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(Circulation. 2003;107:2894.)
© 2003 American Heart Association, Inc.

Clinical Investigation and Reports

Prognostic Impact of Hemodynamic Response to Adenosine in Patients Older Than Age 55 Years Undergoing Vasodilator Stress Myocardial Perfusion Study

Aiden Abidov, MD, PhD; Rory Hachamovitch, MD, MSc; Sean W. Hayes, MD; Chee Keong Ng, MD; Ishac Cohen, PhD; John D. Friedman, MD; Guido Germano, PhD; Daniel S. Berman, MD

From the Department of Imaging (Division of Nuclear Medicine), Department of Medicine (Division of Cardiology), Cedars-Sinai Medical Center (A.A., S.W.H., C.K.N., I.C., J.D.F., G.G., D.S.B.), and Department of Medicine, University of California, Los Angeles School of Medicine (R.H.).

Correspondence to Daniel S. Berman, MD, Department of Imaging, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Taper Building, Room 1258, Los Angeles, CA 90048. E-mail bermand{at}cshs.org

	Abstract

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Background— The prognostic importance of various hemodynamic responses to adenosine infusion in patients undergoing adenosine stress myocardial perfusion stress (MPS) has not been defined.

Methods and Results— We identified 3444 unique patients (53.5% women, mean age 74.0±8.4 years) who underwent adenosine (with no additional exercise) stress myocardial perfusion single photon emission computed tomography (MPS) and were followed up for 2.0±0.8 years. Multivariable Cox proportional hazards analysis was used to assess the prognostic value of hemodynamic variables in predicting cardiac death (CD). Two hundred twenty-four CDs (6.5%) occurred during follow-up. By multivariable analysis, higher rest heart rate (HR) and to a lesser extent lower peak HR were markers of CD. When added to the multivariable model in place of peak and rest HR, the peak/rest HR ratio was an independent predictor of CD. Peak/rest HR ratio additionally risk-stratified patients within each MPS category. A significant interaction was found between gender and peak systolic blood pressure (SBP), in which there was an increased risk associated with a low peak SBP (<90 mm Hg at end of adenosine infusion) in men but not in women.

Conclusions— Patients undergoing adenosine stress MPS with high rest HR and low peak/rest HR ratio have increased risk of CD, as do male patients with a low peak SBP. Assessment of the hemodynamic response to adenosine adds incremental prognostic value to MPS results and enhances identification of patients at risk for CD.

Key Words: adenosine • hemodynamics • prognosis • perfusion • imaging

	Introduction

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Vasodilator stress myocardial perfusion single photon emission computed tomography (SPECT) (myocardial perfusion stress [MPS]) using adenosine or dipyridamole has been shown to have diagnostic and prognostic value similar to exercise MPS^1–4 and is the preferred MPS modality in patients who are unable to exercise. With exercise stress, exercise-induced hypotension is an important marker of severe and extensive coronary artery disease.^5,6 Although mild reduction of blood pressure and increase in heart rate are usually observed during vasodilator stress,^7–9 the clinical significance and prognostic importance of different hemodynamic responses during vasodilator stress have not been extensively evaluated. In the present study, we tested the hypothesis that hemodynamic responses to adenosine infusion provide incremental prognostic information over baseline clinical and MPS results in patients undergoing adenosine MPS.

	Methods

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Study Population
We identified 5046 unique patients older than age 55 years who underwent rest ²⁰¹Tl/adenosine stress ^99mTc-sestamibi MPS between January 1991 and May 2000 at Cedars-Sinai Medical Center. We excluded from additional analysis 934 patients who underwent adenosine stress combined with low-level exercise. Four hundred eight patients were censored for early (within 60 days after the index MPS) revascularization,¹⁰ 201 (4.9%) were lost to follow-up, and 49 (1.2%) had incomplete hemodynamic data; 10 patients with rest systolic blood pressure (SBP) <90 mm Hg were also excluded, leaving a final population of 3444 patients.

Adenosine Stress Protocol
Standard adenosine stress was used as previously described.^11,12 Patients were instructed not to consume caffeine-containing products for 24 hours before MPS and when possible to discontinue ß-blocking medications for 48 hours and calcium channel blockers and long-acting nitrates for 24 hours. After rest ²⁰¹Tl (3.0 to 4.0 mCi) MPS acquisition, adenosine was infused (140 µg/kg per min) for 6 minutes.^99mTc-sestamibi (25 to 35 mCi) was injected at 3 minutes of infusion. Heart rate (HR), blood pressure (BP), and 12-lead ECG were recorded at baseline and every minute thereafter for at least 5 minutes. The ECG was monitored continuously (leads aVF, V₁, and V₅) for arrhythmia or ischemic ST-segment deviation.¹³

Hemodynamic Variables
Peak HR was defined as the heart rate at the end of adenosine infusion (not the maximal HR during infusion); similarly, peak SBP was defined as the end-adenosine infusion SBP. We also calculated ratios of the peak/rest HR.¹⁴ Peak SBP <90 mm Hg was considered end-adenosine hypotension. Hemodynamic data were categorized by terciles.

MPS Protocol
All patients underwent 180-degree separate acquisition dual isotope rest ²⁰¹Tl/stress ^99mTc-sestamibi MPS,¹⁵ initiated 10 minutes after rest and 60 minutes after stress injection. In patients with extensive rest perfusion defects, additional ²⁰¹Tl MPS was performed 18 to 24 hours after injection. All images were subject to quality control measures. Filtered backprojection and automatic reorientation were used¹⁶ without attenuation or scatter correction.

Image Analysis
MPS images were visually assessed using 20-segment, 5-point (0, normal; 4, absent uptake) scoring.¹⁷ Summed stress score (SSS) and summed rest score (SRS) were calculated. The summed difference score (SDS), representing the amount of reversible perfusion defect, was calculated by subtracting SRS from SSS. For patients undergoing additional 18- to 24-hour ²⁰¹Tl MPS, SDS was calculated as stress-late score difference. MPS results were subdivided by SSS as <4 (normal), 4 to 8 (mildly abnormal), 9 to 13 (moderately abnormal), and >13 (severely abnormal).¹⁸ SDS was subdivided as 0 to 1 (no reversibility), 2 to 7 (mild to moderate reversibility), and >7 (severe reversibility).¹⁹

Patient Follow-Up
Patient follow-up (all >1 year) was performed by dedicated research personnel using scripted and blinded telephone interviews or review of medical records. Cardiac death (CD) was defined as death attributable to any cardiac cause (eg, lethal arrhythmia, myocardial infarction [MI], or pump failure) as confirmed by review of death certificate and medical records and was used for all patients, including those undergoing late revascularization.

Statistical Analysis
Comparisons between patient groups were performed using a ² test for categorical variables. Continuous variables were expressed as mean±SD and were compared using an unpaired t test (2-tailed). P<0.05 was significant. Multivariable Cox proportional hazards analysis was also used to assess the incremental prognostic value of hemodynamic variables over clinical, historical, and stress perfusion information. Selection of variables for consideration was based on both univariate statistical significance and clinical judgment.¹² A significant increase in the global ² of a model after addition of a variable indicated incremental prognostic value. Model assumptions were examined, and risk-adjusted survival and predicted CD rates were determined on the basis of the final models. Kaplan-Meier analysis was used to depict risk-adjusted cumulative survival curves comparing patients with different types of hemodynamic response to adenosine. Statistical analysis used SPSS for Windows (version 11.0).

	Results

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Follow-Up Events
Patients were followed up for 2.0±0.8 years; there were 224 CDs.

Patient Characteristics
The patients were elderly (mean age, 74.0±8.4 years), and 53.5% were women (Table 1). Hypertension and hyperlipidemia were common. Historical MI was present in 27.5%, 18.0% had prior coronary artery bypass grafting, and 46.3% presented with anginal symptoms. More than 20% had a rest ECG considered nondiagnostic for stress interpretation. Only a small percentage was under the influence of ß-blockers (11.8%), calcium-channel blockers (15.6%), long-acting nitrates (10.9%), or digoxin treatment (11.9%). With regard to gender, women were older and had more hypertension, hyperlipidemia, and angina, whereas more men had a history of MI and prior revascularization and smoked. Men more frequently had an ischemic ECG response during adenosine stress (P=0.004 versus women), although the overall frequency of this finding was low (5.0%).

View this table: [in this window] [in a new window]   TABLE 1. Characteristics of Study Population

Baseline Hemodynamic Parameters and Changes During Adenosine Stress
In the overall population, HR was normally distributed at rest and stress; mean rest HR was normal, and mean peak HR was >20% higher than rest HR, resulting in the peak/rest HR ratio >1.20 (Table 2). Rest SBP was higher than normal (154.1 mm Hg), and peak SBP was approximately 10% lower than rest SBP, resulting in the peak/rest SBP ratio <1. Slight gender differences were observed in the hemodynamic variables. Rest and peak HR and SBP were higher in women. Women also demonstrated greater increase in HR and decrease in SBP during adenosine infusion, resulting in higher peak/rest HR ratio and minimally lower peak/rest SBP ratio.

View this table: [in this window] [in a new window]   TABLE 2. Baseline Hemodynamic Parameters and Changes During Adenosine Stress

Results of MPS
Women more frequently had normal scans and scans with no reversibility. Men more frequently had severe perfusion defects with higher SSS, SRS, and SDS, as well as more frequent severe reversibility (Table 3).

View this table: [in this window] [in a new window]   TABLE 3. MPS Results by Gender

Results of Multivariable Survival Analysis
The large number of CD events in this population allowed many variables to be tested for contribution to the predictive model for CD (Table 4). The global ² of the multivariable Cox proportional hazards model for prediction of CD was 384 (P<0.001). The overall model included 15 significant variables, the most powerful of which was SSS (²=73). The most powerful clinical variables were age, diabetes, and presence of uninterpretable stress ECG. With regard to hemodynamic data, the most important CD predictors were rest HR (the higher rest HR, the higher CD risk) and to a lesser extent peak HR (the lower peak HR, the higher CD risk). Age was nonlinear, and thus a quadratic term (age²) was added to the model. An interaction between patient gender and peak SBP was found (increased risk associated with low peak SBP in men but not women). Furthermore, an interaction was found between patient gender and diabetes mellitus (higher risk in female than male diabetic patients).

View this table: [in this window] [in a new window]   TABLE 4. Final Multivariable Cox Proportional Hazards Model for Prediction of CD

CD Rates for HR by Gender
With regard to rest HR, CD rate rose in both men and women as rest HR increased (Table 5). In contrast, with regard to peak HR, the predicted CD rate fell as peak HR increased although with a lesser gradation than for rest HR. Thus, the peak/rest HR ratio demonstrated stronger relationships than rest HR or peak HR alone for either observed or predicted CD; the lower the ratio, the higher the risk.

View this table: [in this window] [in a new window]   TABLE 5. Distribution of Predicted and Observed (in Parentheses) CD Rate (% per Year) by Terciles of HR and SBP Variables and Gender

CD Rates for Blood Pressure Variables by Gender
In men, CD rates were higher as rest SBP and peak SBP decreased (Table 5). In women, CD rates did not differ among terciles of rest or peak SBP. With regard to adenosine-induced hypotension (Figure 1), the predicted CD rate was higher in men with peak SBP <90 mm Hg compared with all others.

View larger version (16K): [in this window] [in a new window]   Figure 1. Predicted CD rate in patients with different thresholds of peak SBP.

Relationship Between Ratio Peak/Rest HR ratio and SSS in Risk Stratification of Patients Undergoing Adenosine Stress MPS
When added to the multivariable model in place of peak and rest HR, peak/rest HR ratio was a strong, independent predictor of CD (P<0.001), and the global ² for the overall model with this substitution was 382 (P<0.001). After risk adjustment, there were significant differences in CD-free survival for patients in each tercile of peak/rest HR (Figure 2). Figure 3 shows the relationships between peak/rest HR terciles and SSS risk categories for predicted CD rates. A consistent increase in predicted CD rates was present with increasing abnormality of either variable, illustrating their independent prognostic information.

View larger version (19K): [in this window] [in a new window]   Figure 2. Kaplan-Meier risk-adjusted survival curves for patients in high (1st), medium (2nd), and low (3rd) terciles of peak/rest HR. On the basis of the multivariable model, significant differences were observed in survival as a function of peak/rest HR terciles.

View larger version (63K): [in this window] [in a new window]   Figure 3. Predicted CD rate distribution by terciles of peak/rest HR and SSS categories.

	Discussion

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The value of vasodilator MPS using adenosine or dipyridamole for risk assessment of patients with known or suspected coronary artery disease has been clearly established.^{11–13,20,22} Although we have previously shown that resting tachycardia is predictive of hard cardiac events in women undergoing adenosine MPS,¹¹ the added prognostic value of assessing hemodynamic responses to adenosine stress has not been defined.

In a large cohort of patients undergoing adenosine stress MPS, we demonstrate for the first time that several hemodynamic variables provide independent information in assessing risk. With regard to HR, in both genders higher rest HR was a strong predictor of CD, and to a lesser extent lower peak HR was also associated with increased CD risk. Furthermore, the composite variable of the peak/rest HR ratio during adenosine infusion was a strong independent hemodynamic predictor of CD in both genders, with higher mortality rates in those with the lower ratios. After adjustment for other significant variables, combining peak/rest HR ratio with SSS, the most powerful prognostic predictor in this population, resulted in enhanced risk stratification compared with that provided by SSS alone. With regard to SBP variables, adenosine-induced hypotension was of prognostic importance only in men; men with peak SBP <90 mm Hg had high risk of CD compared with all other groups.

Comparison With Previous Prognostic Vasodilator MPS Studies
SSS has been shown to be a strong incremental and independent prognostic marker in a variety of clinical subsets of patients undergoing adenosine stress MPS.^{11,12,20–22} Recently we have reported the incremental value, role in risk stratification, and impact on referral to early catheterization and revascularization of adenosine MPS in a large cohort of 5333 patients¹² with or without walking as an adjunct to adenosine stress. The only difference in the multivariable model between our prior and current studies was in the hemodynamic variables (not assessed previously) and in hypercholesterolemia, which in the current study was not predictive. In both studies multivariable analysis showed an interaction between gender and diabetes such that diabetic women were at greater risk than the other groups. The consistency between the studies is of particular importance, because in the present study we narrowed the population analyzed to patients >55 years old who were undergoing adenosine stress without walking. Narrowing the study population allowed assessment of the hemodynamic responses to adenosine that might be influenced by low level exercise or young age. The significant clinical predictors of cardiac events in the current study were similar to those previously described.^11,12,23

A strength of this compared with previous adenosine MPS prognostic studies is the assessment of predicted (risk-adjusted) CD rate, more objective and less influenced by possible causality than observed risk. Additionally, as with our prior study,¹² the multivariable model took into account possible nonlinearity, interactions, and confounding among the prognostic variables.

Of interest in this regard is that differences in cardiac medications being taken at the time of adenosine MPS might have explained our observations; however, none of these medications emerged as part of the final model, and there was no interaction between the hemodynamic variables of prognostic significance with the influence of medications. These findings suggest that the hemodynamic changes found in our study and their prognostic meaning were not distorted by the effects of medications. However, the proportion of patients under the influence of medications was low. Whether the findings would be the same if the prevalence of patients taking these medications was higher is unclear.

Mechanisms of Relationship Between Hemodynamic Variables and Prognosis With Vasodilator Stress
With regard to resting HR, the strongest of the hemodynamic predictors in this study, underlying CHF could explain the observation that high rest HR was an independent predictor of CD in patients requiring adenosine stress. In patients with CHF, resting heart rate is often increased because of increased sympathetic activity,²⁴ possibly linked to higher risk of arrhythmia and sudden death. In our population, however, when we examined shortness of breath, SRS, and prior MI—other parameters associated with CHF—we observed no significant interaction between resting tachycardia and any of these variables.

With regard to the peak HR, adenosine produces near-maximal coronary vasodilation²⁵ and a mild systemic vasodilation, resulting in a mild decrease in blood pressure⁹ and a baroreceptor-mediated reflex tachycardia.^7–9 Baseline increase in sympathetic activity in preclinical or early CHF could blunt the reflex increase in HR associated with the systemic vasodilator properties of intravenously infused adenosine attributable to baseline increases in HR or to a reduced baroreflex sensitivity.²⁶

Impairment of the baroreceptor reflex,²⁶ resulting in decreased vascular reactivity in response to vasodilator stimuli, is frequently observed in the absence of CHF and may also be a factor in our observations of HR response and peak/rest HR ratio. It has been previously shown that diabetic or elderly patients have an attenuated reflex tachycardia in response to vasodilator-induced decreased blood pressure,⁹ possibly attributable to autonomic dysfunction.

Attenuation of peak/rest HR ratios in patients with diabetes and normal vasodilator SPECT has been ascribed to cardiac autonomic neuropathy.¹⁴ Reduced baroreflex sensitivity among patients with a healed myocardial infarction without CHF has been associated with increased mortality (predominantly sudden death).²⁷

With regard to the finding that the hypotensive response to adenosine was a predictor of adverse outcome in men, the underlying mechanism is uncertain. Although a link between extensive ischemia and the hypotensive response was considered, no interaction between adenosine hypotension and other signs of ischemia was found.

Gender-specific differences in hemodynamic responses to adenosine stress have been previously described in smaller populations.⁹ Women have been shown to have a greater decrease in SBP and a greater reflex tachycardia than men, possibly explained by a relatively greater volume of distribution of the infused vasodilator in women compared with men attributable to higher fat-to-muscle ratio.²⁸ The cause for the gender differences in the prognostic significance of adenosine-induced hypotension in men but not in women might be related to the greater frequency of a hypotensive response as a normal finding in women.

Limitations
Our results are based on a population referred for nuclear testing and may not be applicable to a broader population. Although all data were collected and entered prospectively, the study is retrospective. Also, 4.9% of the patients were lost to follow-up and 1.2% had incomplete hemodynamic data. Ventricular function was not assessed in this study, because gated MPS was not routinely performed in our laboratory until 1995. Finally, this study is based on data from a single nuclear cardiology center.

Conclusion
Hemodynamic variables are important in assessing risk of patients undergoing adenosine MPS. Patients with high resting heart rate and to a lesser extent those with lower peak heart rates are at higher risk of CD. Peak/rest HR ratio provides incremental prognostic information over MPS results, with increased risk when this ratio is low, and provides enhanced stratification regarding risk of CD, particularly among those with normal perfusion. Additionally, male patients with a SBP <90 mm Hg at the end of adenosine infusion have increased risk of CD. Hemodynamic variables should be considered when assessing risk of patients undergoing adenosine stress.

	Acknowledgments

 
This work was supported in part by grants from Bristol-Myers Squibb Medical Imaging, Inc, Billerica, Mass, and Fujisawa Healthcare, Inc, Deerfield, Ill.

	Footnotes

 
Drs Berman, Hayes, and Hachamovitch have served on the speaker’s bureaus of Fujisawa Healthcare and Bristol-Myers Squibb Medical Imaging. Dr Berman has received research grants from and Dr Hachamovitch has served as a consultant to Fujisawa Healthcare and Bristol-Myers Squibb Medical Imaging. Dr Abidov is a Save A Heart Foundation/Max and Pauline Zimmer Family Foundation Research Fellow at Cedars-Sinai Medical Center.

Received December 20, 2002; revision received March 20, 2003; accepted March 24, 2003.

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