Rho-kinase inhibition with intracoronary fasudil prevents myocardial ischemia in patients with coronary microvascular spasm.
OBJECTIVE
We sought to determine whether a potent Rho-kinase inhibitor fasudil prevents the occurrence of myocardial ischemia in patients with microvascular angina attributable to coronary microvascular spasm.


BACKGROUND
Effective treatment of patients with angina who have normal coronary arteriograms (microvascular angina) has not yet been established. Rho-kinase-mediated calcium sensitization of the myosin light chain in smooth muscle cells has been implicated as substantially contributing to vascular hyperconstriction.


METHODS
We studied consecutive 18 patients with angina and normal epicardial coronaries in whom intracoronary acetylcholine (ACh) induced myocardial ischemia (ischemic electrocardiographic changes, myocardial lactate production, or both) without angiographically demonstrable epicardial coronary vasospasm. All patients underwent a second ACh challenge test after pretreatment with either saline (n = 5) or fasudil (4.5 mg intracoronarily, n = 13).


RESULTS
Myocardial ischemia was reproducibly induced by ACh in the saline group. In contrast, 11 of the 13 patients pretreated with fasudil had no evidence of myocardial ischemia during the second infusion of ACh (p < 0.01). The lactate extraction ratio (median value [interquartile range]) during ACh infusion was improved by fasudil pretreatment, from -0.16 (-0.25 to 0.04) to 0.09 (0.05 to 0.18) (p = 0.0125).


CONCLUSIONS
Fasudil ameliorated myocardial ischemia in patients who were most likely having coronary microvascular spasm. The inhibition of Rho-kinase may be a novel therapeutic strategy for this group of patients with microvascular angina.
Mohri
Masahiro
M
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan. mmohri@med.kyushu-u.ac.jp
Shimokawa
Hiroaki
H
Hirakawa
Yoji
Y
Masumoto
Akihiro
A
Takeshita
Akira
A
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000109:Acetylcholine; D000368:Aged; D002317:Cardiovascular Agents; D003326:Coronary Circulation / Q000187:drug effects; D003329:Coronary Vasospasm / Q000150:complications* / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D005260:Female; D006334:Heart Function Tests / Q000379:methods; D006801:Humans; D007261:Infusions, Intra-Arterial; D047908:Intracellular Signaling Peptides and Proteins; D017566:Microvascular Angina / Q000150:complications* / Q000517:prevention & control*; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000209:etiology* / Q000517:prevention & control*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D014665:Vasodilator Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D054460:rho-Associated Kinases
D002317:Cardiovascular Agents; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D014665:Vasodilator Agents; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D000109:Acetylcholine; C049347:fasudil