PET心肌灌注显像测定心肌血流量及冠状动脉血流储备的研究进展

PET心肌灌注显像可绝对定量测定局部心肌血流量（MBF）和冠状动脉血流储备（CFR）。由于显像剂半衰期短,允许在短时间内重复进行PET心肌灌注显像,获得静息态、冷加压试验和药物负荷试验等不同状态下的MBF,进而评价冠状动脉血管内皮依赖性和非依赖性的CFR功能。在早期诊断冠心病,准确诊断冠状动脉多支病变,评价微血管病变,早期检测冠状动脉内皮细胞功能异常及CFR功能的异常,估测预后,帮助临床治疗方案的制定以及检测疗效等方面,PET心肌灌注显像有重要的临床价值。该文将介绍PET心肌灌注显像相关知识及其在心血管领域的主要应用。     

Advances in Myocardial Perfusion MR Imaging: Physiological Implications,the Importance of Quantitative Analysis,and Impact on Patient Care in Coronary Artery Disease

Stress myocardial perfusion imaging (MPI) is the preferred test in patients with intermediate-to-high clinical likelihood of coronary artery disease (CAD) and can be used as a gatekeeper to avoid unnecessary revascularization. Cardiac magnetic resonance (CMR) has a number of favorable characteristics, including: (1) high spatial resolution that can delineate subendocardial ischemia; (2) comprehensive assessment of morphology, global and regional cardiac functions, tissue characterization, and coronary artery stenosis; and (3) no radiation exposure to patients. According to meta-analysis studies, the diagnostic accuracy of perfusion CMR is comparable to positron emission tomography (PET) and perfusion CT, and is better than single-photon emission CT (SPECT) when fractional flow reserve (FFR) is used as a reference standard. In addition, stress CMR has an excellent prognostic value. One meta-analysis study demonstrated the annual event rate of cardiovascular death or non-fatal myocardial infarction was 4.9% and 0.8%, respectively, in patients with positive and negative stress CMR. Quantitative assessment of perfusion CMR not only allows the objective evaluation of regional ischemia but also provides insights into the pathophysiology of microvascular disease and diffuse subclinical atherosclerosis. For accurate quantification of myocardial perfusion, saturation correction of arterial input function is important. There are two major approaches for saturation correction, one is a dual-bolus method and the other is a dual-sequence method. Absolute quantitative mapping with myocardial perfusion CMR has good accuracy in detecting coronary microvascular dysfunction. Flow measurement in the coronary sinus (CS) with phase contrast cine CMR is an alternative approach to quantify global coronary flow reserve (CFR). The measurement of global CFR by quantitative analysis of perfusion CMR or flow measurement in the CS permits assessment of microvascular disease and diffuse subclinical atherosclerosis, which may provide improved prediction of future event risk in patients with suspected or known CAD. Multi-institutional studies to validate the diagnostic and prognostic values of quantitative perfusion CMR approaches are required.     

Quantitative myocardial perfusion imaging by cardiovascular magnetic resonance and positron emission tomography

Recent studies have demonstrated that a detailed knowledge of the extent of angiographic coronary artery disease (CAD) is not a prerequisite for clinical decision making, and the clinical management of patients with CAD is more and more focused towards the identification of myocardial ischemia and the quantification of ischemic burden. In this view, non-invasive assessment of ischemia and in particular stress imaging techniques are emerging as preferred and non-invasive options. A quantitative assessment of regional myocardial perfusion can provide an objective estimate of the severity of myocardial injury and may help clinicians to discriminate regions of the heart that are at increased risk for myocardial infarction. Positron emission tomography (PET) has established itself as the reference standard for myocardial blood flow (MBF) and myocardial perfusion reserve (MPR) quantification. Cardiac magnetic resonance (CMR) is increasingly used to measure MBF and MPR by means of first-pass signals, with a well-defined diagnostic performance and prognostic value. The aim of this article is to review the currently available evidence on the use of both PET and CMR for quantification of MPR, with particular attention to the studies that directly compared these two diagnostic methods.     

Will 3-dimensional PET-CT enable the routine quantification of myocardial blood flow?

Quantification of myocardial blood flow (MBF) and flow reserve has been used extensively with positron emission tomography (PET) to investigate the functional significance of coronary artery disease. Increasingly, flow quantification is being applied to investigations of microvascular dysfunction in early atherosclerosis and in nonatherosclerotic microvascular disease associated with primary and secondary cardiomyopathies. Fully three-dimensional (3D) acquisition is becoming the standard imaging mode on new equipment, bringing with it certain challenges for cardiac PET, but also the potential for MBF to be measured simultaneously with routine electrocardiography (ECG)-gated perfusion imaging. Existing 3D versus 2D comparative studies support the use of 3D cardiac PET for flow quantification, and these protocols can be translated to PET-CT, which offers a virtually noise-free attenuation correction. This technology combines the strengths of cardiac CT for evaluation of anatomy with cardiac PET for quantification of the hemodynamic impact on the myocardium. High throughput clinical imaging protocols are needed to evaluate the incremental diagnostic and prognostic value of this technology. An erratum to this article is available at .     

PET心肌灌注显像及其定量分析的研究进展

近些年,随着PET/CT设备及心脏正电子示踪剂的快速发展,PET心肌血流灌注显像（PET-MPI）在临床上的作用逐渐加强。心肌血流灌注定量分析提供了心肌血流的客观评价标准,可以客观、准确地发现早期灌注异常,准确地对冠心病进行危险分层、预后评价和客观判断治疗效果,为冠心病临床诊治、心脏的生理和病理生理学领域的活体无创性研究提供重要信息。笔者就PET-MPI及其定量分析的研究进展进行综述。     

PET measurement of adenosine stimulated absolute myocardial blood flow for physiological assessment of the coronary circulation

Considerable awareness has been raised of late of the need to reduce radiation exposure and control costs of x-ray and radionuclide imaging procedures. PET/CT cameras are now widely available and in conjunction with appropriate radionuclides and commercially available software make quantitative measurement of absolute MBF feasible for routine clinical practice. Quantitative measurement of absolute MBF under condition of coronary vasodilation permits independent assessment of the functional status of each of the three major coronary perfusion zones and so obviates the need for rest MBF determination in the great majority of cases. Coronary microvascular function also may be assessed in this same way. Thus, the stress-only protocol with quantitative PET measurement of MBF provides essential information required for clinical decision making related to need for catheterization and intervention for patients with known or suspected ischemic heart disease. Moreover, the single PET determination of maximal MBF in contrast to the usual rest/stress procedure addresses both safety and cost concerns. The present review focuses on: (1) quantitative PET measurements of myocardial blood flow for physiological assessment of the coronary circulation and (2) the value and potential limitations of performing stress only imaging in the clinical context.     

PET: Is myocardial flow quantification a clinical reality?

Positron emission tomography (PET) enables quantitative measurements of myocardial blood flow (MBF) and myocardial flow reserve (MFR). Recent developments and improved availability of PET technology have resulted in growing interest in translation of quantitative flow analysis from mainly a research tool to routine clinical practice. Quantitative PET measurements of absolute MBF and MFR have potential to improve accuracy of myocardial perfusion imaging in diagnosis of multivessel coronary artery disease as well as definition of the extent and functional importance of stenoses. This article reviews recent advances and experience in the quantitative myocardial perfusion imaging together with issues that need to be resolved for quantitative analysis to become clinical reality.     

18F-Flurpiridaz PET绝对定量心肌血流显像的研究进展

PET绝对定量心肌血流（MBF）显像在冠心病的诊断、危险分层和预后评估方面均具有重要的临床增益价值，但由于传统正电子心肌灌注显像剂的限制，其尚未在临床上广泛应用。2-叔丁基-氯-5[4-(2-氟-18F-乙氧基甲基)苯基甲氧基]-3(2H)-哒嗪酮（18F-Flurpiridaz）的成功研发开创了正电子心肌灌注显像剂的新领域，其具有良好的绝对定量MBF和心肌血流储备的性能，且相较于经典的正电子心肌灌注显像剂，其在物理性质、心肌摄取率和临床应用的方便性等方面具有明显优势，目前已进入临床Ⅲ期研究，成为最有前景的18F标记的PET心肌灌注显像剂。笔者就18F-Flurpiridaz PET绝对定量MBF显像的研究进展进行综述。     

SPECT定量心肌血流及冠状动脉血流储备的研究进展

应用SPECT、单光子显像剂及示踪动力学技术能方便地定量心肌血流量（MBF）及冠状动脉血流储备（CFR）。特别是碲锌镉心脏专用SPECT的使用,能更快速、准确地获得定量结果。MBF、CFR的获得对冠心病诊断准确性的提高、患者的再分层及进一步预后评估具有重要意义,并且为冠状动脉微血管疾病的诊断提供客观依据。但是使用SPECT定量MBF及CFR仍存在一些不足之处尚待解决。笔者旨在对SPECT定量MBF及CFR的不同方法、初步应用结果及临床意义作一综述。     

Interobserver and interstudy variability of myocardial blood flow and flow-reserve measurements with nitrogen 13 ammonia-labeled positron emission tomography

Background  

Experimental studies have shown that positron emission tomography (PET) with ¹³N-labeled ammonia provides accurate quantification of regional myocardial blood flow (MBF) under rest and stress conditions. To establish the clinical utility of this method, the interobserver variability and the temporal variability of serial measurements of blood flow and coronary flow reserve (CFR) must be known. This study investigated the interobserver and temporal reproducibility of ¹³N-labeled PET for measurement of MBF and CFR.     

Effect on coronary artery flow reserve and resistance in the remote area after acute coronary artery occlusion in the pig model

BACKGROUND: It has been reported that vasodilator function in remote myocardial regions supplied by "angiographically normal" coronary arteries is impaired in patients after acute myocardial infarction (MI). The aim of this study was to determine whether coronary artery flow reserve and coronary artery resistance in remote, nonischemic areas are also altered in experimental MI. METHODS: Experiments were performed in anesthetized pigs. In group 1 infarction was induced by ligation of the left-anterior descending artery (LAD); group 2 consisted of sham-operated animals. Hemodynamic parameters, coronary artery resistance, and myocardial blood flow (MBF) were measured before and 4 hours after MI under rest and during infusion of adenosine. RESULTS: Coronary artery dilation by adenosine caused a similar increase in MBF before and 4 hours after coronary artery occlusion. Resting MBF after acute MI was not altered, although a significant reduction (15%; P < .04) in mean aortic pressure was observed compared with baseline. Coronary artery resistance was significantly reduced by adenosine (P < .04) before MI, as well as at 4 hours after MI (P < .03). Coronary artery flow reserve was not adversely affected. The sham-operated animals showed similar results without any significant differences between the two study groups. CONCLUSION: This study indicates that an acute MI in pigs did not increase coronary artery resistance in the remote area after MI and therefore did not adversely affect coronary artery flow reserve in the nonischemic vascular bed. Further studies are necessary to fully understand the exact mechanism of the alterations in remote flow reserve of patients after MI.     

Analysis of myocardial perfusion MRI

Rapid MR imaging (MRI) during the first pass of an injected tracer is used to assess myocardial perfusion with a spatial resolution of 2-3 mm, and to detect any regional impairments of myocardial blood flow (MBF) that may lead to ischemia. The spatial resolution is sufficient to detect flow reductions that are limited to the subendocardial layer. The capacity of the coronary system to increase MBF severalfold in response to vasodilation can be quantified by analysis of the myocardial contrast enhancement. The myocardial perfusion reserve (MPR) is a useful concept for quantifying the vasodilator response. The perfusion reserve can be estimated from the ratio of MBFs during vasodilation and at baseline, in units identical to those used for invasive measurements with labeled microspheres, or from dimensionless flow indices normalized by their value for autoregulated flow at rest. The perfusion reserve can be reduced as a result of a blunted hyperemic response and/or an abnormal resting blood flow. The absolute quantification of MBF removes uncertainties in the evaluation of the vasodilator response, and can be achieved without the use of complex tracer kinetic models; therefore, its application to clinical studies is feasible.     

Comparison of MRI and positron emission tomography for measuring myocardial perfusion reserve in healthy humans.

Myocardial perfusion reserve (MPR, defined as the ratio of the maximum myocardial blood flow (MBF) to the baseline) is an indicator of coronary artery disease and myocardial microvascular abnormalities. First-pass contrast-enhanced magnetic resonance imaging (CE-MRI) using gadolinium (Gd)-DTPA as a contrast agent (CA) has been used to assess MPR. Tracer kinetic models based on compartmental analysis of the CA uptake have been developed to provide quantitative measures of MBF by MRI. To study the accuracy of Gd-DTPA first-pass MRI and kinetic modeling for quantitative analysis of myocardial perfusion and MPR during dipyridamole infusion, we conducted a comparison with positron emission tomography (PET) in 18 healthy males (age = 40 +/- 14 years). Five planes were acquired at every second heartbeat with a 1.5T scanner using a saturation recovery turboFLASH sequence. A perfusion-related parameter, the unidirectional influx constant (Ki), was computed in three coronary artery territories. There was a significant correlation for both dipyridamole-induced flow (0.70, P = 0.001) and MPR (0.48, P = 0.04) between MRI and PET. However, we noticed that MRI provided lower MPR values compared to PET (2.5 +/- 1.0 vs. 4.3 +/- 1.8). We conclude that MRI supplemented with tracer kinetic modeling can be used to quantify myocardial perfusion.     

Assessment of coronary endothelial function using PET

Endothelial dysfunction is the earliest abnormality in the development of coronary atherosclerosis. Several coronary risk factors adversely affect endothelial function. Therefore, a finding of endothelial dysfunction may guide interventions for preventing the development of future cardiovascular events. The non-invasive aspects and coronary specificity of measurements of myocardial blood flow (MBF) using positron emission tomography (PET) with sympathetic stress make it widely applicable for the evaluation of endothelial function. PET MBF measurements with sympathetic stress have been applied to a variety of subjects with coronary risk factors and have been shown to have value for risk assessment in these subjects. Endothelial measurement using PET remains an ideal research tool for the study of the pathophysiology of several cardiac diseases. PET is also well suited for the acute and longitudinal evaluation of treatment. Thus, the continued development of this approach for the evaluation of new treatment effects should be expected.     

Clinical value of 13N-ammonia PET in assessment of cardiac disease: meta-analysis

The clinical value of 13N-ammonia PET is reviewed by using previously published articles with significant evidence level. This meta-analysis indicated that due to excellent myocardial blood flow images, 13N-ammonia PET permits better diagnostic accuracy of ischemic heart disease and viability assessment than myocardial perfusion SPECT. Furthermore, quantitative assessment of myocardial blood flow (MBF) in absolute units can be performed using 13N-ammonia PET. MBF measurement is a useful tool to evaluate cardiac pathophysiology and monitor therapeutic effects of cardiac disease and cardiovascular risk factors.     

Global myocardial blood flow and global flow reserve measurements by MRI and PET are comparable

Coronary flow reserve (CFR) measurements have been widely used in assessing the functional significance of coronary artery stenosis because they are more sensitive in predicting major cardiac events than angiographically detected reductions of coronary arteries. Myocardial blood flow can be determined by measuring coronary sinus (CS) flow with velocity-encoded cine magnetic resonance imaging (VEC-MRI). The purpose of this study was to compare global myocardial blood flow (MBF) and CFR measured using VEC-MRI with MBF and CFR measured using positron emission tomography (PET). We measured MBF at baseline and after dipyridamole-induced hyperemia in 12 male volunteers with VEC-MRI and PET. With VEC-MRI, MBF was 0.64 +/- 0.09 (ml/min/g) at baseline and 1.59 +/- 0.79 (ml/min/g) at hyperemia, which yielded an average CFR of 2.51 +/- 1.29. With PET, MBF was 0.65 +/- 0.20 (ml/min/g) at baseline and 1.78 +/- 0.72 (ml/min/g) at hyperemia, which yielded an average CFR of 2.79 +/- 0.97. The correlation of MBFs between these two methods was good (r = 0.82, P < 0.001). The CFRs measured by MRI correlated well with those measured using PET (r = 0.76, P < 0.004). These results suggest that MRI is a useful and accurate method to measure global MBF and CFR. Therefore, it would be suitable for studying risk factor modifications of vascular function at an early stage in healthy volunteers.     

Detecting and assessing severity of coronary artery disease in humans

Quantitation of stenosis severity has become an essential part of cardiac diagnosis and therapy, not only in research but also in clinical practice. Since our introduction of the concept 15 years ago, arterial coronary flow reserve for assessing effects of coronary narrowing has evolved into two independent but complementary measurements: coronary flow reserve and stenosis flow reserve. Coronary artery flow reserve and/or myocardial perfusion reserve takes into account not only stenosis geometry but also collateral function and physiologic conditions of perfusion pressure, vasomotor tone, coronary venous pressure, and myocardial vascular bed size. Coronary artery flow reserve is measured invasively by flowmeter or by Doppler catheter. Its noninvasive equivalent is myocardial perfusion reserve, assessed by myocardial perfusion imaging with positron emission tomography before and after intravenous dipyridamole with hand grip stress. Both have been experimentally and clinically validated for identifying and/or quantifying severity of coronary artery disease. By either invasive or noninvasive methods, coronary artery or myocardial perfusion reserve may be subcategorized as either absolute flow or perfusion reserve (max flow/resting flow) and/or relative flow or perfusion reserve (max flow through stenotic artery/max flow through normal artery). Absolute flow reserve depends not only on stenosis severity but also on unrelated physiologic parameters such as aortic pressure and the vasodilatory state of the distal coronary vascular bed; in contrast, relative flow reserve is independent of these physiologic variables and reflects stenosis severity alone. Stenosis flow reserve is invasively determined by automated, quantitative coronary arteriography accounting for all stenosis dimensions and is independent of ambient physiologic conditions such as pressure, vasomotor tone, or other variables affecting the distal coronary vascular bed. It has also been validated experimentally, tested clinically, and is applicable to cine x-ray film-based systems or to on-line digital angiographic cath lab facilities for quantifying effects of therapeutic interventions. Both functional and anatomic measurements are necessary to completely define stenosis severity. Of noninvasive functional approaches for assessing stenosis severity, cardiac positron emission tomography (PET) is the optimum for assessing relative and absolute myocardial perfusion reserve. Of the invasive anatomic approaches, quantitative coronary arteriography is the optimum for determining stenosis flow reserve from all stenosis dimensions under standard conditions.     

Magnetic resonance imaging for the assessment of myocardial viability

The identification of myocardial viability in the setting of left ventricular (LV) dysfunction is crucial for the prediction of functional recovery following revascularization. Although echocardiography, positron emission tomography (PET), and nuclear imaging have validated roles, recent advances in cardiac magnetic resonance (CMR) technology and availability have led to increased experience in CMR for identification of myocardial viability. CMR has unique advantages in the ability of magnetic resonance spectroscopy (MRS) to measure subcellular components of myocardium, and in the image resolution of magnetic resonance proton imaging. As a result of excellent image resolution and advances in pulse sequences and coil technology, magnetic resonance imaging (MRI) can be used to identify the transmural extent of myocardial infarction (MI) in vivo for the first time. This review of the role of CMR in myocardial viability imaging describes the acute and chronic settings of ventricular dysfunction and concepts regarding the underlying pathophysiology. Recent advances in MRS and MRI are discussed, including the potential for dobutamine MRI to identify viable myocardium and a detailed review of the technique of delayed gadolinium (Gd) contrast hyperenhancement for visualization of viable and nonviable myocardium.     

Quantitative assessment of regional myocardial blood flow using oxygen-15-labelled water and positron emission tomography: a multicentre evaluation in Japan

Recently, a method has been proposed for the quantitative measurement of regional myocardial blood flow (MBF) using oxygen-15-labelled water and positron emission tomography (PET). A multicentre project was organized with the intention of evaluating the accuracy of this method, particularly as a multicentre clinical investigative tool. Each of seven institutions performed PET studies on more than five normal volunteers following a specified protocol. The PET study included a transmission scan, a 15O-carbon monoxide static scan and a 15O-water dynamic scan, thereby yielding MBF values which should have been independent of the spatial resolution of the PET scanner employed. Fifty-three subjects (aged 20-63 years, mean+/-SD 36+/-12 years) were studied at rest, and 31 of these subjects were also studied after dipyridamole in five institutions. Inter-institution consistency and intra-subject variation in MBF values were then evaluated. MBF averaged for all subjects was 0.93+/-0.34 ml min(-1) g(-1) at rest and 3.40+/-1.73 ml min(-1) g(-1) after the administration of dipyridamole, and the flow reserve (defined as the ratio of the two MBF values) was 3.82+/-2.12; these values are consistent with previous reports. Resting MBF values were significantly correlated with the heart rate-blood pressure product (RPP) (y=0.31+6.56E-5x, P<0.010), and RPP was in resting MBF observed in all institutions was well explained by the age-dependent RPP. No significant difference was observed in resting MBF among the institutions. Except in one institution, no significant difference was seen in dipyridamole MBF or myocardial flow reserve. No significant difference was found among the myocardial segments. Regional variation was reasonably small in five institutions, but was not acceptable in two institutions, which was attributed to the scanner performance. These observations suggest that the 15O-water PET technique is useful for a multicentre clinical study if the PET scanner can provide time-activity data with good count statistics.     

Reversible impairment of coronary flow reserve in takotsubo cardiomyopathy: A myocardial PET study

Background. The precise etiology of takotsubo cardiomyopathy remains unclear. The study of myocardial blood flow (MBF) and coronary flow reserve (CFR) by use of positron emission tomography might help in understanding this syndrome. Methods and Results. Three postmenopausal women underwent adenosine/rest perfusion with nitrogen 13 ammonia and metabolism with fluorine 18 fluorodeoxyglucose positron emission tomography, coronary angiography, cardiac magnetic resonance, and echocardiography in the acute phase of takotsubo cardiomyopathy and at 3 months’ follow-up, after normalization of left ventricular function. PET study was performed in 2 parts: the perfusion analysis with nitrogen ammonia and the metabolism of the heart using FDG. MBF and CFR were analyzed quantitatively in the acute phase and at follow-up. The images highlighted the impairment of tissue metabolism in the dysfunctioning left ventricular segments in the acute phase, mainly in the apical segments and progressively less in the medium segments. At the same time, a clear inverse metabolic/perfusion mismatch emerged, which normalized 3 months later. The quantitative analysis of MBF showed a reduction in the acute phase in apical segments in comparison to basal segments without differences between midventricular and basal segments. In the acute phase CFR proved to be reduced in apical versus basal segments. CFR impairment of apical segments recovered completely after 3 months. Conclusion. The acute phase of takotsubo cardiomyopathy is characterized by an inverse perfusion/metabolism mismatch with a reduction in CFR in the apical segments. However, the impairment of CFR and the reduction of metabolism in the apical segments recovered completely after 3 months.