Impact of oxygen extraction fraction on long-term prognosis in patients with reduced blood flow and vasoreactivity because of occlusive carotid artery disease

Abstract

Background

Reduced cerebral blood flow and cerebrovascular reactivity to acetazolamide (type 3 ischemia) is believed as an independent predictor for subsequent ischemic stroke in patients with occlusive carotid artery diseases. However, recent studies have shown that type 3 patients can be divided into 2 pathophysiologically different subgroups as follows: those with elevated OEF and those with normal OEF. This study was aimed to clarify whether there is a difference in the prognosis between patients with type 3 and elevated OEF and those with type 3 but normal OEF.

Methods

Twenty type 3 patients were enrolled in this prospective, longitudinal cohort study. Hemodynamic and metabolic parameters were quantitatively determined by ¹⁵O-gas PET. All of them were medically treated.

Results

Oxygen extraction fraction was elevated in 9 patients but was normal in other 11. During an average follow-up period of 45.6 months, 3 of 9 patients with type 3 and elevated OEF developed ipsilateral ischemic stroke. The annual risk was 10.6%. The location and shape of cerebral infarction strongly suggested a key role of hemodynamic compromise in their recurrence. On the other hand, no subsequent stroke occurred in none of 11 patients with type 3 but normal OEF. There was a statistically significant difference in the incidence of ipsilateral ischemic stroke between 2 groups (P = .0303).

Conclusion

Type 3 patients may be categorized into 2 subgroups as follows: those with elevated OEF and higher stroke risk and those with normal OEF and lower stroke risk, although larger number of subjects should be analyzed.

Introduction

Nowadays, it has been widely accepted that patients with hemodynamic compromise because of ICA occlusion are at higher risk for subsequent ischemic stroke [4], [27], [10], [22], [26], [32]. Positron emission tomography can determine OEF by assessing the balance between blood flow supply and metabolic demand. An elevation of OEF is called a “misery-perfusion syndrome” or “stage II ischemia” and has been accepted as a gold standard to verify hemodynamic compromise for these 25 years [1], [23]. Thus, several prospective studies have shown that elevated OEF is an independent predictor for subsequent stroke in patients with symptomatic ICA occlusion. The relative risk conferred by an elevated OEF was 6.4 to 7.3 for ipsilateral stroke [4], [27]. Recently, CVR to acetazolamide has been proven as an alternative predictor in patients with occlusive carotid artery diseases [10], [22], [26], [32]. Thus, the relative risk conferred by reduced CBF and CVR (type 3 ischemia) was 8.0 for ipsilateral stroke [10]. The findings suggest that the patients at higher risk for subsequent stroke can be identified at lower cost than PET because CVR can be determined by SPECT [10], [22].

However, it is still controversial whether impaired CVR is directly linked to OEF elevation in patients with occlusive carotid artery diseases. Thus, previous studies have reported a significant correlation between OEF and CVR [7], [8], [19]. On the other hand, recent studies have clarified that an elevated OEF and impaired CVR do not always represent same conditions in ischemic brain [13], [20]. Thus, Nemoto et al (2004) [20] measured OEF and CVR in 12 patients with ICA occlusion and found that 37.5% of the hemispheres had reduced CVR but normal OEF. Kuroda et al (2006) [13] also measured PET parameters in 46 patients with reduced CBF and CVR (type 3 ischemia) because of occlusive carotid artery diseases. As a result, OEF was significantly elevated in 20 (43.5%) of 46 type 3 patients. They also determined the binding potential for ¹¹C-FMZ, a radioactive ligand for neuron-specific receptor, and showed that OEF was significantly correlated with CMRo₂ and ¹¹C-FMZ binding potential. These findings strongly suggest that type 3 patients with a reduced CBF and CVR can be divided into 2 pathophysiologically different subgroups as follows: misery perfusion because of hemodynamic compromise and matched hypometabolism because of incomplete infarction. However, it is still undetermined if there is a clinical significance to evaluate OEF values in type 3 patients. For example, is there any difference in long-term prognosis between 2 subgroups? Can hemodynamic ischemia be a main mechanism for subsequent ischemic stroke? These questions are quite important to predict their outcome and decide therapeutic options in clinical situation. Therefore, in this prospective study, we determined PET parameters in type 3 patients with occlusive carotid artery diseases and assessed their long-term prognosis and the pattern of recurrent cerebral infarction.