which to assess the “relative” perfusion defects. We have developed methods for the routine quantification of absolute myocardial blood flow (MBF mL/min/g) and coronary flow reserve (stress/rest MBF) using rubidium-82 dynamic PET imaging. The incremental diagnostic and prognostic value of absolute flow quantification over conventional MPI has been demonstrated in several recent studies. Clinical use of this added information for patient management to direct optimal therapy and the potential to improve cardiac outcomes remains unclear, but may be informed by recent progress and widespread clinical adoption of invasive fractional flow reserve(FFR)-directed revascularization. This paper presents recent progress in this field, toward noninvasive CFR image-guided therapy with cardiac PET and SPECT.
KeywordsNoninvasive cardiac imaging Myocardial ischemia Myocardial blood flow Coronary flow reserve Positron emission tomography
Improvements in diagnostic imaging and therapeutic methods have helped to reduce the cardiac death rate in Canada and other developed nations over the past decade . However, cardiovascular disease is still the number one cause of death in most industrialized countries . Noninvasive diagnostic imaging is used increasingly as a “gatekeeper” to help optimize the most effective use of higher-risk invasive (and costly) diagnostic and interventional procedures, such as coronary angiography and revascularization.
This work is motivated in part by the recent FAME trials [7, 38] showing that impaired flow reserve, when used to identify “flow-limiting” epicardial stenoses for revascularization, improved clinical outcomes (reduced cardiac death and myocardial infarction rates) and lowered the total cost of treatment. The FAME trials used invasive angiography measurements of fractional flow reserve (FFR), but with associated risks of embolic stroke and other complications of coronary artery catheterization that may be avoided with the use of noninvasive imaging methods.
Flow reserve terminology
Coronary artery disease (CAD)
Focal or diffuse narrowing of an epicardial coronary artery lumen due to the formation of atherosclerotic plaque (stenosis or lesion) in the arterial wall
Microvascular disease (uVD)
Damage to the inner lining (endothelium) of the subepicardial small arteries or arterioles that regulate blood flow to the heart muscle
Myocardial blood flow (MBF)
Microvascular perfusion [mL/min/g] of blood to the heart muscle
Myocardial perfusion (flow) reserve (MPR, MFR)
Ratio of maximal hyperemic stress/rest perfusion (tissue flow), including the effects of epicardial and microvascular disease, typically measured using noninvasive PET imaging (Fig. 12.1)
Microvascular reserve (uVR)
Ratio of endothelium-dependent stress/rest MBF in the small resistance arteries and arterioles
Epicardial flow reserve (EFR)
Ratio of epicardial vessel-dependent stress/rest MBF in the large conduit arteries. The sum total of uVR + EFR is equal to MPR
Coronary flow reserve (CFR)
Ratio of maximal hyperemic stress/rest blood flow in the epicardial coronary arteries, reflecting the effects of epicardial and microvascular disease. CFR is typically measured invasively during adenosine stress using the indicator dilution technique
Fractional flow reserve (FFR)
Fraction of pressure maintained across an epicardial stenosis during hyperemic stress, measured using invasive angiography. It is analogous to the relative MPR value, in single-vessel disease without uVD
Current international practice guidelines [1, 2] recommend the use of treadmill exercise-ECG testing and stress perfusion imaging for the diagnosis of ischemia (benefit class I, evidence levels A,B) and the use of invasive flow reserve (FFR) measurements to direct invasive revascularization (benefit class I, IIa, evidence level A) for the treatment of symptoms in patients with suspected ischemic heart disease. Despite a wealth of observational data, stress MPI is still not a class 1(A) indication to direct revascularization in patients with stable ischemic heart disease because there remains insufficient evidence that ischemia-directed therapy reduces the risk of death and/or myocardial infarction.
In conjunction with, or following exercise-ECG testing, stress myocardial perfusion imaging (MPI) is used widely in North America for the noninvasive diagnosis of coronary artery disease. While single-photon emission computed tomography (SPECT) is used most commonly, rubidium-82 (82Rb) PET has been available in the USA since 1989 for the diagnosis of obstructive coronary artery disease (CAD). We recently completed enrolment of >15,000 patients in the Canadian multicenter trial  evaluating 82Rb PET as an alternative radiopharmaceutical for myocardial perfusion imaging (Rb-ARMI). Initial results confirmed the high accuracy (>90 %) of low-dose 82Rb PET-CT for diagnosis of obstructive coronary artery disease in patients with epicardial stenoses ≥ 50–70 % . Recent meta-analyses also confirm that PET has higher accuracy for diagnosis of CAD compared to SPECT, even when using current cameras with attenuation correction and ECG-gating .
12.2 Myocardial Blood Flow (Perfusion) Imaging
12.3 Fractional Flow Reserve Assessment
12.4 Noninvasive PET (MPR) vs. Invasive Coronary Angiography (FFR)
Reductions in the supply of blood to the myocardium are caused by two separate consequences of disease: (1) epicardial coronary stenoses and (2) microvascular dysfunction. The “flow-limiting” epicardial stenoses should be identified ideally as targets for revascularization, whereas patients with diffuse or microvascular disease may be better treated with targeted aggressive medical therapies such as lipid-lowering statins or other novel drug treatments under development to improve endothelial function by increasing nitric-oxide bioavailability, for example.
As illustrated in Fig. 12.1, noninvasive PET imaging of MPR measures the capacity to increase perfusion (and tracer delivery) in the downstream microvasculature within the myocardium, reflecting the combined “total” effects of microvascular and epicardial disease. Invasive FFR measures the pressure drop across a single epicardial stenosis during hyperemic stress, representing the peak flow compared to the (restored or expected) normal flow in the absence of stenosis. FFR determines whether a particular epicardial lesion is “flow limiting”; however, this measurement assumes that maximal peak-stress vasodilatation was achieved in the downstream microvasculature. Therefore, in the presence of microvascular dysfunction, FFR can be overestimated (i.e., the severity of disease underestimated) due to a submaximal stress flow response, resulting in underdiagnosis and potential undertreatment of the disease .
We have proposed a simple model describing MPR as the sum total of uVR and epicardial CFR as shown in Fig. 12.15c. This model is consistent with previous observations that MFR decreases with increasing lesion stenosis%, but at different reference levels depending on the burden of microvascular disease. uVR is presumed to be independent of epicardial stenosis severity, also consistent with previous invasive measurements of microcirculatory resistance (IMR) . The model predicts that a particular threshold value (EFR = MPR – uVR) for epicardial coronary revascularization will only improve symptoms of ischemia in patients without severe microvascular disease, e.g., with uVR > 0, as shown in Fig. 12.15d. Conversely, myocardial ischemia may be overestimated in young patients without uVD, where an “apparent ischemic” stress perfusion defect in a patient with very high peak-MFR may still be above the true ischemic threshold of stress MBF.
Noninvasive nuclear imaging of myocardial blood flow (MBF) and coronary flow reserve (CFR) is now feasible as part of the clinical routine using positron emission tomography (PET) imaging. PET measurements of absolute MBF are reliable and reproducible between imaging centers and software methods, with test–retest repeatability below 10 % coefficient of variation. Ischemic thresholds have been proposed for stress MBF and coronary flow reserve in the range of 1.5 [mL/min/g] and 1.0 [stress/rest MBF], respectively. Prospective trials are needed to determine whether patient outcomes can be improved using these ischemic thresholds to direct appropriate revascularization vs. optimal medical therapies.
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