CLINICAL RESEARCH: NUCLEAR IMAGING
Positron Emission Tomography-Measured Abnormal Responses of Myocardial Blood Flow to Sympathetic Stimulation Are Associated With the Risk of Developing Cardiovascular Events
Thomas H. Schindler, MD*, ,*,
Egbert U. Nitzsche, MD ,
Heinrich R. Schelbert, MD, PhD*,
Manfred Olschewski, MSc,
James Sayre, PhD*,
Michael Mix, MSc, PhD,
Ingo Brink, MD,
Xiao-Li Zhang, MD, PhD*,
Michael Kreissl, MD*,
Nobuhisa Magosaki, MD,
Hanjoerg Just, MD and
Ulrich Solzbach, MD
* Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California
Division of Cardiology and Nuclear Medicine, and Department for Medical Statistics, University Freiburg, Freiburg, Germany
University of Basel, School of Medicine, Division of Nuclear Medicine, Kantonsspital Aarau, Aarau, Switzerland.
Manuscript received September 26, 2004;
revised manuscript received January 19, 2005,
accepted January 25, 2005.
* Reprint requests and correspondence: Dr. Thomas H. Schindler, Department of Pharmacology, David Geffen School of Medicine at UCLA, B2-045J CHS, Box 956948, Los Angeles, California 90095-6948. (Email: tschindler{at}mednet.ucla.edu).
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Abstract
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OBJECTIVES: We sought to assess prospectively whether patients with normal coronary angiograms but with impaired myocardial blood flow (MBF) increases to cold pressor testing (CPT) are at increased risk for cardiovascular events.
BACKGROUND: Invasive angiographic assessments of coronary vasomotor function have demonstrated an impairment of endothelium-related coronary flow increases to independently predict future cardiovascular events. It is unknown whether noninvasive positron emission tomography (PET)-measured MBF alterations to sympathetic stimulation with CPT are associated with the risk of developing cardiovascular events.
METHODS: A total of 72 patients (44 men, 28 women, age 58 ± 8 years) referred for diagnostic cardiac catheterization were studied. Myocardial blood flow was measured in absolute units with 13N-ammonia using PET, at baseline and during CPT in each patient. Cardiovascular events (cardiovascular death, acute coronary syndrome, myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, ischemic stroke, or peripheral revascularization) were assessed as clinical outcome parameters over a mean follow-up period of 66 ± 8 months. Patients were assigned to three groups: group 1, patients with  40% increase in MBF (% MBF), n = 22; group 2, patients with >0 and <40% increases in MBF, n = 32; and group 3, patients with decreases in MBF ( 0%), n = 18.
RESULTS: During follow-up, one of the group 1 patients developed a cerebral stroke. In group 2, 15 cardiovascular events occurred in 9 patients and in group 3, 7 patients experienced 9 cardiovascular events (p 0.0001, univariate by log-rank test). Impaired MBF increases in group 2 and group 3 were associated with a significantly higher incidence of cardiovascular events by Kaplan-Meier analysis (p = 0.033, log-rank test). After adjusting for known coronary risk factors, MBF responses to CPT revealed a nonsignificant trend to be independently associated with a higher incidence for cardiovascular events (p = 0.065, multivariate by Cox regression model).
CONCLUSIONS: Noninvasive PET-measured impaired MBF increases to sympathetic stimulation are associated with the risk of developing cardiovascular events.
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Abbreviations and Acronyms
| | BP = blood pressure | | CPT = cold pressor test | | CVR = coronary vascular resistance | | HR = heart rate | | MBF = myocardial blood flow | | PET = positron emission tomography | | RPP = rate-pressure product | | SPECT = single-photon emission computed tomography |
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Normal functioning of the vascular endothelium guarantees important antiatherosclerotic and antithrombotic effects (1). Endothelial dysfunction, on the other hand, is considered an independent predictor of subsequent cardiovascular events, implying important diagnostic and prognostic information (2–5).
The techniques currently and commonly used for the assessment of coronary vasomotor function are invasive (1,6), namely, quantitative angiography and intracoronary velocity probes for evaluating changes in coronary flow to acetylcholine-stimulation of endothelial-derived nitric oxide release or flow-dependent alterations of the lumen of the epicardial conduit vessels. Coronary flow increases can be induced by either intracoronary administration of smooth-muscle-cell-relaxing substances such as papaverine and adenosine, by the use of physical exercise as hyperemic stimulus, or by sympathetic stimulation with cold pressor testing (CPT) (3,7–10). Changes in the luminal area of the epicardial vessel during sympathetic stimulation with CPT were observed to significantly correlate with increases in coronary blood flows. Thus, information on flow-dependent and endothelium-related coronary vasomotion can be derived from measurements of coronary blood flow (6,8,11). However, the invasiveness of coronary angiography does not allow a more widespread clinical use (11,12). Therefore, an optimal test for prognostic evaluation of coronary circulatory function should be noninvasive. In this regard, positron emission tomography (PET)-measured myocardial blood flow (MBF) combined with CPT has proven to be a reliable noninvasive index of flow-mediated and, at least in part, endothelium-related coronary circulatory function (8,9).
With this in mind, we aimed to evaluate whether patients presenting impaired MBF increases to CPT but without angiographic evidence for coronary artery disease, as assessed noninvasively with PET imaging, are at increased risk for cardiovascular events.
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Methods
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Patient population and study design.
The study population consisted of 72 patients (44 men and 28 women, mean age, 58 ± 8 years) who were referred for diagnostic coronary angiography between January 1997 and October 2000 for evaluation of persistent chest pain. A prerequisite for study inclusion was the absence of angiographic evidence for coronary artery disease, as indicated by smooth coronary vessels without evidence of luminal wall irregularities or diffuse caliber reduction and stenosis. Within 20 days (mean 12 ± 5 days), PET measurements of MBF at baseline and during CPT were performed (8). All patients demonstrated normal wall motion on left ventriculography (n = 38) or on echocardiography (n = 34). Screening was accomplished by obtaining a complete history, physical examination, and laboratory analyses. Patients with a history of acute coronary syndrome; myocardial infarction; hypertrophic obstructive and nonobstructive cardiomyopathy; congestive heart failure; malignant hypertension; valvular heart disease; or significant endocrine, hepatic, renal, or inflammatory disease were excluded from the study. Vasoactive medications, including calcium-channel blockers, angiotensin-converting enzyme inhibitors, statins, long-acting nitrates, and beta-blockers were withheld from the participant at least 24 h before the PET study.
Risk factors such as hypertension, hypercholesterolemia, smoking, and a positive family history for coronary artery disease were evaluated at the time of registering the alterations of MBF by PET combined with CPT. Hypertension was defined as a well-established history of chronically (at least two years) elevated blood pressure (BP) (140/90 mm Hg) without any apparent underlying cause that was treated with antihypertensive drugs by the primary physician. Hypercholestertolemia was defined as fasting total serum cholesterol values 240 mg/dl. Moreover, elevated low-density lipoprotein cholesterol and triglycerides were defined by levels 155 mg/dl and 200 mg/dl, respectively, and normal high-density lipoprotein cholesterol by 35 mg/dl.
Diabetes mellitus was identified based on standard criteria implying fasting plasma glucose obtained consistently on more than two occasions at 126 mg/dl. Chronic smoking was defined as a history of smoking one pack of cigarettes for at least the past 10 years, consecutively (13). However, all smokers refrained from smoking 12 h before assessment of MBF changes to sympathetic stimulation by PET. A positive family history for coronary artery disease was defined as evidence of premature coronary artery disease in a parent with respect to gender before 60 years of age. Body mass index was calculated as weight (kg) divided by height (m)2. Furthermore, in each patient, traditional C-reactive protein plasma levels were routinely measured (turbidimetric test, Boehringer Mannheim, Mannheim, Germany), and the normal range was determined to be between 0 to 0.5 mg/dl. The noninvasive assessment of MBF changes to CPT by PET imaging and clinical follow-up were approved by the local ethics committee of the University of Freiburg. All patients gave written informed consent.
PET study protocol.
Within 20 days of diagnostic coronary angiography, quantitative estimates of MBF in ml/g/min were assessed noninvasively with intravenous 13N-ammonia, serial image acquisition by PET (951 ECAT, Siemens, Erlangen, Germany) and a two-compartment tracer kinetic model as described previously (14). The relative myocardial perfusion was assessed visually on reorientated static 13N-ammonia images. Measurements were performed first at baseline and then during CPT (8,9). Time-activity curves were generated from the first 12 serially acquired short-axis slices on 3 midventricular slices, after assigning the myocardial regions-of-interest to the territories of the left anterior descending artery, left circumflex artery, and right coronary artery (14,15). The regional MBF values were averaged to calculate mean MBF.
Heart rate (HR), BP, and a 12-lead electrocardiogram were recorded continuously. From the average of HR and BP during the first 2 min of each image acquisition, the rate-pressure product (RPP) was determined as an index of cardiac work. Further, an index of coronary vascular resistance (CVR) was calculated as the ratio of mean arterial BP to MBF in order to account for interindividual variations in the coronary driving pressure. Thus, in each patient, MBF evaluated at baseline and during CPT with PET established coronary circulatory function (8,9). The decision to divide patients into three different groups was based on the previously described close association between CPT-induced changes of epicardial luminal area and MBFs (8). In the latter study, a flow-related increase of epicardial vessel diameter during CPT, indicative for normal endothelium-dependent vasomotion, was associated with an approximate 30% to 40% increase in MBF. Accordingly, we defined normal flow-mediated coronary vasoreactivity as an MBF increase higher than 40% to CPT (MBF 40%), while an impaired or even decreased MBF during CPT was regarded as abnormal coronary vasoreactivity (MBF <40% and MBF 0%) (8). Based on these assumptions, patients were assigned to 3 groups: group 1, patients with MBF 40% (n = 22); group 2, patients with MBF between >0 and <40% (n = 32); and group 3, patients with MBF 0% (n = 18). In addition, patients were grouped into MBF <28% (n = 45) and MBF 28% (n = 27) to CPT according to flow values deviating outside ± 2 SD limits of normal values on the basis of MBF responses obtained previously in a normal study population (8).
Long-term follow-up.
After a minimum of 12 months, all patients were contacted for the assessment of clinical end points. In view of previous investigations (2–4), cardiovascular death, myocardial infarction, acute coronary syndrome, percutaneous transluminal coronary angioplasty, coronary bypass grafting, ischemic stroke, and peripheral revascularization were defined as cardiovascular events. The assessment of clinical end points was based on responses to a questionnaire that was sent to patients and primary physicians. All information regarding potential cardiovascular events was validated by documentation, including the analysis of repeated coronary angiograms, hospital discharge letters, or hospital chart reviews. Death from any cause was documented. Cardiovascular death was defined as death attributable to myocardial or cerebral infarction or documented sudden cardiac death. Acute coronary syndrome was defined as hospitalization due to unstable angina pectoris of Braunwald classification IIB or IIIB. Myocardial infarction was defined as an elevation of creatine kinase levels 2 x the upper limit of normal and/or new ST elevations (0.1 mV) in 2 leads. Percutaneous transluminal coronary angioplasty was counted when performed in a newly developed (de novo) stenosis (luminal narrowing >50%), which was estimated as hemodynamically significant, or when performed in acute coronary syndromes due to plaque rupture without hemodynamically significant coronary lesions during the follow-up. Ischemic stroke was defined as clinical evidence of stroke without intracranial hemorrhage on brain imaging studies. Cardiovascular medication such as angiotensin-converting enzyme inhibitors, statins, calcium-channel blockers, and beta-blockers, diuretics, oral anti-diabetics (such as metformin, sulfonylurea, or alpha-glucosidase inhibitors), insulin therapy, and nitroglycerin that could affect both coronary vasomotor function to CPT and/or disease progression were documented.
Statistical analysis.
Data of baseline characteristics, MBF responses to CPT, and cardiovascular events during follow-up are expressed as mean ± SD or n (%). Comparison between groups was performed by the Wilcoxon or the Kruskal-Wallis test for quantitative variables and by the Fisher exact test for qualitative data with Bonferroni after adjusting for multiple comparisons. Cumulative event rates for both groups were estimated by the method of Kaplan-Meier by log-rank test. The log-rank test was used for univariate comparisons of groups with no event. Multivariate analysis using Cox regression techniques was applied to evaluate the potential interactions among the entered covariates. The variables included in the model were age, gender, arterial hypertension, serum cholesterol levels, smoking, diabetes mellitus, positive family history for coronary artery disease, body mass index, C-reactive protein levels, and MBF responses to CPT. Medical therapy was not entered into the multivariate model as co-medication was highly correlated with its indications (coronary risk factors). Results are presented as relative risks with corresponding 95% confidence intervals and p values from Wald’s test. Statistical significance was assumed if the null hypothesis could be rejected at the p 0.05 level.
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Results
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Clinical characteristics at baseline.
Patients characteristics are summarized in Table 1. Group 2 and group 3 presented more coronary risk factors than group 1. In group 1, the lipid profile was within normal range. In groups 2 and 3, total cholesterol and low-density lipoprotein levels were significantly higher than group 1 (p 0.05). No significant differences in total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol were noted between groups 2 and 3 (p = NS). Although the glucose levels in all three groups were within normal limits, groups 2 and 3 had significantly higher levels than group 1 (p 0.05). The body mass index, however, was not significantly different between the groups (p = NS). Finally, groups 2 and 3 had significantly higher C-reactive protein levels than group 1 (0.05), although there were no significant differences between groups 2 and 3 (p = NS).
Hemodynamics.
Hemodynamic parameters of all three groups during PET-measured MBFs at baseline and during CPT are given in Table 2. The RPP served as an index of cardiac work and as a measure of the effectiveness of sympathetic stimulation attributable to cold exposure. In all three groups, CPT stimulated a significant increase in HR, systolic and diastolic BP (p 0.05) that was comparable among the groups (p = NS). In each group, the corresponding RPP significantly increased during CPT (p 0.05), indicative for a marked sympathetic activation due to CPT. However, the percent change of RPP (%RPP) in response to CPT was not significantly different between the groups (p = NS), indicating comparable hemodynamic study conditions during the PET study.
MBF responses to CPT.
Table 3 demonstrates the mean values of MBF at baseline and during CPT and the corresponding absolute and percent change in MBF (MBF and %MBF) in each study group. At baseline, MBF did not differ significantly between group 1 and group 2 (p = NS) (Table 3), while group 3 presented a significantly higher MBF (p 0.01). Cold pressor test-induced changes revealed a significantly impaired increase in MBF in groups 2 and 3 compared to group 1, respectively (Table 3) (p < 0.0001). In addition, the decrease of MBF during CPT in group 3 was significantly different from the diminished increase of MBF in group 2 (p < 0.0001). Because changes of CVR mirrored the MBF responses to CPT for each study group (Table 3), differences in hemodynamic responses do not account for the observed alterations in MBFs.
Clinical events during follow-up.
Cardiovascular events are summarized in Table 4. The mean period of follow-up was 66 ± 8 months. During follow-up, 17 of 72 patients (24%) suffered at least one cardiovascular event. In group 1, only one patient experienced a transient ischemic stroke. However, in group 2, 15 cardiovascular events, and, in group 3, 9 cardiovascular events occurred in 9 and 7 patients, respectively (p < 0.0001, univariate by log-rank test).
The cumulative proportion of cardiovascular event-free survival according to the MBF responses to CPT for all three groups is shown in Figure 1. As a rule, patients with abnormal MBF increases to CPT (groups 2 and 3) demonstrated a significantly higher incidence of cardiovascular events compared to patients with normal MBF increases (group 1) (p = 0.033, log-rank test). It is noteworthy that the incidence of cardiovascular events increased with the degree of an abnormal MBF response to CPT in groups 2 and 3 compared to group 1 (p = 0.024, respectively) (Fig. 2). In addition, patients with MBF <28% to CPT revealed a significantly higher incidence of cardiac events compared with the group of MBF 28% (p = 0.026, log-rank test) (Fig. 3).
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Figure 1 Kaplan-Meier analysis demonstrating the proportion of patients without cardiovascular events during long-term follow-up in patients with normal (group 1), impaired (group 2), and decreased (group 3) myocardial blood flow to cold pressor test.
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Figure 2 Patients with at least one cardiovascular event, n (%). Open bar = group 1; striped bar = group 2; solid bar = group 3.
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Determinants of prognosis.
Impaired MBF increases to CPT, C-reactive protein levels, smoking, hypercholesterolemia, and diabetes were significantly associated with the occurrence of cardiovascular events during the follow-up on univariate analysis (Table 5). Age, gender, body mass index, hypertension, and a positive family history of coronary artery disease were not associated with a poor clinical outcome (Table 5). In addition, in group 2 and 3, neither statin therapy nor angiotensin-converting enzyme inhibition was associated with improved long-term outcome by Cox models.
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Table 5. Univariate and Multivariate Cox Regression Analysis in the Study Group (n = 72) Implying Cardiovascular Events (A) or Cardiac Events (B)
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In order to test whether impaired MBF increases to CPT were independent predictors of developing cardiovascular events, a multivariate analysis was performed. As shown in Table 5A, impaired MBF increases to CPT approached a nonsignificant trend (p = 0.065) to independently predict future cardiovascular events. C-reactive protein levels, age, gender, and a positive family history of coronary artery disease did not have a significant effect on the multivariate analysis. Conversely, independent predictors of cardiovascular events were hypercholesterolemia, hypertension, smoking, and increases in body mass index (Table 5A). Thus, in the current study population, impaired MBF responses to CPT were not entirely independent from coronary risk factors associated with a higher risk to develop cardiovascular events. The additional multivariate analysis implying cardiac events only (Table 5B) yielded similar results. However, impaired MBF responses to CPT no longer showed a trend to independently predict future cardiac events.
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Discussion
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The present study is the first of its kind to demonstrate that patients with normal coronary angiograms but with impaired MBF increases in response to CPT, as measured noninvasively with PET, are at increased risk for cardiovascular events. These observations are in accordance with findings of recent invasive angiographic studies (2–5,16) in patients with either no apparent or with more advanced stages of coronary artery disease. The latter findings extend to the site of coronary arteriolar vessels by noninvasive estimates of MBF responses to sympathetic stimulation.
Abnormal coronary vasomotion and prognosis.
The univariate analysis revealed that classical coronary risk factors such as hypercholesterolemia, diabetes mellitus, smoking, C-reactive protein plasma levels, and impaired MBF increases attributable to sympathetic activation were significantly associated with the occurrence of future cardiovascular events. After adjusting for known coronary risk factors by multivariate analysis, diminished MBF increases to CPT revealed a nonsignificant trend to be independently associated with a higher incidence for cardiovascular events. Further, patients with severely impaired MBF increases to sympathetic activation demonstrated a higher incidence of cardiovascular events than patients with moderately impaired MBF increases, despite a similar profile in coronary risk factors. Thus, with regard to the early development of atherosclerosis, this study may provide some first evidence, but certainly not the final answer, that noninvasively PET-measured impaired MBF increases to sympathetic activation could be useful as an integrating index of the overall stress burden imposed by various risk factor states on the arterial wall at the level of the coronary resistance vessels.
Clinical assessment of coronary vasomotor function has demonstrated that impaired endothelium-dependent vasomotion of the coronary circulation in response to various stimuli such as sympathetic stimulation with CPT, intracoronary acetylcholine application, or coronary flow increases with flow-mediated changes in vessel diameter is significantly associated with the occurrence of cardiovascular events (2–5,16). Increased attention has been focused on the concept that the integrity of the coronary resistance vessels constitutes an important factor in counteracting the development and progression of coronary atherosclerotic disease (1,17). This is due to the magnitude of coronary blood flow increases during times of increased metabolic demand that determines the amount of flow-mediated endothelial release of nitric oxide of the epicardial conduit vessels (6,11,18,19), implying numerous antithrombotic and antiatherosclerotic effects. If this holds true, then conversely, impaired flow-mediated and, thus, endothelium-related vasodilation of epicardial arteries, reflecting the integrity of shear-stress-induced nitric oxide release, should be predictive for the occurrence of cardiovascular events. And indeed, diminished flow-mediated vasodilatory responses at the site of the epicardial conduit vessels to coronary flow increases have been demonstrated to independently predict future cardiovascular events (3). This is in line with the observation of the current study as the noninvasive assessment of impaired MBF increases to sympathetic stimulation with PET imaging in patients with normal coronary angiograms proved to be significantly associated with a subsequent risk of developing cardiovascular events.
However, there is abundant evidence for the prognostic value of exercise-induced ischemic myocardial perfusion single-photon emission computed tomography (SPECT) (20–23). In the clinical setting, myocardial perfusion SPECT imaging has emerged as an important tool for improving the diagnostic assessment and risk stratification of patients with suspected coronary artery disease. Nevertheless, there may be a substantial number of patients with subclinical atherosclerosis and normal myocardial perfusion SPECT studies (23). Conceptually, in patients with normal myocardial perfusion SPECT the noninvasive-assessment of MBF alterations to sympathetic stimulation with CPT could help to unmask a subset of patients at increased risk for cardiovascular events. The current study, although small in number, provides first evidence that PET-measured MBF alterations in response to sympathetic activation is associated with a higher risk for future cardiovascular events. Of note, the incidence of cardiovascular events increased with the degree of the CPT-induced abnormal MBF response. Similar findings of increasing incidence of cardiovascular events with the magnitude of vasoconstriction of epicardial conduit arteries and of coronary arteriolar vessels in response to intracoronary acetylcholine application has been reported in previous invasive angiographic investigations (4,5). Importantly, these studies also suggest diminished coronary blood flow increases to acetylcholine stimulation, reflecting endothelium-dependent vasoreactivity at the site of the coronary resistance vessels, to identify patients at increased risk for future cardiovascular events. Thus, the latter observations (4,5) and the findings of the present study indicate that impaired coronary flow increases are associated with a poor clinical outcome.
It is worthy to note that even though there is a close relationship between coronary risk factor burden and abnormal coronary vasomotor function (1), a considerable variability in the magnitude of impaired endothelium-dependent vascular function in individuals with comparable risk profiles may exist (4,24). In this scenario, abnormal coronary vasomotor function may indeed be regarded as an useful integrating index of the overall stress burden imposed by various coronary risk factors on the arterial wall, taking into account the cumulative risk of coronary risk factors and as yet unknown variables and genetic predispositions (1,25). This notion is supported by findings in the clinical assessment of coronary vascular function (3,4), which have demonstrated that, even in the presence of atherosclerosis, endothelial dysfunction of the coronary circulation remains an independent predictor of disease progression and cardiovascular events. These important findings attest to the results of Nishimura et al. (26), which revealed a dissociation between endothelial-dependent coronary vasoreactivity to acetylcholine stimulation and the atherosclerotic burden of the arterial wall as assessed by intravascular ultrasound. It then follows that functional alterations of coronary vasomotion may provide a reflection of on-going processes that modify the functional status of the vessel wall. In contrast, morphological changes of the epicardial vessels as assessed by intravascular ultrasound or the noninvasive with X-ray-computed-tomography-measured epicardial calcification may represent the propensity of the individual to develop atherosclerotic plaque burden as a consequence to long-lasting effects of coronary risk factors (23,26). In this setting, it may be intriguing to speculate that functional alterations of coronary vasomotion may provide a reliable measure in predicting short-term risk, while noninvasive measures of coronary calcium burden may reflect more the long-term risk (3,4,23,26). Because abnormal coronary vascular function has been implicated as an early event in the development and progression of atherosclerosis, improvement of functional disorders of the coronary vessels by a variety of interventions such as angiotensin-converting enzyme inhibitors, statins, physical exercise, and antioxidants has become of general interest (1,17). Importantly, whether medical intervention tailored to reverse abnormal coronary vascular function is, indeed, related to an improvement in clinical outcome remains to be established (27). The assessment of MBF alterations to sympathetic stimulation and/or pharmacologically induced hyperemia by PET imaging could be a promising tool in patient care management to successfully guide preventive medical intervention. Conceptually, PET-determined changes in MBF could also be used as a surrogate marker for the evaluation of new therapeutic strategies.
Study limitations.
There are limitations worthy of consideration in interpreting our data. First, although only a minority of the study population had diabetes, we cannot exclude that, in these patients, diabetic neuropathy could have potentially affected the MBF responses to CPT (28). Second, we did not perform intravascular ultrasound to assess the epicardial wall structure. Therefore, we cannot rule out the presence of diffuse atherosclerosis or eccentric plaques of the epicardial coronary arteries. Third, the results presented were obtained from a group of patients referred for coronary angiography to evaluate persistent chest pain. Thus, these findings may not necessarily be generalizable to patients in a primary care setting. Fourth, the three groups in our study differed significantly with regard to traditional coronary risk factors. This fact univariately explains some of the differences in the incidence of cardiovascular events between the groups. Yet, as shown in a multivariate analysis, adjusting for traditional coronary risk factors, impaired MBF increases to CPT revealed a trend to be independently associated with the risk of developing cardiovascular events, though statistically the trend only reached borderline significance (p = 0.065). When the analysis was limited to cardiac end points, however, no trend of an independent predictive value of impaired MBF increases to CPT was found any longer (p = 0.506). In view of the relatively small sample size of the study population and the borderline predictive value of impaired MBF increases to CPT for a poor clinical outcome, the current study does not provide definite answers but may stimulate further clinical investigations in this evolving research field. Consequently, to determine definite conclusions regarding an incremental prognostic value of abnormal MBF responses to CPT, larger prospective investigations in patients with hemodynamically nonobstructive coronary artery disease, similar risk profile, and/or at low risk are needed. Finally, because we did not determine the MBF increase to pharmacologic vasodilation in these patients, further clinical studies are necessary to explore the prognostic implications of noninvasive PET-measured MBF increases to pharmacologic vasodilation.
Conclusions.
In patients with normal coronary angiograms, impaired MBF increases attributable to sympathetic activation, as assessed noninvasively with PET, are associated with the risk of developing cardiovascular events.
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Footnotes
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This work was supported by grants from the German Research Foundation (So 241/2-2) and Baden-Württemberg (Projekt: Sch-A1/A2) and by grant HL 331777, National Heart, Lung, and Blood Institute, Bethesda, Maryland.
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