Response to Letter by Tsivgoulis et al
We greatly appreciate the interest shown by Tsivgoulis and colleagues in their letter commenting on our recent article about the sex differences in the impact of metabolic syndrome (MetS) on the response to intravenous thrombolysis for acute middle cerebral artery (MCA) ischemic stroke.1 In our study, performed in a series of 125 consecutive patients with a documented acute MCA occlusion who were treated with intravenous tissue plasminogen activator (t-PA) according to SITS-MOST criteria, we observed that the effect of MetS enhancing the resistance to thrombolysis seemed to be more pronounced in women than in men.2 In this response we will try to address the valuable criticisms raised by Tsivgoulis et al in their letter.
The first comment refers to the use of echo-contrast agents in patients without an adequate temporal acoustic window precluding transcranial Doppler (TCD) assessment of MCA. We agree with the authors that contrast agents influence residual flow signatures by artificially increasing velocities detected by TCD, the so-called “blooming effect.”3 This being true, we believe that this methodological issue is not likely to have affected our main results because of several reasons. First, the proportion of patients with poor temporal windows for TCD in our laboratory is low (10% to 15%), which implies that only around 15 participants in our study may have needed contrast agents for TCD assessment. Second, the potential influence of the blooming effect on the reliability of TCD diagnosis in acute stroke can be minimized by considering the following aspects in the examination protocol: (1) the blooming effect reaches its maximal intensity during the first moments after contrast injection, and therefore the examiner should wait until the signal-to-noise ratio is less distorted; (2) stable echo-contrasts, such as the one used in our study (Sonovue), have a longer active life, allowing us to obtain well defined TCD signals during longer time-periods; (3) to best evaluate the blooming effect, we should also study the nonaffected MCA after injecting the contrast, paying attention to side-to-side asymmetries to define the TIBI grade; (4) TCD gain and power controls can be modified in order to progressively adapt the signal-to-noise ratio to the echo-contrast concentration. And third, regarding the possibility that contrast agents may give an erroneous impression of partial recanalization, this potential limitation cannot affect our study results, given that in our protocol we only considered complete MCA recanalization (TIBI grades 4 and 5) as assessed by TCD performed 24 hours after t-PA administration.
The second observation refers to the insonation depth used to identify MCA. The authors claim that the specified depth in our protocol (40 to 65 mm) may have lead to a misdiagnosis of MCA occlusion. We believe that the identification of proximal and distal MCA based on rigid ranges of depth, as suggested by the authors, is only an approximate approach. Therefore, our definition of proximal and distal MCA occlusion is not based on insonation depth, but on the worst flow signal determined at the presumed occlusion site.4 This way of classifying MCA occlusions has been validated in the literature by groups with large experience in acute stroke TCD.5 Anyhow, although TCD is a well established method to detect acute intracranial arterial occlusions, its main limitations may be overcome by transcranial color-coded ultrasound (TCCD), and therefore we are currently trying to replicate our findings in a prospective study using TCCD-based criteria to define arterial occlusion and recanalization.
Their third criticism is related to the fact that the MetS-gender interaction observed despite atherothrombotic infarction was more frequent in men, being resistant to lysis more frequently in patients with atherothrombotic stroke (Table 2). This finding was also very intriguing for us, as we explicitly mentioned in the Discussion section of the article. The MetS was associated with a higher resistance to t-PA–induced recanalization in both genders, but this association was more powerful in women. Of note, this sex-interaction was independent of stroke etiology, given that the multivariable logistic-regression model was also adjusted by this variable. Our hypothesis to explain these findings is that the derangement of the endogenous fibrinolytic system related to MetS may be more pronounced in postmenopausal women than in men. Of course, this important issue raised by Tsivgoulis et al warrants further study.
Finally, the authors of the letter argue that response to thrombolysis at 24 hours was not included as a potential confounder in the multivariate regression model that identified MetS as a predictor of poor long-term outcome. Arterial status at 24 hours is the result of the recanalization process and therefore a well indicator of the response to t-PA therapy. Therefore, in our study we have considered 24-hour recanalization as an outcome variable and not as a baseline variable. One of the main interests in our group is to identify clinical, radiological and biological factors which may characterize those patients with a lower probability of achieving early arterial recanalization after thrombolysis, who may benefit from more aggressive reperfusion modalities. In this context, our predictive model included only those variables that could be determined at baseline before t-PA administration.
The potential role of MetS enhancing the resistance to thrombolysis for acute ischemic stroke represents a fascinating scientific challenge and has become one important research line for our group.6 Further studies are needed to confirm the hypothesis raised by our first works in this field, and also to go beyond trying to identify the underlying molecular pathways.
Tsivgoulis G, Voumvourakis K, Stamboulis E. Sex-differences in the impact of metabolic syndrome on tPA-induced recanalization. Stroke. 2009; [e-pub ahead of print].
Arenillas JF, Sandoval P, Pérez de la Ossa N, Millán M, Guerrero C, Escudero D, Dorado L, López-Cancio E, Castillo J, Dávalos A. The metabolic syndrome is associated with a higher resistance to thrombolysis for acute ischemic stroke in women than in men. Stroke. 2009; 40: 344–349.
Forsberg F, Liu JB, Burns PN, Merton DA, Goldberg BB. Artifacts in ultrasonic contrast agent studies. J Ultrasound Med. 1994; 13: 357–365.
Demchuk AM, Burgin WS, Christou I, Felberg RA, Barber PA, Hill MD, Alexandrov AV. Thrombolysis in brain ischemia (TIBI) transcranial Doppler flow grades predict clinical severity, early recovery, and mortality in patients treated with intravenous tissue plasminogen activator. Stroke. 2001; 32: 89–93.
Molina CA, Montaner J, Abilleira S, Arenillas JF, Ribó M, Huertas R, Romero F, Alvarez-Sabín J. Time course of tissue plasminogen activator-induced recanalization in acute cardioembolic stroke: a case-control study. Stroke. 2001; 32: 2821–2827.
Arenillas JF, Ispierto L, Millán M, Escudero D, Pérez de la Ossa N, Dorado L, Guerrero C, Serena J, Castillo J, Dávalos A. Metabolic syndrome and resistance to IV thrombolysis in middle cerebral artery ischemic stroke. Neurology. 2008; 71: 190–195.