RECENT RESEARCH IN Heart-Brain Medicine

Protective effects of beta-blockers in cerebrovascular disease

Somchai Laowattana, MD, PhD

 

Stephen M. Oppenheimer, MD, PhD

soppenh@hotmail.com

ABSTRACT

Because activated sympathetic tone is associated with poorer outcome after stroke, we investigated whether beta-blocker treatment was associated with lesser stroke severity and improved outcome.

METHOD

We prospectively studied 111 patients with stroke. Stroke severity on presentation gauged by Canadian Neurologic Scale (CanNS) and medication use verified from medical records. Power spectral analysis of heart rate variability estimated cardiac sympathovagal tone. Coagulation and inflammatory activity were assessed.

RESULTS

On multiple linear regression, beta-blocker use was the sole independent predictor of less severe stroke on presentation (95% CI: 0.12 to 1.86: p 0.03). When CanNS was dichotomized, multiple logistic regression revealed that beta-blocker use (odds ratio [OR] 3.70, 95% CI: 1.24 to 11.01,
p 0.02) and female gender (OR 2.96, 95% CI: 1.14 to 7.69, p 0.03) were independent predictors of CanNS score 8.5. There was no difference in blood pressure and blood glucose between these two groups. Beta-blocker treatment was associated with lower sympathovagal tone (p 0.001), thrombin (p 0.009), hemoglobin A1C levels (p 0.02), and erythrocyte sedimentation rate (p 0.003).

CONCLUSION

Beta-blocker use is associated with less severe stroke on presentation and may be cerebroprotective due to a sympatholytic effect associated with decreased thrombin, inflammation, and hemoglobin A1C.

CITATIONS

  1. Hachinski VC, Smith KE, Silver MD, Gibson CJ, Ciriello J.
    Acute myocardial and plasma catecholamine changes in experimental stroke. Stroke 1986;17:387–390.
    http://www.ncbi.nlm.nih.gov/pubmed/3715933

  2. Cechetto DF, Wilson JX, Smith KE, Wolski D, Malcolm DS, Hachinski VC.
    Autonomic and myocardial changes in middle cerebral artery occlusion: stroke models in rat. Brain Res 1989;502:296–305.
    http://www.ncbi.nlm.nih.gov/pubmed/2819468
  3. Smith KE, Ciriello J, Hachinski VC, Gibson C.
    Altered sympathetic activity after experimental stroke. Can J Neurol Sci 1985;12:177–178.
  4. Myers M, Norris JW, Hachinski VC.
    Plasma norepinephrine in stroke. Stroke 1981;12:200–204.
    http://www.ncbi.nlm.nih.gov/pubmed/7233464
  5. Sander D, Winbeck K, Klingelhofer J, Etgen T, Conrad B.
    Prognostic relevance of pathological sympathetic activation after acute thromboembolic
    stroke. Neurology 2001;57:833–838.
    http://www.ncbi.nlm.nih.gov/pubmed/11552013
  6. Amory DW, Grigore A, Amory JK ,.
    Neuroprotection is associated with beta-adrenergic receptor antagonists during cardiac surgery: evidence from 2575 patients. J Cardiothorac Vasc Anesth 2002;16:270–277.
    http://www.ncbi.nlm.nih.gov/pubmed/12073195
  7. Savitz SI, Erhardt JA, Anthony JV, et al.
    The novel beta-blocker, Carvedilol, provides neuroprotection in transient focal stroke. J Cereb
    Blood Flow Metab 2000;20:1197–1204.
    http://www.ncbi.nlm.nih.gov/pubmed/10950380
  8. Pendleton RG, Newman DJ, Sherman SS, et al.
    Effect of propanolol upon the hemoglobin-oxygen dissociation curve. J Pharmacol Exp Ther
    1962;180:647–656.
    http://www.ncbi.nlm.nih.gov/pubmed/4401159
  9. Anderson R, Ramafil G, Theron AJ.
    Membrane stabilizing, antioxidative interactions of propanolol and dexpropanolol with neutrophils. Biochem Pharmacol 1996;52:341–349.
    http://www.ncbi.nlm.nih.gov/pubmed/8694859
  10. Osborne NN, Wood JPM, Childlow G, Casson R, DeSantis L, Schmidt KG.
    Effectiveness of levobetaxolol and timolol at blunting retinal ischaemia is related to their calcium and sodium blocking activities: relevance to glaucoma. Brain Res Bull 2004;62:525–528.
    http://www.ncbi.nlm.nih.gov/pubmed/15036567
  11. Sozzani S, Agwu DE, McCall CE, et al.
    Propanolol, a phosphatidate phosphohydrolase inhibitor, also inhibits protein kinase C. J Biol Chem 1992;267:20481–20488.
    http://www.ncbi.nlm.nih.gov/pubmed/1328200
  12. Koul O, Hauser G.
    Modulation of rat brain cytosolic phosphatidate phosphohydrolase: effect of cationic amphiphilic drugs and divalent cations. Arch Biochem Biophys 1987;253:453–461.
    http://www.ncbi.nlm.nih.gov/pubmed/3032105
  13. Stavem K, Lossius M, Ronning OM.
    Reliability and validity of the Canadian Neurological Scale in retrospective assessment of initial
    stroke severity. Cerebrovasc Dis 2003;16:286–291.
    http://www.ncbi.nlm.nih.gov/pubmed/12865618
  14. Cote R, Hachinski VC, Shurvell BL, Norris JW, Wolfson C.
    The Canadian Neurological Scale: a preliminary study in acute stroke. Stroke 1986;17:731–737.
    http://www.ncbi.nlm.nih.gov/pubmed/3738958
  15. Cote R, Battista RN, Wolfson C, Boucher J, Adam J, Hachinski VC.
    The Canadian Neurological Scale: validation and reliability assessment. Neurology 1989;39:638–643.
    http://www.ncbi.nlm.nih.gov/pubmed/2710353
  16. Muir KW, Weir CJ, Marray GD, Povey C, Lees KR.
    Comparison of neurological scales and scoring for acute stroke prognosis. Stroke 1996;
    27:1817–1820.
    http://www.ncbi.nlm.nih.gov/pubmed/8841337
  17. Jalife J, Michales DC.
    Neural control of sinoatrial pacemaker activity. In Levy MN, Schwartz PJ, eds. Vagal control of the heart: experimental basis and clinical implications. Armonk, NY: Futura 1994:173–205.
  18. Akselrod S, Gordon D, Ubel FA, Shannon DC, Barger AC, Cohen RJ.
    Power spectrum analysis of heart rate fluctuation: a quantitative probe of beat to beat cardiovascular control. Science 1981;213:220–222.
    http://www.ncbi.nlm.nih.gov/pubmed/6166045
  19. Natelson BH.
    Neurocardiology: an interdisciplinary area of the 80s. Arch Neurol 1985;42:178–184.
    http://www.ncbi.nlm.nih.gov/pubmed/3883960
  20. Pomeranz M, Macaulay RJB, Caudill MA, Kutz I, Adam D, Gordon D, et al.
    Assessment of autonomic function in humans by heart rate spectral analysis. Am J Physiol 1985;248:h351–h353.
    http://www.ncbi.nlm.nih.gov/pubmed/3970172
  21. Malliani A, Pagani M, Lombardi F, Cerutti S.
    Cardiovascular neural regulation explored in the frequency domain. Circulation 1991;84:1482–
    1492.
    http://www.ncbi.nlm.nih.gov/pubmed/1860193
  22. Oppenheimer SM.
    The broken heart: noninvasive measurement of cardiac autonomic tone. J R Soc Med 1962;68:939–941.
  23. Kamath MV, Fallen EL.
    Power spectral analysis of heart rate variability: a noninvasive signature of cardiac autonomic function. Crit Rev Biomed Eng 1993;21:245–311.
    http://www.ncbi.nlm.nih.gov/pubmed/8243093
  24. Martin WM.
    Changes in cardiovascular autonomic tone in patients suffering from left insular cortex lesions, as studied using a specially designed portable cardiovascular autonomic data acquisition platform. Master of Science in Engineering Thesis. Johns Hopkins University, 1993.     
    February 13, 2007 NEUROLOGY 68 513
  25. Sanossian N, Saver JL, Rajajee V, et al.
    Premorbid antiplatelet use and ischemic stroke outcome. Neurology 2006;66:319–323.
    http://www.ncbi.nlm.nih.gov/pubmed/16382033
  26. Elkind MSV, Flint AC, Sciacca RR, Sacco RL.
    Lipid-lowering agent use at ischemic stroke onset is associated with decreased mortality. Neurology 2005;65:253–258.
    http://www.ncbi.nlm.nih.gov/pubmed/16043795
  27. Hasko G, Szabo C.
    Regulation of cytokine and chemokine production by transmitters and co-transmitters of the autonomic nervous system. Biochem Pharmacol 1998;56:1079–1087.
    http://www.ncbi.nlm.nih.gov/pubmed/9802316
  28. Madden KS, Sanders VM, Felten DL.
    Catecholamine influences and sympathetic neural mechanism of immune responsiveness. Annu Rev Pharmacol Toxicol 1995;35:417–448.
    http://www.ncbi.nlm.nih.gov/pubmed/7598501
  29. Audebert HJ, Rott MM, Eck T, Haberl RL.
    Systemic inflammatory response depends on initial stroke severity but is attenuated by successful thrombolysis. Stroke 2004;35:2128–33.
    http://www.ncbi.nlm.nih.gov/pubmed/15272127
  30. Smith CJ, Emsley HC, Gavin CM, et al.
    Peak plasma interleukin-6 and other peripheral markers of inflammation in the first week of ischemic stroke correlate with brain infarct volume, stroke severity and longterm outcome. BMC Neurol 2004;4:2–.
    http://www.ncbi.nlm.nih.gov/pubmed/14725719
  31. Zaremba J, Losy J.
    Early TNF-alpha levels correlate with ischemic stroke severity. Acta Neurol Scand 2001;104:288–95.
    http://www.ncbi.nlm.nih.gov/pubmed/11696023
  32. Kawano TA, Aoki N, Homori M, et al.
    Mental stress and physical exercise increase platelet-dependent thrombin generation. Heart Vessels 2000;15:280–288.
    http://www.ncbi.nlm.nih.gov/pubmed/11766066
  33. Rashid SR, Shi ZQ, Niwa M, et al.
    Beta-blockade, but not normoglycemia or hyperinsulinemia, markedly diminishes stress-induced hyperglycemia in diabetic dogs. Diabetes 2000;49:253–262.
    http://www.ncbi.nlm.nih.gov/pubmed/10868942
  34. Geor RJ, Hinchcliff KW, Sams RA.
    Beta-adrenergic blockade augments glucose utilization in horses during graded exercise. J Appl Physiol 2000;89:1086–1098.
    http://www.ncbi.nlm.nih.gov/pubmed/10956355
  35. Kaarisalo MM, Raiha I, Sivenius J, et al.
    Diabetes worsens the outcome of ischemic stroke. Diabetes Res Clin Pract 2005;69:293–298.
    http://www.ncbi.nlm.nih.gov/pubmed/16098927
  36. Megherbi SE, Milan C, Minier D, et al.
    Association between diabetes and stroke subtype on survival and functional outcome 3 months after stroke: data from European BIOMED Stroke Project. Stroke 2003;34:
    688–694.
    http://www.ncbi.nlm.nih.gov/pubmed/12624292
  37. Oppenheimer SM, Hoffbrand BI, Oswald GA, Yudkin JS.
    Diabetes mellitus and early mortality from stroke. BMJ 1985;291:1014–1015.
    http://www.ncbi.nlm.nih.gov/pubmed/3931771
  38. Ricci S, Lewis S, Sandercock P, et al.
    Previous use of aspirin and baseline stroke severity: an analysis of 17,850 patients in the International Stroke Trial. Stroke 2006;37:1737–1740.
    http://www.ncbi.nlm.nih.gov/pubmed/16741185
  39. Greisenegger S, Mullner M, Tentschert S, Lang W, Lalouschek W.
    Effect of pretreatment with statins on the severity of acute ischemic cerebrovascular events. J Neurol Sci 2004;221:5–10.
    http://www.ncbi.nlm.nih.gov/pubmed/15178206
  40. Dahlof B, Devereux RB, Kjeldsen SE, et al.
    Cardiovascular morbidity and mortality in the Losartan Intervention for Endpoint Reduction in
    Hypertension Study (LIFE): a randomised trial against atenolol. Lancet 2002;359:995–1003.
    http://www.ncbi.nlm.nih.gov/pubmed/11937178
  41. Lindholm LH, Carlberg B, Samuelsson O.
    Should beta-blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet 2005;366:1545–1553.
    http://www.ncbi.nlm.nih.gov/pubmed/16257341
  42. Rashid P, Leonardi-Bee J, Bath P.
    Blood pressure reduction and secondary prevention of stroke and other vascular events: a systemic review. Stroke 2003;34:2741–2748.
    http://www.ncbi.nlm.nih.gov/pubmed/14576382
  43. Sacco RL, Adams R, Albers G, et al.
    Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: A statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke. Stroke 2006;37:577–617.
    http://www.ncbi.nlm.nih.gov/pubmed/16432246
  44. Dulli D, Stanko H, Levine RL.
    Atrial fibrillation is associated with severe acute ischemic stroke. Neuroepidemiology 2003;22:118–123.
    http://www.ncbi.nlm.nih.gov/pubmed/12629277
  45. Hajat C, Hajat S, Sharma P.
    Effects of poststroke pyrexia on stroke outcome. A meta-analysis of studies in patients. Stroke 2000;31:410– 414.
    http://www.ncbi.nlm.nih.gov/pubmed/10657414
  46. Castillo J, Da´valos A, Marrugat J, Noya M.
    Timing for fever-related brain damage in acute ischemic stroke. Stroke 1998;29:2455–2460.
    http://www.ncbi.nlm.nih.gov/pubmed/9836750
  47. Marquardt L, Ruf A, Mansmann U et al..
    Inflammatory response after acute ischemic stroke. J Neurol Sci 2005;236:65–71.
    http://www.ncbi.nlm.nih.gov/pubmed/15961109
  48. Macin SM, Perna ER, Farias EF, et al.
    Atorvastatin has an important acute anti-inflammatory effect in patients with acute coronary syndrome: results of a randomized, double-blind, placebo-controlled study.
    Am Heart J 2005;149:451–457.
    http://www.ncbi.nlm.nih.gov/pubmed/15864233