Sex-Differences in the Impact of Metabolic Syndrome on Tissue Plasminogen Activator–Induced Recanalization
To the Editor:
We read with interest the recent article by Arenillas and colleagues investigating gender-specific differences in the impact of metabolic syndrome (MetS) on the resistance of intravenous thrombolysis in stroke patients with acute middle cerebral artery (MCA) occlusions.1 The authors detected sex differences in the impact of MetS on tissue plasminogen activator (tPA)-induced thrombolysis and concluded that MetS was associated with a higher resistance to systemic thrombolysis in women than in men.
Before accepting these provocative findings, we consider that certain methodological issues of this interesting study may need further clarification. First, the authors used the TIBI (Thrombolysis in Brain Infarction) criteria for diagnosing MCA occlusions as well as defining recanalization status.2 Moreover, they state that in patients with absent temporal windows bolus injections of echocontrast agents were administered to identify and grade residual flow signatures. However, it should be noted that the TIBI criteria were specifically developed to grade residual flow in patients with acute proximal arterial occlusions in the absence of administration of any contrast agents, which greatly influence residual blood flow signatures by changing the signal-to-noise ratio and artificially increasing velocities detected by spectral Doppler (“blooming effect”).3 Furthermore, the ultrasound diagnosis of partial or complete recanalization on the basis of improvement of 1 TIBI flow grade may lead to false-positive results, because small flow aberrations or improved flow attributable to changing quality of flow detection due to the “blooming effect” of contrast agents may give an erroneous impression of recanalization.4
Second, Arenillas et al evaluated both proximal and distal MCA occlusions. Of note though is that the ultrasonographic criteria used for detection of these proximal arterial lesions warrant further discussion. More specifically, the insonation depth used to explore MCA was set between 40 and 65 mm. Because the range of depth for identification of proximal and distal MCA lies between 30 to 44 mm and 45 to 65 mm, respectively,2,4,5 one may assume that numerous patients with distal MCA occlusions may have been excluded from the present study on the basis of the adopted ultrasonographic criteria. Third, it seems counterintuitive that men with MetS had higher recanalization rates in comparison to women, because tandem ICA (internal carotid artery)/MCA occlusions were almost 4 times more common in men than in women (atherothrombotic infarction: 39% in men and 10% in women). Given the fact that tandem ICA/MCA occlusions have been repeatedly shown to be the most resistant to tPA-induced recanalization,6 it would be interesting for the authors to provide a likely explanation reconciling the gender-specific disparities between location of occlusion/clot burden (tandem ICA/MCA occlusion versus isolated MCA occlusion) and recanalization rates. Fourth, the statement that MetS was an independent predictor of poor functional outcome at 3 months seems to overinterpret the study findings, because in the multivariate logistic regression models the response to thrombolysis at 24 hours was not included as a potential confounder.
In conclusion, we agree with the closing statement of the authors that the documented gender-difference in the impact of MetS on tPA-induced recanalization is an intriguing finding that cannot be sufficiently explained by the available data and needs to be replicated in a larger and independent series of patients.
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 intravenous thrombolysis for acute ischemic stroke in women than in men. Stroke. 2009; 40: 344–349.
Demchuk AM, Burgin WS, Christou I, Felberg RA, Barber PA, Hill MD, Alexandrov AV. Thrombolysis in Brain Ischemia (TIBI) TCD flow grades predict clinical severity, early recovery and mortality in intravenous tPA treated subjects. Stroke. 2001; 32: 89–90.
Forsberg F, Liu JB, Burns PN, Merton DA, Goldberg BB. Artifacts in ultrasonic contrast agent studies. J Ultrasound Med. 1994; 13: 357–365.
Alexandrov AV, Mikulik R, Ribo M, Sharma VK, Lao AY, Tsivgoulis G, Sugg RM, Barreto A, Sierzenski P, Malkoff MD, Grotta JC. A pilot randomized clinical safety study of sonothrombolysis augmentation with ultrasound-activated perflutren-lipid microspheres for acute ischemic stroke. Stroke. 2008; 39: 1464–1469.
Tsivgoulis G, Saqqur M, Sharma VK, Lao AY, Hill MD, Alexandrov AV; CLOTBUST Investigators. Association of pretreatment blood pressure with tissue plasminogen activator-induced arterial recanalization in acute ischemic stroke. Stroke. 2007; 38: 961–966.
Kim YS, Garami Z, Mikulik R, Molina CA, Alexandrov AV; CLOTBUST Collaborators. Early recanalization rates and clinical outcomes in patients with tandem internal carotid artery/middle cerebral artery occlusion and isolated middle cerebral artery occlusion. Stroke. 2005; 36: 869–871.