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Archived Comments for: Effect of pre-stroke use of ACE inhibitors on ischemic stroke severity

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  1. ACEI and ischemic stroke: hope versus clinical reality

    Vinod Gupta, Dubai Police Medical Services, Dubai, United Arab Emirates

    7 July 2005

    Selim and colleagues evaluate the effect of pre-treatment with angiotensin-converting enzyme inhibitors (ACEI) on the severity of ischemic stroke [1]. Despite finding no significant difference in clinical and magnetic resonance imaging findings between patients on ACEI prior to their strokes and non-ACEI treated patients, these authors maintain the belief that ACEI may reduce the clinical severity of (ischemic) stroke and suggest further large-scale prospective studies. Unfortunately, it is a clinical truism that large clinical studies – trials or meta-analyses – hardly ever elucidate disease mechanisms; in fact, these studies are not designed to obtain further mechanistic insights into pathophysiology [2, 3]. Larger the clinical study, greater is the dependence on statistics (mathematical logic) with distancing from biological commonsense. While large clinical studies or meta-analyses might disprove a hypothesis, they seldom (never?) prove a hypothesis. A multitude of known factors and possibly several unknown factors influence the development of stoke in an individual. It is highly unlikely that the statistically insignificant result in this study will, as suggested by these authors [1], translate into a biologically meaningful result in a larger prospective study. If there is indeed a direct brain neuroprotective effect of ACEI without any significant reduction in the blood pressure (BP) [4], we must consider in detail not only the possible underlying mechanisms but the clinical context in which such a study has been conducted. The next practical step in this direction is to consider whether ACEI might be added to the standard therapeutic regimen of stroke-prone patients without congestive heart failure (CHF) to prevent strokes or reduce their clinical impact.

    CHF itself, is probably the most important factor that confounds this study in a manner that cannot be resolved by statistics. Second, all ACEI have a prominent peripheral vasodilator effect independent of their anti-hypertensive effect; in effect, all ACEI are potent cerebral vasodilators [5]. The vasodilator effect of ACEI is probably mediated by bradykinin [6,7]. Whereas CHF is unambiguously associated with sympathetic nervous system hyperexcitation and peripheral arterial vasoconstriction (that includes the cerebral circulation), ACEI induce peripheral arterial vasodilatation. Use of ACEI in CHF, therefore, induces a state of cerebral arterial flux, a variability that cannot be comparable between patients. Third, not only did the investigators not collect data about duration and compliance with ACEI therapy [1], they have grouped and compared patients with and without CHF. The direct effects of sympathetic activation on platelet activation and aggregation are well known; its association with vasopressin activation is less well known [8] but is clinically relevant. The results of the study have not (and cannot be) mathematically adjusted for differences in autonomic nervous system activation between patients with and without CHF.

    CHF has a prominent decremental effect on coronary atherosclerosis, an influence best seen in dilated (congestive) cardiomyopthy (DCM). The coronary arteries are normal in DCM and even in Western countries atheroma is usually conspicuous by its absence [9]. Most patients (59%) with DCM do not manifest enhancement during gadolinium cardiovascular magnetic resonance [10]. There do no appear to be any studies on the influence of CHF on ischemic stroke. Barring stasis-induced thromboembolism, there is no known predilection of CHF to manifest ischemic stroke. The ostial and peri-bifurcation location of atherosclerotic plaques, nevertheless, indicates a critical role for rheological stress. With fall in cardiac stroke volume, rheological stress in the cranial arteries including the internal carotids and the vertebro-basilar systems would decrease proportionately. Increasing the cardiac stroke volume to normal or near-normal levels by ACEI restores the rheological stress that underlies atherosclerosis.

    The propensity of ACEI-treated patients to develop lacunar infarcts, while statistically insignificant [1], is biologically significant. ACEI are basically vasodilators and lacunar infarcts appear related to brain hyperperfusion [11,12]. Also, in patients with CHF, because of the increased afterload, the BP no longer remains an accurate marker of peripheral tissue perfusion. Given the tendency of perindopril to increase cerebral blood flow beyond alteration of BP [13], ACEI should probably not be prescribed to patients with lacunar infarction. Finally, the discrepancy between clinical and radiological measures of stroke severity seen in this study [1] is not reconcilable since non-dominant hemisphere strokes were evenly distributed. There is no reason why a generalized circulatory defect should preferentially or randomly affect the non-dominant hemisphere, and, such reasoning is circular.

    In summary, studies of long-term ACEI administration for ameliorating the effects of or preventing ischemic stroke in patients with CHF face formidable difficulties primarily involving disturbance of circulatory physiological mechanisms by CHF itself. The key question is: would we use ACEI for ischemic stroke prevention or amelioration for a normotensive patient without CHF? Currently, the answer appears to be in the negative. Future studies of the role of ACEI in neuroprotection must not ignore the fundamental alterations in neuro-cardiac circulation discussed herein.


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    Competing interests