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Original Article

Rho-Associated Kinase Activity Is a Predictor of Cardiovascular Outcomes

Masato Kajikawa, Kensuke Noma, Tatsuya Maruhashi, Shinsuke Mikami, Yumiko Iwamoto, Akimichi Iwamoto, Takeshi Matsumoto, Takayuki Hidaka, Yasuki Kihara, Kazuaki Chayama, Ayumu Nakashima, Chikara Goto, James K. Liao, Yukihito Higashi
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https://doi.org/10.1161/HYPERTENSIONAHA.113.02296
Hypertension. 2013;HYPERTENSIONAHA.113.02296
Originally published December 30, 2013
Masato Kajikawa
From the Department of Cardiovascular Medicine (M.K., T. Maruhashi, S.M., Y.I., A.I., T. Matsumoto, T.H., Y.K.), Hiroshima University Graduate School of Biomedical Sciences, and Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences (K.C.), Hiroshima, Japan; Division of Regeneration and Medicine, Hiroshima University Hospital, Hiroshima, Japan (K.N., Y.H.); Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan (K.N., A.N., Y.H.); Department of Physical Therapy, Hiroshima International University, Hiroshima, Japan (C.G.); and Section of Cardiology, University of Chicago Medical Center, Chicago, IL (J.K.L.).
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Kensuke Noma
From the Department of Cardiovascular Medicine (M.K., T. Maruhashi, S.M., Y.I., A.I., T. Matsumoto, T.H., Y.K.), Hiroshima University Graduate School of Biomedical Sciences, and Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences (K.C.), Hiroshima, Japan; Division of Regeneration and Medicine, Hiroshima University Hospital, Hiroshima, Japan (K.N., Y.H.); Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan (K.N., A.N., Y.H.); Department of Physical Therapy, Hiroshima International University, Hiroshima, Japan (C.G.); and Section of Cardiology, University of Chicago Medical Center, Chicago, IL (J.K.L.).
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Tatsuya Maruhashi
From the Department of Cardiovascular Medicine (M.K., T. Maruhashi, S.M., Y.I., A.I., T. Matsumoto, T.H., Y.K.), Hiroshima University Graduate School of Biomedical Sciences, and Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences (K.C.), Hiroshima, Japan; Division of Regeneration and Medicine, Hiroshima University Hospital, Hiroshima, Japan (K.N., Y.H.); Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan (K.N., A.N., Y.H.); Department of Physical Therapy, Hiroshima International University, Hiroshima, Japan (C.G.); and Section of Cardiology, University of Chicago Medical Center, Chicago, IL (J.K.L.).
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Shinsuke Mikami
From the Department of Cardiovascular Medicine (M.K., T. Maruhashi, S.M., Y.I., A.I., T. Matsumoto, T.H., Y.K.), Hiroshima University Graduate School of Biomedical Sciences, and Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences (K.C.), Hiroshima, Japan; Division of Regeneration and Medicine, Hiroshima University Hospital, Hiroshima, Japan (K.N., Y.H.); Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan (K.N., A.N., Y.H.); Department of Physical Therapy, Hiroshima International University, Hiroshima, Japan (C.G.); and Section of Cardiology, University of Chicago Medical Center, Chicago, IL (J.K.L.).
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Yumiko Iwamoto
From the Department of Cardiovascular Medicine (M.K., T. Maruhashi, S.M., Y.I., A.I., T. Matsumoto, T.H., Y.K.), Hiroshima University Graduate School of Biomedical Sciences, and Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences (K.C.), Hiroshima, Japan; Division of Regeneration and Medicine, Hiroshima University Hospital, Hiroshima, Japan (K.N., Y.H.); Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan (K.N., A.N., Y.H.); Department of Physical Therapy, Hiroshima International University, Hiroshima, Japan (C.G.); and Section of Cardiology, University of Chicago Medical Center, Chicago, IL (J.K.L.).
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Akimichi Iwamoto
From the Department of Cardiovascular Medicine (M.K., T. Maruhashi, S.M., Y.I., A.I., T. Matsumoto, T.H., Y.K.), Hiroshima University Graduate School of Biomedical Sciences, and Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences (K.C.), Hiroshima, Japan; Division of Regeneration and Medicine, Hiroshima University Hospital, Hiroshima, Japan (K.N., Y.H.); Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan (K.N., A.N., Y.H.); Department of Physical Therapy, Hiroshima International University, Hiroshima, Japan (C.G.); and Section of Cardiology, University of Chicago Medical Center, Chicago, IL (J.K.L.).
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Takeshi Matsumoto
From the Department of Cardiovascular Medicine (M.K., T. Maruhashi, S.M., Y.I., A.I., T. Matsumoto, T.H., Y.K.), Hiroshima University Graduate School of Biomedical Sciences, and Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences (K.C.), Hiroshima, Japan; Division of Regeneration and Medicine, Hiroshima University Hospital, Hiroshima, Japan (K.N., Y.H.); Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan (K.N., A.N., Y.H.); Department of Physical Therapy, Hiroshima International University, Hiroshima, Japan (C.G.); and Section of Cardiology, University of Chicago Medical Center, Chicago, IL (J.K.L.).
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Takayuki Hidaka
From the Department of Cardiovascular Medicine (M.K., T. Maruhashi, S.M., Y.I., A.I., T. Matsumoto, T.H., Y.K.), Hiroshima University Graduate School of Biomedical Sciences, and Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences (K.C.), Hiroshima, Japan; Division of Regeneration and Medicine, Hiroshima University Hospital, Hiroshima, Japan (K.N., Y.H.); Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan (K.N., A.N., Y.H.); Department of Physical Therapy, Hiroshima International University, Hiroshima, Japan (C.G.); and Section of Cardiology, University of Chicago Medical Center, Chicago, IL (J.K.L.).
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Yasuki Kihara
From the Department of Cardiovascular Medicine (M.K., T. Maruhashi, S.M., Y.I., A.I., T. Matsumoto, T.H., Y.K.), Hiroshima University Graduate School of Biomedical Sciences, and Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences (K.C.), Hiroshima, Japan; Division of Regeneration and Medicine, Hiroshima University Hospital, Hiroshima, Japan (K.N., Y.H.); Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan (K.N., A.N., Y.H.); Department of Physical Therapy, Hiroshima International University, Hiroshima, Japan (C.G.); and Section of Cardiology, University of Chicago Medical Center, Chicago, IL (J.K.L.).
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Kazuaki Chayama
From the Department of Cardiovascular Medicine (M.K., T. Maruhashi, S.M., Y.I., A.I., T. Matsumoto, T.H., Y.K.), Hiroshima University Graduate School of Biomedical Sciences, and Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences (K.C.), Hiroshima, Japan; Division of Regeneration and Medicine, Hiroshima University Hospital, Hiroshima, Japan (K.N., Y.H.); Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan (K.N., A.N., Y.H.); Department of Physical Therapy, Hiroshima International University, Hiroshima, Japan (C.G.); and Section of Cardiology, University of Chicago Medical Center, Chicago, IL (J.K.L.).
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Ayumu Nakashima
From the Department of Cardiovascular Medicine (M.K., T. Maruhashi, S.M., Y.I., A.I., T. Matsumoto, T.H., Y.K.), Hiroshima University Graduate School of Biomedical Sciences, and Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences (K.C.), Hiroshima, Japan; Division of Regeneration and Medicine, Hiroshima University Hospital, Hiroshima, Japan (K.N., Y.H.); Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan (K.N., A.N., Y.H.); Department of Physical Therapy, Hiroshima International University, Hiroshima, Japan (C.G.); and Section of Cardiology, University of Chicago Medical Center, Chicago, IL (J.K.L.).
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Chikara Goto
From the Department of Cardiovascular Medicine (M.K., T. Maruhashi, S.M., Y.I., A.I., T. Matsumoto, T.H., Y.K.), Hiroshima University Graduate School of Biomedical Sciences, and Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences (K.C.), Hiroshima, Japan; Division of Regeneration and Medicine, Hiroshima University Hospital, Hiroshima, Japan (K.N., Y.H.); Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan (K.N., A.N., Y.H.); Department of Physical Therapy, Hiroshima International University, Hiroshima, Japan (C.G.); and Section of Cardiology, University of Chicago Medical Center, Chicago, IL (J.K.L.).
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James K. Liao
From the Department of Cardiovascular Medicine (M.K., T. Maruhashi, S.M., Y.I., A.I., T. Matsumoto, T.H., Y.K.), Hiroshima University Graduate School of Biomedical Sciences, and Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences (K.C.), Hiroshima, Japan; Division of Regeneration and Medicine, Hiroshima University Hospital, Hiroshima, Japan (K.N., Y.H.); Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan (K.N., A.N., Y.H.); Department of Physical Therapy, Hiroshima International University, Hiroshima, Japan (C.G.); and Section of Cardiology, University of Chicago Medical Center, Chicago, IL (J.K.L.).
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Yukihito Higashi
From the Department of Cardiovascular Medicine (M.K., T. Maruhashi, S.M., Y.I., A.I., T. Matsumoto, T.H., Y.K.), Hiroshima University Graduate School of Biomedical Sciences, and Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences (K.C.), Hiroshima, Japan; Division of Regeneration and Medicine, Hiroshima University Hospital, Hiroshima, Japan (K.N., Y.H.); Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan (K.N., A.N., Y.H.); Department of Physical Therapy, Hiroshima International University, Hiroshima, Japan (C.G.); and Section of Cardiology, University of Chicago Medical Center, Chicago, IL (J.K.L.).
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Abstract

Cardiovascular diseases are associated with chronic activation of Rho-associated kinase. Rho-associated kinase activity is significantly correlated with endothelial function and Framingham risk score. However, there is no information on the prognostic value of Rho-associated kinase activity. We evaluated Rho-associated kinase activity in peripheral leukocytes by Western blot analysis in 633 subjects who underwent health-screening examination at Hiroshima University Hospital. We assessed the associations between Rho-associated kinase activity and first major cardiovascular events (death from cardiovascular causes, myocardial infarction, and stroke), death from cardiovascular causes, acute myocardial infarction, stroke, revascularization (percutaneous coronary intervention, coronary artery bypass grafting), and hospitalization for heart failure. During a median period of 42.0 months (interquartile range, 24.4–56.6 months) of follow-up, 29 subjects died (10 from cardiovascular causes), 2 myocardial infarction, 20 revascularization, 15 stroke, and 17 hospitalization for heart failure. After adjustment for age, sex, cardiovascular risk factors, and other relevant variables, Rho-associated kinase activity remained a strong independent indicator of first major cardiovascular events (hazard ratio, 2.19; 95% confidence interval, 1.35–3.70; P=0.002), death from cardiovascular disease (hazard ratio, 2.57; 95% confidence interval, 1.18–6.60; P=0.002), stroke (hazard ratio, 2.14; 95% confidence interval, 1.24–3.86; P=0.006), and revascularization (hazard ratio, 2.68; 95% confidence interval, 1.60–4.66; P<0.001). Leukocyte Rho-associated kinase activity may be a new biomarker of cardiovascular events. These findings suggest that inhibition of Rho-associated kinase activity may be a therapeutic target for prevention of cardiovascular events.

  • atherosclerosis
  • biological markers
  • cardiovascular events
  • cardiovascular risk factors
  • Rho-associated kinase
  • Received August 24, 2013.
  • Revision received September 11, 2013.
  • Accepted December 6, 2013.
  • © 2013 American Heart Association, Inc.
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    Rho-Associated Kinase Activity Is a Predictor of Cardiovascular Outcomes
    Masato Kajikawa, Kensuke Noma, Tatsuya Maruhashi, Shinsuke Mikami, Yumiko Iwamoto, Akimichi Iwamoto, Takeshi Matsumoto, Takayuki Hidaka, Yasuki Kihara, Kazuaki Chayama, Ayumu Nakashima, Chikara Goto, James K. Liao and Yukihito Higashi
    Hypertension. 2013;HYPERTENSIONAHA.113.02296, originally published December 30, 2013
    https://doi.org/10.1161/HYPERTENSIONAHA.113.02296

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    Masato Kajikawa, Kensuke Noma, Tatsuya Maruhashi, Shinsuke Mikami, Yumiko Iwamoto, Akimichi Iwamoto, Takeshi Matsumoto, Takayuki Hidaka, Yasuki Kihara, Kazuaki Chayama, Ayumu Nakashima, Chikara Goto, James K. Liao and Yukihito Higashi
    Hypertension. 2013;HYPERTENSIONAHA.113.02296, originally published December 30, 2013
    https://doi.org/10.1161/HYPERTENSIONAHA.113.02296
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