CLINICAL RESEARCH: CARDIAC IMAGING
Quantitative relation between hemodynamic changes during intravenous adenosine infusion and the magnitude of coronary hyperemia
Implications for myocardial perfusion imaging
Rakesh K. Mishra, MD, FACC*,
Sharmila Dorbala, MD, FACC*,
Giridhar Logsetty, MD*,
Alita Hassan, MPH ,
Therese Heinonen, PhD ,
Heinrich R. Schelbert, MD, FACC ,
Marcelo F. Di Carli, MD, FACC*,* RAMPART Investigators
* Division of Nuclear Medicine, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
Pfizer Global Research and Development, Ann Arbor, Michigan
Montreal Heart Institute, Montreal, Canada
UCLA School of Medicine, Los Angeles, California
Manuscript received July 6, 2004;
revised manuscript received October 20, 2004,
accepted October 26, 2004.
* Reprint requests and correspondence: Dr. Marcelo F. Di Carli, Division of Nuclear Medicine, Brigham and Women's Hospital, Boston, Massachusetts (Email: mdicarli{at}partners.org).
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Abstract
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OBJECTIVES: The goal of this study was to determine the relationship between changes in cardiac hemodynamics during intravenous adenosine (ADO) infusion, and myocardial blood flow (MBF).
BACKGROUND: The relationship between changes in MBF and the peripheral hemodynamic effects during peak adenosine infusion is unknown.
METHODS: We studied 348 (age 57 ± 11 years; 106 females) without evidence of obstructive coronary artery disease by positron emission tomography (PET). Patients underwent [13N]ammonia PET imaging to measure MBF and coronary vascular resistance (CVR) at rest and during a standard 6-min ADO infusion. Changes in heart rate (HR) and mean arterial pressure (MAP) were measured at baseline and during peak hyperemia.
RESULTS: During ADO, HR increased (delta: 24 ± 11 beats/min) and MAP decreased (delta: –2 ± 10 mm Hg). Overall, delta HR correlated poorly with hyperemic MBF (R = 0.10, p = 0.06) and with CVR (R = 0.11, p = 0.04). Delta MAP also showed a weak correlation with hyperemic MBF (R = 0.04, p = 0.44) and with CVR (R = 0.11, p = 0.04). Patients in the lowest tertile for delta HR showed a 7% lower hyperemic MBF (1.84 ± 0.6 ml/min/g vs. 1.98 ± 0.6 ml/min/g, p = 0.022) and an 8% higher CVR (54 ± 20 mm Hg/ml/min/g vs. 50 ± 17 mm Hg/ml/min/g, p = 0.056) compared with those in the highest tertile. Patients in the lowest tertile for delta MAP (i.e., greatest decline) showed similar hyperemic MBF, and an 8% lower CVR compared with those in the highest tertile (p = NS for both). These small differences between tertiles remain, even after adjusting for differences in age, gender, smoking status, and lipid profile.
CONCLUSIONS: Changes in cardiac hemodynamics during intravenous ADO are generally poor predictors of changes in MBF and CVR during peak hyperemia, and, thus, they should not be used to assess the effectiveness of vasodilator stress in myocardial perfusion imaging.
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Abbreviations and Acronyms
| | CAD = coronary artery disease | | CFR = coronary flow reserve | | CVR = coronary vascular resistance | | HR = heart rate | | MAP = mean arterial pressure | | MBF = myocardial blood flow | | MPI = myocardial perfusion imaging | | PET = positron emission tomography |
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Adenosine is a common agent for stress myocardial perfusion imaging (MPI) in patients who are unable to exercise. The sensitivity and specificity of adenosine MPI is comparable to that of exercise (1,2). It is a powerful vasodilator causing significant hyperemia in the coronary arteries.
Hemodynamic changes during adenosine infusion, particularly changes in blood pressure and heart rate (HR), are often used in the clinical setting to assess the adequacy of hyperemia. Prior studies have shown that, generally, there is a significant increase in HR and a decrease in systolic blood pressure during adenosine infusion (3,4). Consequently, a low resting blood pressure is often cited as a reason not to infuse adenosine due to the potential for further significant reduction in blood pressure. In a previous study, the diagnostic accuracy of adenosine sestamibi single-photon emission computed tomography was not affected by the presence or absence of peripheral hemodynamic evidence of adenosine effect (5).
To date, there have not been any studies that have directly assessed the relationship between changes in myocardial blood flow (MBF) and the peripheral hemodynamic effects during peak adenosine infusion. This study sought to determine the relationship between hemodynamic changes during adenosine infusion and measurements of coronary hyperemia, as quantified by [13N]ammonia and positron emission tomography (PET).
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Methods
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Patient population.
We included men and women (18 to 75 years of age) without documented coronary artery disease (CAD) who completed the screening phase of the Relative and Absolute Myocardial Perfusion changes as measured by Positron Emission Tomography to Assess the Effects of ACAT Inhibition: A Double-Blind, Randomized, Controlled, Multicenter Trial (RAMPART) (6). The RAMPART trial was a phase II study designed to determine the effects of Avasimibe (ACAT inhibitor) on MBF in patients with documented or at risk for CAD. For the current analysis, patients in the RAMPART study with a history of stable angina, a positive stress electrocardiogram, an abnormal stress myocardial perfusion or stress echocardiography study, an abnormal coronary angiogram, or prior revascularization were excluded (n = 114). Women of childbearing potential were excluded from the RAMPART study as were patients with known diabetes, advanced renal dysfunction, active liver disease or hepatic dysfunction, skeletal myopathy, uncontrolled hypertension, valvular heart disease, symptomatic heart failure, historical and/or diagnostic evidence of left ventricular hypertrophy, unstable angina pectoris, or dilated cardiomyopathy (left ventricular ejection fraction <40%).
Measurements of MBF.
Patients underwent PET imaging for assessment of MBF using whole-body PET tomographs (Siemens/CTI, Knoxville, Tennessee) at 12 U.S. sites. All subjects refrained from caffeine-containing beverages or theophylline-containing medications for 24 h before the PET study. Patients using calcium channel blockers or beta-blockers were instructed to withhold the medications for 24 h before the PET study. All subjects were studied in the fasted state.
Using [13N]ammonia, MBF was measured at rest and during peak hyperemia as described previously (7). A 10- to 15-min transmission scan was acquired for correction of photon attenuation. Beginning with the intravenous bolus administration of [13N]ammonia (0.286 mCi/kg), serial images were acquired for 19 min. A total of 30 min later, intravenous adenosine (0.14 mg/kg/min) was infused for 6 min. Three minutes into the adenosine infusion, a second dose of [13N]ammonia was injected, and images were recorded in the same acquisition sequence. The HR, systemic blood pressure, and 12-lead electrocardiogram were recorded at baseline and throughout the infusion of adenosine. Image acquisition protocols were standardized at each site, and measurements of MBF were performed at the core laboratory (UCLA). For the purpose of this analysis, changes in hemodynamics (HR and blood pressure) are the average of values during the 2 min after the injection of [13N]ammonia corresponding to min 4 and 5 of the adenosine infusion, during which most of the myocardial uptake of [13N]ammonia takes place and there is maximal hemodynamic effect of adenosine (8).
Data analysis.
The serially acquired transaxial images were reoriented into short-axis slices of the left ventricular myocardium and assembled into serial polar maps, as described previously (7). Regions of interest were assigned to the territory of the left anterior descending, left circumflex, and right coronary arteries on the last 15-min polar map and copied to the serial polar maps acquired during the initial 2 min after intravenous [13N]ammonia injection (7). An additional, small circular region on interest was assigned to the center of the left ventricular blood pool. Regional myocardial and blood pool time activity curves were then generated. In each coronary territory, MBF was calculated by fitting the [13N]ammonia time-activity curves with a validated two-compartment tracer kinetic model (9). The coronary flow reserve (CFR) (primary study end point) was defined as the ratio between hyperemic and basal MBF. An index of coronary vascular resistance (CVR) was calculated by dividing the mean aortic blood pressure by MBF. The MBF, CFR, and CVR values are an average of the entire left ventricular myocardium.
Laboratory analyses.
A central laboratory (Medical Research Laboratories, Highland Heights, Kentucky) performed all clinical laboratory analyses and lipid analyses as specified by the standardization program of the Centers for Disease Control and Prevention and the National Heart, Lung, and Blood Institute (10).
Statistical analysis.
Data are presented as mean ± SD. Differences in baseline characteristics of patients, coronary blood flow, CVR, and CFR between groups were compared using single factor analysis of variance. Significant main effects for group were followed with Tukey post-hoc tests to identify differences between groups. A multivariate analysis of covariance design was used to investigate differences in adjusted MBF, CVR, and flow reserve between groups. Independent predictors of changes in CFR in response to adenosine were investigated using multiple regression analysis. For all analyses an alpha of 0.05 was used to define statistical significance.
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Results
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Baseline characteristics of patients.
We studied 348 persons, age 22 to 80 years, considered to be at risk for CAD as defined by a low-density lipoprotein cholesterol  130 mg/dl with two or more coronary risk factors (Table 1). However, none had objective evidence of obstructive CAD as determined by the lack of regional perfusion defects on stress myocardial perfusion PET imaging.
Hemodynamic changes during adenosine infusion.
As expected, the HR and rate-pressure product increased significantly with the infusion of adenosine (Table 2). However, the systolic and mean aortic blood pressure remained unchanged during the infusion of adenosine.
Relation between hemodynamic changes and PET measures of coronary hyperemia.
Overall, changes in HR during adenosine correlated poorly with peak MBF (R = 0.10, p = 0.06) (Fig. 1), CVR (R = 0.11, p = 0.04), and CFR (R = 0.02, p = 0.77). Likewise, changes in mean arterial blood pressure showed weak correlations with peak MBF (R = 0.04, p = 0.44) (Fig. 1), CVR (R = 0.11, p = 0.04), and CFR (R = 0.27, p < 0.001).
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Figure 1 Scatter plots showing the relationships between hyperemic myocardial blood flow and the delta change in heart rate (left panel), and the delta change in mean arterial pressure (right panel) during adenosine infusion.
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To further explore the relation between changes in HR and PET measures of coronary hyperemia, the study patients were then divided into tertiles of HR change during adenosine infusion (lower:  HR change <19 beats/min, intermediate: HR change 19 to 29 beats/min, and upper: HR change >29 beats/min) (Table 3). Compared with the upper tertile, peak MBF in the lower tertile was 7% lower and CVR was 8% higher (Fig. 2). However, there were no significant differences in CFR between the two groups. These small differences in peak MBF and CVR persisted after adjusting for baseline differences in age, gender, smoking status, as well as total cholesterol and low-density lipoprotein cholesterol levels (data not shown).
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Figure 2 Bar charts depicting the differences in mean hyperemic myocardial blood flow (MBF) (left panel), coronary vascular resistance (middle panel), and coronary flow reserve (right panel) between the upper (UP), intermediate (INT), and lower (LOW) tertiles of delta heart rate during adenosine infusion. *p = 0.046 vs. LOW.
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A similar analysis was used to define the relation between changes in mean arterial blood (MAP) pressure (a close estimate of coronary pressure) and PET measures of coronary hyperemia. Accordingly, the study patients were divided into tertiles of MAP change during adenosine infusion (lower: MAP change <–5.9 mm Hg, intermediate: MAP change –5.9 to 2.7 mm Hg, and upper: MAP change >2.7 mm Hg). Compared with patients in the upper tertile, those in the lower tertile (i.e., greatest decline in MAP during adenosine infusion) showed similar peak MBF, CVR (Fig. 3). However, CFR was higher among patients in the upper compared with those in the lower tertile, reflecting the fact that the former had a lower resting MBF (Table 4). These small differences in peak MBF and CVR persisted after adjusting for baseline differences in age, gender, smoking status, as well as total high-density lipoprotein cholesterol levels (data not shown).
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Figure 3 Bar charts depicting the differences in mean hyperemic myocardial blood flow (left panel), coronary vascular resistance (middle panel), and coronary flow reserve (right panel) between the upper (UP), intermediate (INT), and lower (LOW) tertiles of delta mean arterial pressure during adenosine infusion. *p = 0.02 vs. LOW; **p < 0.001 vs. LOW.
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Discussion
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Detection of CAD with stress myocardial perfusion scintigraphy (MPS) relies on regional differences in radiotracer uptake resulting from stress-induced coronary flow heterogeneity. During exercise, augmentation in MBF is proportional to increases in myocardial oxygen demand through changes in HR, blood pressure, and contractility. Consequently, a blunted blood flow increase downstream of an obstructed coronary artery in the setting of an exercise-induced increase in oxygen demand results in myocardial ischemia, and a regional perfusion deficit on myocardial perfusion scintigraphy. Thus, exercise-induced changes in HR and rate-pressure product are generally useful clinical indicators of the adequacy of stress and the resulting coronary hyperemia. During vasodilator stress (e.g., adenosine or dipyridamole), however, augmentation in MBF (and consequently flow heterogeneity) is the direct result of vascular smooth muscle cell relaxation and endothelial release of nitric oxide, and largely independent of changes in myocardial oxygen demand (11,12). Nevertheless, changes in hemodynamic parameters such as HR and blood pressure are often used in the clinical setting to assess the adequacy of vasodilator-induced coronary hyperemia.
The findings of this study demonstrate in a large number of subjects that changes in hemodynamics during adenosine-stress are rather poor indicators of the magnitude of coronary hyperemia. We found that patients in the upper tertile of HR change during adenosine infusion showed only 8% higher hyperemic blood flow and 7% lower CVR, compared with those in the lower tertile. Further, changes in MAP during adenosine infusion were even poorer markers of the magnitude of hyperemic blood flow. Indeed, patients in the upper tertile (i.e., lowest decline) of blood pressure change during adenosine infusion showed virtually identical hyperemic blood flow and CVR, compared with those in the lower tertile (i.e., highest decline). Importantly, these small differences in coronary circulatory dynamics persisted after adjusting for baseline differences in age, gender, smoking status, as well as total lipid levels (Tables 3 and 4). These findings suggest that changes in HR or blood pressure during adenosine should not be used to assess the effectiveness of vasodilator stress in patients undergoing MPI.
Comparison with previous studies.
In this study, adenosine induced a significant increase in HR (mean: 39%, range: –24% to 129%) and, consequently, a modest increase in the rate-pressure product. There were no significant changes in systolic, diastolic, or mean arterial blood pressure during adenosine infusion. These findings are consistent with prior reports in experimental (13) and human studies (3–5,14). The increase in HR with adenosine is likely the result of sympathetic activation caused by direct stimulation of chemoreceptors in the carotid body (15) and, in some patients, by an exaggerated peripheral vasodilator response (14).
In our study, patients with the lowest increase in HR with adenosine had slightly lower hyperemic blood flow (7% less) and higher CVR (8% greater) than those with greatest increase in HR. However, these small changes in coronary hemodynamics and flow heterogeneity are unlikely to result in significant differences in radiotracer uptake during MPI and, therefore, are unlikely to affect the sensitivity of adenosine myocardial perfusion scintigraphy for the detection of CAD. Indeed, Amanullah et al. (5) demonstrated that the sensitivity, specificity, and diagnostic accuracy of adenosine myocardial perfusion single-photon emission computed tomography for detecting CAD were not affected by the presence or lack of significant changes in HR and blood pressure in response to adenosine. Our results are not only consistent with these findings but, importantly, they clearly demonstrate a lack of relationship between hemodynamic changes and coronary hyperemia.
The average peak adenosine-stimulated coronary blood flow and CFR were slightly lower than those reported previously in healthy controls using the same methodology (16). This most likely reflects the fact that patients included in the RAMPART trial were recruited on the basis of documented dyslipidemia (i.e., low-density lipoprotein cholesterol levels >130 mg/dl) and/or a history of CAD. The rest and peak blood flows, as well as the coronary vasodilator reserve values, in our study are comparable and entirely consistent with previous work in patients with risk factors or documented CAD (17,18).
Conclusions.
We found that peripheral hemodynamic changes with adenosine are poor correlates of hyperemic MBF and CVR. Therefore, these changes cannot be used to assess the adequacy of a hyperemic response to adenosine.
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Acknowledgments
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The authors thank the women and men who participated in this study. We also acknowledge the valuable contributions of other RAMPART investigators and their clinical and technical staff.
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Footnotes
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Alita Hassan is employed by Pfizer Global Research and Development.
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References
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Abstract
Methods