Comparison of myocardial blood flow and coronary flow reserve during dobutamine and adenosine stress: implications for pharmacologic stress testing in coronary artery disease

BACKGROUND: Mechanistic differences between pharmacologic stressors may offer different clinical benefits. Therefore the effects of dobutamine and adenosine on absolute myocardial blood flow (MBF) and coronary flow reserve (CFR) were compared. METHODS AND RESULTS: We divided 36 patients (mean age, 61 +/- 8 years) with coronary artery disease into 2 groups based on stenosis severity as follows: greater than 50% but less than 75% (n = 16) and greater than 75% (n = 20). In addition, 18 normal volunteers (mean age, 46 +/- 7 years) served as control subjects. Groups of equal sizes received either dobutamine or adenosine. MBF at rest and peak MBF were measured by use of positron emission tomography in territories subtended by the stenosis (ischemic) and remote myocardium (remote), whereas left ventricular MBF was used in control subjects. CFR was calculated as peak MBF divided by MBF at rest. CFR was significantly greater with adenosine than with dobutamine stress in control subjects and remote CFR. Ischemic CFR was blunted to a similar degree with each stressor. Therefore adenosine achieved flow heterogeneity across all coronary stenosis severities greater than 50%. However, dobutamine achieved flow heterogeneity only in the presence of a severe coronary stenosis greater than 75% despite provoking a greater ischemic stimulus. CONCLUSION: Adenosine stress demonstrated a higher sensitivity and dobutamine demonstrated a higher specificity with quantitative perfusion imaging. Therefore adenosine is superior for diagnostic perfusion imaging, whereas dobutamine is better suited in combination with visual imaging and in the functional assessment of a known coronary stenosis.     

用腺苷负荷心肌灌注显像评价高血压患者冠状动脉血流储备

目的　用腺苷负荷心肌灌注显像评价高血压患者冠状动脉 (简称冠脉 )血流储备(CFR)。方法　冠脉造影正常的高血压患者 4 7例 ,其中无左心室肥厚 (LVH) 2 5例 ,合并LVH 2 2例 ;正常对照组 17例。分别行静息及腺苷负荷心肌灌注显像。结果　腺苷负荷心肌灌注显像高血压组呈缺血性改变 2 6例 (5 5 3% ) ,对照组 1例 (5 9% ,χ2 =31 12 ,P <0 0 0 1) ;高血压组共 87个节段(2 0 6 % )呈放射性异常分布 ,对照组有 1个节段 (0 7% ,χ2 =32 90 ,P <0 0 0 1)。高血压组自身前后对照 :腺苷注射前心肌灌注显像有 6例 (12 8% )呈缺血性改变 ,共 14个节段 (3 3% ) ;腺苷负荷后 2 6例 (5 5 3% )呈缺血性改变 (χ2 =6 96 ,P <0 0 0 1) ,共 87个节段 (2 0 6 % )呈放射性异常分布 (χ2 =5 9 92 ,P <0 0 0 1)。LVH组腺苷负荷心肌灌注显像呈缺血性改变 17例 (77 3% ) ,无LVH组 9例(36 0 % ,χ2 =8 0 6 ,P <0 0 1) ,LVH组共 6 7个节段 (33 8% )呈放射性异常分布 ,无LVH组为 2 0个节段 (8 9% ,χ2 =4 0 13,P <0 0 0 1)。结论　腺苷负荷心肌灌注显像评价高血压患者CFR安全、易行 ;高血压患者CFR明显异常 ,合并LVH者更为明显。     

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.     

Coronary flow reserve and relative flow reserve measured by N-13 ammonia PET for characterization of coronary artery disease

Objective

We evaluated the relationships between coronary flow reserve (CFR) and relative flow reserve (RFR) measured by N-13 ammonia positron emission tomography (PET) for characterization of epicardial coronary artery disease (CAD).

Methods

Sixty-nine consecutive stable angina patients underwent N-13 ammonia PET, coronary computed tomography angiography (CCTA), and if necessary, invasive coronary angiography (CAG) within 2 weeks. Myocardial blood flow (MBF), CFR, RFR, and coronary vascular resistance of the reference arterial territory (CVR_ref) were measured by N-13 ammonia PET. The presence of significant stenosis (SS) and diffuse atherosclerosis (DA) was evaluated on CCTA and CAG. Functional parameters measured by PET were compared among arteries with and without SS and DA.

Results

Arteries with SS and those with DA showed significantly lower stress MBF, as compared to those without. RFR was significantly lower in arteries with SS as compared to those without, while CFR was not. CFR was significantly lower in arteries with DA as compared to those without, while RFR was not. Among arteries without SS, CFR was significantly lower in those with DA as compared to those without. However, among arteries with SS, CFR was similar between those with and without DA. In contrast, RFR was significantly lower in arteries with SS, regardless of the presence of DA. CFR and RFR showed a weak positive correlation (r = 0.269) with discordance in 24 cases (35%). Among the arteries with CFR-RFR discordance, the prevalence of DA was significantly higher in those with low CFR but preserved RFR, as compared to those with preserved CFR but low RFR (75 vs 25%, p = 0.028). CVR_ref was significantly higher in arteries with DA, implicating a correlation of DA with underlying microvascular disease.

Conclusions

CFR and RFR measured by myocardial perfusion PET could provide a comprehensive information for characterization of epicardial CAD.

     

对比不同剂量腺苷对小型猪左冠状动脉血流及血流储备的影响

目的对比不同剂量的腺苷对巴马系小型猪左冠状动脉(冠脉)血流(CBF)及其储备(CFR)测量的影响。方法经导管于巴马系小型猪(n=10)左冠脉内团注不同剂量的腺苷(12、18、24和36μg),分别记录基础及充血状态下的心率、血压、基础CBF(rCBF)和最大充血时CBF(hCBF),以及CFR进行比较。结果冠脉内注射18μg腺苷可使血管最大扩张,18、24和36μg 3种不同剂量下测得的心率、血压、rCBF及CFR差异无统计学意义。而12μg腺苷剂量测得的hCBF分别同24和36μg测得的hCBF差异有统计学意义(P<0.05)。结论腺苷18～24μg剂量可使巴马系小型猪左冠脉最大扩张,并能获得CBF及CFR的有效测量。     

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.     

ATP负荷与运动负荷心肌灌注断层显像对冠心病的诊断价值

目的　探讨ATP负荷心肌灌注断层显像 (ATP MPI)诊断冠心病 (CAD)的价值。方法　6 1例无心肌梗死病史的疑诊CAD患者 ,均在不同时间分别行静息、ATP负荷及运动负荷99Tcm 甲氧基异丁基异腈 (MIBI)心肌灌注断层显像 (一日法静息 ATP、隔日运动或一日法静息 运动、隔日ATP ,分别简称为ATP MPI和ST MPI) ,其中 4 6例行冠状动脉造影。结果　ATP MPI诊断CAD的灵敏度、特异性和准确性分别为 90 9% ,91 7%和 91 3% ,ST MPI分别为 86 4 % ,91 7%和 89 1% ,差异无显著性(P >0 0 5 )。ATP MPI检测冠状动脉血管狭窄的灵敏度、特异性和准确性分别为 84 6 % ,86 9%和86 2 % ,ST MPI则分别为 84 6 % ,84 8%和 84 8% ,差异无显著性 (P >0 0 5 )。ATP负荷试验时不良反应发生率明显高于运动负荷试验 (88 5 %vs 5 4 1% ,χ2 =17 6 6 9,P <0 0 1) ,但均轻微而短暂 ,恢复时间明显短于后者。结论　ATP MPI诊断CAD的价值与ST MPI相似。ATP负荷试验安全性与耐受性良好 ,尤其适用于老年、无法运动和高血压患者。     

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。     

Novel doppler assessment of intracoronary volumetric flow reserve: validation against PET in patients with or without flow-dependent vasodilation.

Volumetric blood flow (Q) determination requires simultaneous assessment of mean blood flow velocity and vessel cross-sectional area. At present, no method provides both values. Intracoronary Doppler-based assessment of coronary flow velocity reserve (CFVR) relies on average peak velocity (APV). Because this does not account for changes in velocity profile or vessel area usually occurring with flow-dependent vasodilation, results can be misleading. The aim of this clinical study was to validate against the current gold standard (measurement of myocardial perfusion reserve [MPR] by PET) a new, Doppler-based method for calculating coronary Q and coronary flow reserve (CFR). METHODS: Doppler-based intracoronary Q was measured with a proprietary guidewire device in a nonstenotic coronary artery at baseline and during adenosine-induced hyperemic flow (140 mug/kg/min intravenously during 7 min). Three gate positions were assessed, of which 2 were lying within the vessel and 1 was intersecting the vessel. The zeroth (M(0)) and the first (M(1)) Doppler moments of the intersecting gate were used to calculate mean blood flow velocity (M(1)/M(0)) and vessel area (M(0)), and M(0) of the 2 proximal gates was used to correct for scattering and attenuation. CFR was calculated as hyperemic/resting flow with Q and compared with APV-derived CFVR and with the corresponding segmental MPR obtained with (15)O-labeled water and PET. RESULTS: Q (CFR, 2.60 +/- 1.07) correlated well with PET (MPR, 2.58 +/- 1.11) (r = 0.832, P < 0.005; Bland-Altman limits, -1.42 to 1.09), whereas CFVR did not (r = 0.09, P = not statistically significant; Bland-Altman limits, -3.36 to 2.24). However, in vessels without dilation, there was no difference between CFR, CFVR, and MPR. CONCLUSION: This procedure for intracoronary Q measurement using the proprietary Doppler guidewire system, which accounts for both changes in flow profile and changes in vessel area, allows invasive, accurate assessment of CFR even in the presence of flow-dependent vasodilation.     

Reduction of coronary flow reserve in areas with and without ischemia on stress perfusion imaging in patients with coronary artery disease: A study using oxygen 15-labeled water PET

BACKGROUND: Myocardial perfusion single photon emission computed tomography (SPECT) occasionally fails to detect coronary stenosis in patients with coronary artery disease (CAD). We evaluated coronary flow reserve (CFR) using oxygen 15-labeled water in areas with and without ischemia on technetium 99m tetrofosmin stress perfusion SPECT in patients with angiographically documented CAD. METHODS AND RESULTS: Twenty-seven patients with CAD and eleven age-matched normal subjects were studied. Baseline myocardial blood flow (MBF) and MBF during hyperemia induced by intravenous adenosine triphosphate infusion (0.16 mg. kg(-1). min(-1)) were determined with the use of O-15-labeled water positron emission tomography, and the CFR was calculated. Tc-99m tetrofosmin stress/rest SPECT was performed for comparison. On the basis of the results of coronary angiography and SPECT, coronary segments were divided into 3 types: segments with coronary stenosis and a perfusion abnormality on stress SPECT imaging (group A, n = 16), segments with coronary stenosis without a perfusion abnormality (group B, n = 42), and remote segments with no coronary stenosis or perfusion abnormality (group C, n = 18). Baseline MBF values were similar among the 3 groups. CFR in group A was lower (1.82 +/- 0.54) than in group B (2.22 +/- 0.87, P <.05), in group C (2.92 +/- 1.21, P <.01), and in normal segments (3.86 +/- 1.24, P <.001). CFR in group B was lower than in group C (P <.02) and in normal segments (P <.001). CFR in group C was lower than in normal segments (P <.02). CONCLUSIONS: Areas with a perfusion abnormality on stress SPECT had reduced CFR. In the areas without a perfusion abnormality and with coronary stenosis, lowering of CFR was intermediate between the areas with a perfusion abnormality and remote segments. Moreover, CFR was slightly, but significantly, lower in remote segments in patients with CAD compared with normal segments.     

Hybrid CT angiography and quantitative 15O-water PET for assessment of coronary artery disease: comparison with quantitative coronary angiography

Purpose

CT angiography (CTA) can rule out significant stenoses with a very high reliability, whereas its ability to confirm significant stenoses is suboptimal. In contrast, measurements of myocardial blood flow (MBF) provide information on the haemodynamic consequences of stenoses. Therefore, a combination of the two might improve diagnostic accuracy. We conducted a head-to-head comparison of CTA, measurement of MBF by ¹⁵O-water PET, and hybrid PET/CTA for the detection of significant coronary artery stenoses.

Methods

The study group comprised 44 outpatients scheduled for invasive coronary angiography (ICA) with an intermediate pretest likelihood of coronary artery disease. The patients underwent 64-slice CTA and baseline and hyperaemic PET before ICA with quantitative coronary angiography analysis.

Results

On a per-patient basis, the negative predictive values (NPV; 95 % confidence intervals in parentheses) were 88 % (64 – 97 %) for CTA, 90 % (71 – 97%) for PET and 92 % (74 – 98%) for PET/CTA, and the positive predictive values (PPV) were 71 % (53 – 85%) for CTA, 87 % (68 – 95%) for PET and 100 % (84 – 100%) for PET/CTA. Similarly, on a per-vessel basis the NPVs (which were generally high) were 97 % (94 – 100%) for CTA, 95 % (90 – 99%) for PET and 97 % (95 – 100%) for PET/CTA, and the PPVs (which were lower, but higher with PET/CTA) were 53 % (39 – 66%) for CTA, 53 % (40 – 66%) for PET and 85 % (73 – 97%) for PET/CTA. In six patients, CTA analysis was hampered by the presence of severe calcifications. However, with the addition of the PET data, all six patients were correctly categorized.

Conclusion

Cardiac quantitative hybrid PET/CTA imaging has better diagnostic accuracy than CTA alone and PET alone. CTA has a suboptimal PPV, suggesting that hybrid PET/CTA imaging should be used to assess the significance of coronary stenoses diagnosed by CTA.     

Quantitative myocardial perfusion and coronary reserve in rats with 13N-ammonia and small animal PET: impact of anesthesia and pharmacologic stress agents.

The purpose of this study was to evaluate the effects of 2 anesthetic agents on myocardial perfusion and coronary reserve in rats under resting and stress conditions with small animal PET. METHODS: Twenty-four rest/stress studies were performed in 6 rats. Each animal received all 4 possible combinations of anesthetic agents (propofol, isoflurane) and pharmacologic stress agents (dobutamine, adenosine) to increase myocardial perfusion. For each stress or rest study, a 10-min dynamic acquisition was performed in list mode with 185 MBq of (13)N-NH(3). Data analysis was performed according to a 3-compartment myocardial blood flow model. Pharmacologic stimulation by either dobutamine or adenosine was performed to increase myocardial perfusion. RESULTS: The perfusion values (mean +/- SD) for the various experimental conditions were as follows: propofol/dobutamine, 7.8 +/- 2.4 mL/g/min (rest, 3.7 +/- 0.8 mL/g/min; mean +/- SD); isoflurane/dobutamine, 9.3 +/- 3.1 mL/g/min (rest, 4.3 +/- 1.0 mL/g/min); propofol/adenosine, 6.8 +/- 1.7 mL/g/min (rest, 3.2 +/- 0.4 mL/g/min); and isoflurane/adenosine, 5.2 +/- 1.3 mL/g/min (rest, 3.7 +/- 0.7 mL/g/min). All perfusion data showed a significant increase after pharmacologic stimulation relative to baseline (P < 0.05). The coronary reserve (mean +/- SD) measured by PET was slightly lower with the combination of isoflurane and adenosine (1.4 +/- 0.5) than with propofol and adenosine (2.1 +/- 0.5). CONCLUSION: Noninvasive quantitative measurements of myocardial perfusion in small animals at rest and during stress are feasible using PET. Evaluation of the coronary reserve must take into account the initial state of the anesthetized animal. The coronary reserve could be measured with both anesthetic agents using either dobutamine or adenosine stimulation.     

Coronary pressure-derived fractional flow reserve in the assessment of coronary artery stenoses

Objectives

Catheter-based angiography is the reference-standard to establish coronary anatomy. While routinely employed clinically, lumen assessment correlates poorly with physiological measures of ischaemia. Moreover, functional studies to identify and localise ischaemia before elective angiography are often not available. This article reviews fractional flow reserve (FFR) and its role in guiding patient management for patients with a potentially haemodynamic significant coronary lesion.

Methods

This review discusses the theory, evidence, indications, and limitations of FFR. Also included are emerging non-invasive imaging FFR surrogates currently under evaluation for accuracy with respect to standard FFR.

Results

Coronary pressure-derived fractional flow reserve (FFR) rapidly assesses the haemodynamic significance of individual coronary artery lesions and can readily be performed in the catheterisation laboratory. The use of FFR has been shown to effectively guide coronary revascularization procedures leading to improved patient outcomes.

Conclusions

FFR is an invaluable modality in guiding coronary disease treatment decisions. It is safe, cost-effective and leads to improved patient outcomes. Non-invasive imaging modalities to assess the physiologic significance of CAD are currently being? developed and evaluated.

Key points

? Coronary pressure-derived fractional flow reserve (FFR) is an important adjunct to angiography. ? FFR is an invaluable technique in guiding coronary disease treatment decisions. ? FFR is safe, cost-effective and leads to improved patient outcomes. ? New directions include CT-based non-invasive conventional FFR surrogates for functional lesion significance.     

冠状动脉血流储备分数、心肌血流储备和微循环阻力指数在冠心病患者中的临床应用价值

通过对冠状动脉性心脏病（CAD）进行准确、有效地冠状动脉生理学功能状况评估,有利于客观评价CAD的危险程度、选择合适的治疗策略以改善患者预后。目前临床上评价冠状动脉生理学功能的常用的指标包括血流储备分数（FFR）、心肌血流储备（MFR）和微循环阻力指数（IMR）,可通过无创或有创的方法获得。笔者就FFR、MFR和IMR在CAD患者中的临床应用价值作一综述。     

腺苷试验与运动试验201Tl心肌灌注显像对冠心病诊断价值的比较

目的比较腺苷试验与运动试验^201Tl心肌灌注显像对冠心病的诊断价值。方法将41例临床疑诊冠心病患者随机分为两组,一组进行腺苷试验^201Tl心肌灌注显像,一组进行运动试验^201Tl心肌灌注显像。两组试验对象均同期（2周内）行冠状动脉造影术。以冠状动脉狭窄≥50%作为冠心病诊断的“金标准”,比较两种负荷方法对冠心病的诊断价值。结果腺苷试验^201Tl心肌灌注显像对冠心病诊断的灵敏度、特异度、阳性预测率、阴性预测率、准确率分别为92.86%、57.14%、81.25%、80.0%、80.95%,运动试验^201Tl心肌灌注显像分别为100%、60.0%、71.43%、100%、80.0%,两种负荷方法对病变冠状动脉的检出率分别为66.67%和72.22%。结论两种负荷方法诊断冠心病的总体效能无显著差异。