Selective adenosine agonists and myocardial perfusion imaging

Selective adenosine receptor agonists have several advantages for use as stress agents in conjunction with myocardial perfusion imaging compared to the non selective agents such as adenosine and dipyridamole. This review will summarize the pre-clinical and clinical data on the selective adenosine agonist stress agents regadenoson (Lexiscan^®), binodenoson (CorVue?) and apadenoson (Stedivaze?) that have been studied so far with focus on regadenoson that has the most clinical data published so far. The article will review the adenosine receptor types and properties. It will also review the various attributes of the selective adenosine agonists including their pharmacology, pharmacokinetics and pharmacodynamics, their coronary vasodilatory and hemodynamic effects, their safety and side effects, their interactions with other drugs and their use with myocardial perfusion imaging. The landmark trials of the selective adenosine agonists will be reviewed as well as their use in special patient populations undergoing stress myocardial perfusion imaging.     

Pharmacological stress with adenosine for myocardial perfusion imaging

Adenosine is a ubiquitous purine base that has many physiological actions in the body, including arterial vasodilation in all vascular beds, with the exception of the kidneys. Myocardial ischemia causes an immediate breakdown of adenosine triphosphate and generates adenosine, thereby producing coronary vasodilation and restoring flow. Adenosine produces vasodilation by interacting with the adenosine receptors in the cell wall. Exogenously administered adenosine has a very short half-life (less than 10 seconds) and produces maximal or near-maximal coronary vasodilation in a dose-dependent fashion. The underlying mechanism for production of myocardial perfusion defects by adenosine thallium 201 scintigraphy is a greater coronary flow increase in the normal arteries and a lesser increase in the stenotic arteries. The ultra-short half-life of adenosine requires a continuous intravenous infusion for its use. Adenosine is often administered as a continuous intravenous infusion at a dose of 140 micrograms/kg per minute for 6 minutes, with the thallium injection given midway through the infusion. The safety of this regimen has been demonstrated in several thousand patients around the country. Side effects, due in great part to the potent vasodilatory effect of the drug, occur in most patients during adenosine infusion. Chest pain also occurs often and in some cases may be due to a true coronary steal phenomenon. First-degree atrioventricular (AV) block occurs in approximately 10% and second- or third-degree AV block in approximately 4% of patients due to the inhibitory effect of adenosine on the AV node conduction. The side effects are very short-lived and typically disappear within 1 or 2 minutes after discontinuing the adenosine infusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute myocardial perfusion imaging for the technologist

Conclusion  Acute myocardial perfusion imaging involves careful planning from the nuclear medicine or nuclear cardiology laboratory to ensure optimal results are achieved. The role of the technologist is to ensure a high-quality study is performed on every patient who is referred to the laboratory. This is one of the most important roles because the decision for further evaluation can be based on the interpretation of the acute images. When acute myocardial perfusion imaging is used appropriately, in conjunction with standard methods of evaluation for patients presenting to the emergency department with chest pain syndromes perceived to be cardiac in origin, it can be of great benefit. It offers a more definitive diagnosis of chest pain syndromes and can be used to reduce the expense of otherwise costly hospital stays, even in patients with moderate risk of ischemic heart disease.     

腺苷负荷心肌灌注显像评价心肌血流供应异常的临床研究

目的 回顾性分析腺苷负荷/静息心肌灌注显像用于评价冠心病心肌血流供应异常的准确性和临床价值.方法 1858例临床确诊或可疑冠心病患者行常规标准程序两日法腺苷负荷/静息99Tcm-甲氧基异丁基异腈心肌灌注断层显像,由2位以上核医学科医师共同阅片定性分析图像.所有患者在显像前后1个月内行冠状动脉（简称冠脉）造影检查.方法间的一致性分析用Kappa检验,Kappa＞0.45为一致性较好.结果 1858例患者中,冠脉造影有1支及1支以上冠脉狭窄≥50%的患者957例,其中单支病变506例,双支病变256例,三支病变195例;共累及冠脉1603支,其中左前降支（LAD）765支、左回旋支（LCX）399支、右冠脉（RCA）439支.腺苷负荷/静息心肌灌注显像示心肌缺血或心肌梗死者1126例,与冠脉造影对照,其诊断冠心病的灵敏度为91.54%（876/957）,特异性为72.25%（651/901）,阳性预测值为77.80%（876/1126）,阴性预测值为88.93%（651/732）,2种方法一致性好（Kappa=0.641）.对LAD、LCX和RCA病变诊断的灵敏度分别为81.31%（622/765）,56.64%（226/399）和70.62%（310/439）;对单支、双支和三支冠脉病变的灵敏度分别为87.55%（443/506）,94.92%（243/256）和97.44%（190/195）.腺苷不良反应的发生率为84.12%（1563/1858）,无严重心脏事件发生.结论 腺苷负荷心肌灌注断层显像诊断冠心病有较高的灵敏度、特异性和准确性,对评价心肌血流供应异常有重要的临床价值.     

Acute rest myocardial perfusion imaging for chest pain

Conclusions  Rest radionuclide MPI has made a substantial impact on how patients presenting with acute chest pain are triaged in EDs. Because of the high negative predictive value and favorable prognosis of patients with acute chest pain and normal rest MPI, emergency medicine physicians feel more confident that these patients can be safely discharged. The practice of performing subsequent stress testing in patients with normal rest MPI or normal serial biomarkers has substantially improved the quality of care of patients presenting to the ED with acute chest discomfort. Patients with acute chest pain who undergo a full diagnostic workup as outlined above, including acute rest MPI, benefit from a quick and complete cardiologic evaluation. This is in contrast to the old practice of unnecessary hospitalization for several days or unfortunate discharge from the ED with an evolving acute coronary syndrome. When incorporated into clinical pathways, rest MPI has contributed to improved clinical outcomes by decreasing the number of missed myocardial infarcts, reducing unnecessary admissions, and lowering overall costs when compared with standard patient management.     

A comparison of adenosine and arbutamine for myocardial perfusion imaging

We have compared our standard stress protocol (adenosine combined with exercise) with the new stress agent arbutamine, for thallium-201 myocardial perfusion imaging (MPI) in order to assess the comparative value of arbutamine. We studied 23 patients referred for MPI, and each patient had two studies (18 males, median age 66 years, five with previous myocardial infarction). Uptake scores were assigned to each of nine segments, and the extent and severity of defects were measured using a polar plot. Haemodynamic changes were greater with arbutamine (rate-pressure product increase 78% vs 51%, P = 0.003). Symptoms were experienced by 21 patients with arbutamine and 16 with adenosine (P = 0.07). Agreement between the techniques for classification of patients as normal or as having reversible, fixed or mixed defects was good (19 of 23 studies, 83%, κ = 0.76). Agreement for similar classification of segments was also good (82%, κ = 0.71). Segmental agreement for stress scores was good (86%, κ = 0.77). However, mean size of stress defect was larger with adenosine (83±52 pixels vs 65±48 pixels, P<0.05), though severity and reversibility were similar (P = NS). We conclude that arbutamine provides comparable results to those obtained with adenosine and exercise and that the observed differences are not clinically significant. Received 6 October and in revised form 23 December 1997     

Prognostic value of myocardial perfusion imaging with adenosine triphosphate.

BACKGROUND: Pharmacologic stress with scintigraphy can predict prognosis in patients with coronary disease. Adenosine triphosphate (ATP) has been used in stress testing, but its efficacy in assessing prognosis has not been studied. METHODS AND RESULTS: A total of 150 patients (95 men, aged 64 +/- 10 years) were studied with thallium 201 during intravenous infusion of ATP and at rest. Perfusion defects were classified as reversible or mixed. The lung-heart ratio was calculated. During a maximum follow-up of 4.5 years, the following final events were considered: death, nonfatal myocardial infarction, angina or heart failure requiring hospitalization, or clinical need for myocardial revascularization. The prognostic value of different variables was analyzed with Cox regression. Groups with significantly worse prognosis were as follows: men, smokers, those with previous myocardial infarction, those with total cholesterol/high-density lipoprotein greater than 5, and those with lung-heart ratio greater than 0.5. Multivariate Cox regression showed the presence of perfusion defects as the only variable predictive of prognosis. It was time-dependent, with the highest risk at the beginning of follow-up. Mixed defects had the highest risk, followed by moderate to severe reversible defects. CONCLUSIONS: ATP with Tl-201 gamma-tomography is useful in predicting prognosis of patients with coronary artery disease.     

Prognostic value of adenosine Tl-201 myocardial perfusion imaging after acute myocardial infarction: Results of a prospective clinical trial

BACKGROUND: We have previously shown in retrospective studies that adenosine myocardial perfusion imaging (MPI) done after acute myocardial infarction (AMI) can effectively predict the risk of future cardiac events in these patients. The objective of this study was to validate these observations in a prospective clinical trial. METHODS AND RESULTS: One hundred twenty-six stable patients underwent quantitative adenosine MPI at a mean of 4.5 +/- 2.9 days after AMI. On the basis of the MPI results, they were divided into 3 risk groups: low risk (< 20% perfusion defect), intermediate risk (> or = 20% perfusion defect with < 10% ischemia), and high risk (> or = 20% perfusion defect with > 10% ischemia). The patients were followed up for 11 +/- 5 months for the occurrence of cardiac events: death, myocardial infarction, unstable angina, or congestive heart failure. The actual event rates correlated very well with the prespecified risk groups (19% for the low-risk group, 28% for the intermediate-risk group, and 78% for the high-risk group; P < .001). The significant multivariate predictors for events were female gender (relative risk [RR], 2.90; P = .002), left ventricular ejection fraction (RR, 1.34; P = .04), and ischemic defect size (RR, 1.46; P = .001), with a global chi2 value of 26.7. CONCLUSION: This study demonstrates, in a prospectively designed clinical trial, that quantitative adenosine MPI performed soon after AMI can effectively predict the risk of future cardiac events. These findings are currently being validated in an ongoing, large, multicenter, international clinical trial.     

Bradycardia progressing to cardiac arrest during adenosine thallium myocardial perfusion imaging in occult sino-atrial disease

Adenosine is used increasingly as an alternative to dynamic exercise during myocardial perfusion imaging because it is a powerful coronary vasodilator with a short half-life. Minor side-effects are common but life-threatening events are rare. We report two cases of provocation by adenosine infusion of profound sinus bradycardia progressing to atrial and ventricular asystole. Despite discontinuation of the infusion, asystole persisted for up to 1 min in one case and was accompanied by a grand mal seizure. Normal sinus rhythm returned spontaneously in both cases without long-term sequelae. Sino-atrial disease was later suggested in both cases by 24-h electrocardiographic monitoring. We conclude that patients to whom adenosine is given may have occult sino-atrial disease and may be susceptible to life-threatening arrhythmias. Significant sinus bradycardia during the infusion may provide a warning of its presence.     

The effect of beta blocker withdrawal on adenosine myocardial perfusion imaging

Background

The effect of beta blockers on myocardial blood flow (MBF) under vasodilators has been studied in several SPECT and PET myocardial perfusion imaging (MPI) studies with divergent results. The present study evaluated the effect of a beta blocker withdrawal on quantitative adenosine MBF and on MPI results.

Methods

Twenty patients with beta blockers and CAD history were studied with quantitative adenosine N-13 ammonia PET. The first study was performed under complete medication and the second after beta blocker withdrawal. The PET studies were independently read with respect to MPI result and clinical decision making.

Results

Global MBF showed an increase from 180.2 ± 59.9 to 193.6 ± 60.8 mL·minute^?1/100 g (P = .02) after beta blocker withdrawal. The segmental perfusion values were closely correlated (R ² = 0.82) over the entire range of perfusion values. An essentially different interpretation after beta blocker discontinuation was found in two cases (10%).

Conclusion

A beta blocker withdrawal induces an increase in adenosine MBF. In the majority of cases, MPI interpretation and decision making are independent of beta blocker intake. If a temporary beta blocker withdrawal before MPI is not possible or was not realized by the patient, it is appropriate to perform adenosine stress testing without loss of the essential MPI result.     

Prognostic significance of ischemic electrocardiographic changes during adenosine infusion in patients with normal myocardial perfusion imaging

BACKGROUND: The development of ST-segment depression during adenosine myocardial perfusion imaging (MPI) has been shown to be an independent predictor of subsequent cardiac events and worse outcome, particularly in association with ischemic defects. However, the prognostic significance of ST-segment depression with adenosine in patients with normal MPI is not known. METHODS AND RESULTS: We performed a retrospective analysis of 3231 patients undergoing adenosine MPI. Patients with baseline electrocardiographic (ECG) abnormalities were excluded. Overall, 228 patients (7%) had ischemic ECG changes develop during adenosine infusion. Of these, 66 (29% [2% of all patients]) had normal MPI (+ECG group). An age- and sex-matched group of 200 patients with normal MPI without ECG changes served as control subjects (-ECG group). During a mean follow-up of 29 +/- 12 months, patients in the +ECG group had significantly more adverse cardiac events than those in the -ECG group (nonfatal myocardial infarction, 7.6% vs 0.5%, respectively, P = .004; subsequent revascularization, 13.6% vs 2.5%, respectively, P = .0015). Although cardiac death alone did not differ between the 2 groups (+ECG, 3.0%, vs -ECG, 1.0%; P = .25), cumulative survival free from cardiac death and nonfatal myocardial infarction was worse in patients with ST-segment depression during adenosine infusion and normal MPI (+ECG, 10.6%, vs -ECG, 1.5%; log-rank chi(2) = 11.82; P = .0006). CONCLUSIONS: Patients with normal myocardial perfusion images in whom ST-segment depression develops during adenosine administration appear to be at increased risk for future cardiac events compared with similar patients without ECG evidence of ischemia. Ischemic ECG changes during adenosine MPI should warrant further evaluation, even when perfusion images are reassuring.     

心肌灌注显像腺苷负荷试验致心电图改变分析

目的 评价腺苷负荷心肌灌注显像中患者的心电图变化.方法 回顾性分析2008年5月至12月完成腺苷负荷心肌灌注显像的641例患者腺苷药物负荷试验心电图变化和心肌灌注显像结果.统计学分析采用SAS 8.0软件,单因素分析采用t检验和χ2检验,多因素分析采用Logistic 回归分析.结果 腺苷注射前,641例患者中心电图正常436例（68.0%）,心电图异常205例（32.0%）.腺苷注射过程中新出现心律失常132例（20.6%,132/641）,其中房性早搏39例（29.5%）,室性早搏45例（34.1%）,窦房阻滞8例（6.1%）,一度房室传导阻滞7例（5.3%）,二度Ⅰ型房室传导阻滞26例（19.7%）,二度Ⅱ型房室传导阻滞6例（4.5%）,三度房室传导阻滞1例（0.8%）;需停药13例（9.8%）.腺苷注射终止后新出现心律失常28例（4.4%,28/641）,其中房性早搏16例（57.1%）,室性早搏11例（39.3%）,窦房阻滞1例（3.6%）.641例患者腺负荷试验中共35例（5.5%）出现心电图ST段压低＞0.1 mV,39例（6.1%）予停药处理,无一例急性心肌梗死及猝死;心肌灌注显像结果：36例心肌缺血改变,8例心肌梗死改变.Logistic回归分析示,用腺苷药前、中、后心律失常并不增加出现心肌缺血及心肌梗死改变的风险[P=0.9613,比值比（OR）=0.982,95%可信区间（CI）0.471～2.046;P=0.9511,OR＜0.001,95%CI：＜0.001,＞999.999;P=0.9931,OR＜0.001,95%CI：＜0.001,＞999.999],并且腺苷注射过程中出现与未出现房室传导阻滞患者的阳性心肌灌注显像结果及ST段压低的发生率差异均无统计学意义（χ2=2.5298,0.5317,P均＞0.05）.ST段压低＞0.1 mV的患者出现阳性心肌灌注显像结果的风险增加（P=0.0005,OR=5.608,95%CI2.110～14.905）.结论 腺苷负荷试验过程中心电图异常发生率较高,但多为一过性,出现心律失常并不意味着有心肌缺血.     

Safety of adenosine stress myocardial perfusion imaging by a one-route infusion protocol

When adenosine stress testing is performed, a vein is generally accessed in each arm. To determine whether the one-route infusion protocol, that is, infusion via one upper arm vein, is safe, myocardial perfusion imaging was performed during adenosine stress testing in patients with angina pectoris. Sixty-six consecutive patients (43 men, 68 +/- 11 years of age) with suspected coronary artery disease were enrolled in this study. For the stress test, adenosine was injected at 120 microg/kg/min for 6 minutes. Systolic blood pressure, diastolic blood pressure, and heart rate did not show any significant changes after injection of the adenosine and radioisotope (RI) tracer. Adverse events during infusion of the adenosine were seen in 42 (64%) patients and included chest discomfort/oppression in 17 (26%) and dyspnea/throat discomfort in 15 (23%). On the other hand, adverse events just after infusion of the RI tracer occurred in 5 (8%) patients and included chest oppression in 2 (3%) and dyspnea in 1 (2%). Almost all adverse events disappeared quickly without treatment. Therefore, we concluded that adenosine stress myocardial perfusion imaging using a one-route infusion protocol is safe and useful to do for patients unable to secure veins in both arms.     

腺苷负荷99Tcm—MIBI心肌显像在冠状动脉造影慢血流患者中的应用

目的探讨腺苷负荷99Tcm-甲氧基异丁基异腈（MIBI）心肌显像与冠状动脉（简称冠脉）造影慢血流现象的关系。方法44例患者均经冠脉造影及腺苷负荷99TcmMIBI心肌血流灌注显像,分析比较冠脉造影阳性组（P—CAG）12例,冠脉慢血流组（CSF）22例以及冠脉正常血流组（NCF）10例患者临床资料、腺苷心肌负荷显像改变、冠脉造影结果与腺苷负荷心肌显像的关系。结果采用方差分析、t检验或X^2检验比较。结果3组临床资料（包括年龄、性别和危险因素：高血压史、高脂血症及糖尿病发病率）差异均无统计学意义（年龄：t=0．27,0．54和0．59;性别：矿：0．92;危险因素：X^2=1．23;P均〉0．05）;CSF组冠脉心肌梗死溶栓疗法（TIMI）血流帧数明显多于NCF组（33．7±5．5和17．6±3．9,t=-9．58,P〈0．001）。P—CAG组12例,腺苷负荷心肌显像阳性率100％（12／12）;CSF组22例,阳性率77．3％（17／22）;NCF组10例,2例阳性。半定量靶心图分析示腺苷负荷试验心肌缺血范围（人均缺血节段数）CSF组多于NCF组（1．06±0．77和0．91±0．80,t=-2．02,P〈0．05）,少于P—CAG组（2．41±0．79,t=4．54,P〈0．001）。靶心图记分心肌缺血程度显示CSF组大于NCF组（8．01±6．06和2．73±2．60,t=-2．07,P〈0．05）,小于P—CAG组,但差异无统计学意义（14．07±12．77,t=1．44,P〉0．05）。结论腺苷负荷心肌灌注阳性显像中部分患者伴有冠脉造影慢血流现象,这为有明显胸痛症状但冠脉造影阴性的患者提供了诊断和治疗依据。     

心肌灌注显像腺苷负荷试验致心电图改变分析

目的 评价腺苷负荷心肌灌注显像中患者的心电图变化.方法 回顾性分析2008年5月至12月完成腺苷负荷心肌灌注显像的641例患者腺苷药物负荷试验心电图变化和心肌灌注显像结果.统计学分析采用SAS 8.0软件,单因素分析采用t检验和χ2检验,多因素分析采用Logistic 回归分析.结果 腺苷注射前,641例患者中心电图正常436例(68.0%),心电图异常205例(32.0%).腺苷注射过程中新出现心律失常132例(20.6%,132/641),其中房性早搏39例(29.5%),室性早搏45例(34.1%),窦房阻滞8例(6.1%),一度房室传导阻滞7例(5.3%),二度Ⅰ型房室传导阻滞26例(19.7%),二度Ⅱ型房室传导阻滞6例(4.5%),三度房室传导阻滞1例(0.8%);需停药13例(9.8%).腺苷注射终止后新出现心律失常28例(4.4%,28/641),其中房性早搏16例(57.1%),室性早搏11例(39.3%),窦房阻滞1例(3.6%).641例患者腺负荷试验中共35例(5.5%)出现心电图ST段压低＞0.1 mV,39例(6.1%)予停药处理,无一例急性心肌梗死及猝死;心肌灌注显像结果:36例心肌缺血改变,8例心肌梗死改变.Logistic回归分析示,用腺苷药前、中、后心律失常并不增加出现心肌缺血及心肌梗死改变的风险[P=0.9613,比值比(OR)=0.982,95%可信区间(CI)0.471～2.046;P=0.9511,OR＜0.001,95%CI:＜0.001,＞999.999;P=0.9931,OR＜0.001,95%CI:＜0.001,＞999.999],并且腺苷注射过程中出现与未出现房室传导阻滞患者的阳性心肌灌注显像结果及ST段压低的发生率差异均无统计学意义(χ2=2.5298,0.5317,P均＞0.05).ST段压低＞0.1 mV的患者出现阳性心肌灌注显像结果的风险增加(P=0.0005,OR=5.608,95%CI2.110～14.905).结论 腺苷负荷试验过程中心电图异常发生率较高,但多为一过性,出现心律失常并不意味着有心肌缺血.     

磁共振心肌灌注成像及心肌活力分析诊断急性心肌梗死的价值

目的:研究磁共振心肌灌注成像及心肌活力分析在诊断急性心肌梗死中的价值。方法:选择37例急性心肌梗死患者作为观察组,同时选出37例无心血管疾病的正常志愿者作为对照组,均行灌注成像和心肌活力分析,观察2组相应心肌信号强度平均值、首过最大上升斜率及首过时间。结果:磁共振心肌灌注成像延迟期观察组梗死心肌的信号强度平均值为73.23±35.24,对照组正常心肌(对应观察组梗死区)为17.99±8.15,2组对比差异具有统计学意义(P<0.01);观察组梗死心肌的首过最大上升斜率平均值为32.85±20.69,对照组正常心肌(对应观察组梗死区)为44.68±23.60,2组对比差异具有统计学意义(P<0.01)。观察组患者心肌梗死区首过时间平均为(5.04±1.74)s,对照组正常心肌(对应观察组梗死区)为(2.82±1.82)s,2组对比差异具有统计学意义(P<0.01)。结论:磁共振心肌灌注成像及心肌活力分析可用于诊断急性心肌梗死。     

静息心肌灌注显像判断梗塞相关动脉的作用

目的　评价静息心肌显像的缺血缺损部位对于判断梗塞相关动脉 (IRA)的价值。方法对 44例心肌梗死患者进行99Tcm 甲氧基异丁基异腈 (MIBI)静息心肌断层显像和冠状动脉造影(CAG)。结果　CAG提示IRA 44支 ,其中左前降支 (LAD) 2 7支 ,左旋支 (LCX) 9支 ,右冠脉 (RCA) 8支。当IRA是LAD时出现间壁受累 ,IRA是LCX时出现侧壁受累和IRA是RCA时表现下后壁受累的意义较大 (χ2 =8.98和 8.96 ,P均 <0 .0 5 ;χ2 =43.82 ,P <0 .0 0 5 )。前壁、心尖部、间壁和广泛前壁稀疏缺损对于判断IRA LAD的灵敏度较高 ,分别是 89% ,86 % ,80 %和 89% ;特异性以间壁最高 ,达 80 % ;侧壁和后侧壁判断IRA LCX的灵敏度和特异性分别是 75 % ,6 7%和 85 % ,83% ;下后壁病变判断IRA RCA的灵敏度和特异性分别是 71%和 91%。结论　心肌灌注显像对于判断心肌梗死的IRA有一定价值