European Heart Journal (2018) 39, 960–962 EDITORIAL

doi:10.1093/eurheartj/ehx757

The Rho(ad)-kinase for individualized

treatment of vasospastic angina
R. Jay Widmer1, Lilach O. Lerman2, and Amir Lerman1*

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1
Department of Cardiovascular, Mayo Clinic and College of Medicine, Rochester, MN, USA; and 2Division of Nephrology and Hypertension, Department of Internal Medicine,
Mayo Clinic and College of Medicine, Rochester, MN, USA

Online publish-ahead-of-print 25 December 2017

This editorial refers to ‘Prognostic impacts of Rho-kinase ..
..
activity in circulating leucocytes in patients with vasospastic ..
angina’†, by T. Nihei et al., on page 952.
..
..
..
Coronary vasospasm involves sudden, unexpected near obliteration
..
..
of a native coronary artery, producing incapacitating chest pain and ..
..
myocardial ischaemia. This disabling, and seemingly unresolved, vas- ..
cular pathology can usually be treated medically, if correctly diag- ..
..
nosed,1 although prognostic information is limited to risk scores ..
derived from retrospective cohort studies.2 However, its proper ..
..
identification and diagnosis have, to date, remained elusive. Coronary ..
vasospasm is particularly prevalent in Asian populations, with a ...
potential recent slight upward trend in diagnosis.3,4
..
..
Rho-kinases work through GTP-binding protein in vascular ..
smooth muscle cells (VSMCs) to reduce the bioavalability of nitric
..
..
oxide (NO) and also enhance VSMC contraction and remodelling.5
Rho-kinase A (RhoA) serves as a switch between an inactive GDP-
bound state and an active GTP-bound form that activates down-
stream targets. When triggered, RhoA induces VSMC contraction by
increasing cytosolic Ca2þ and Rho-kinase activity. Downstream tar-
gets of this activation include stimulating myosin light chain in VSMCs
and endothelial NO synthase (eNOS) in endothelial cells, thus pro-
moting enhanced vascular tone. Secondarily, reduced eNOS enhan-
ces the concentration and activity of reactive oxygen species, further
degrading the ability of VSMCs to relax. Thus, Rho-kinase is a reason-
able candidate to evaluate in the vascular pathobiology of coronary
vasospasm.
In their unique investigation into vascular dysfunction of the coro-
nary circulation in this issue of the journal, Nihei et al. provide some
of the first insights into a novel way to evaluate and potentially ameli-
orate vasospastic angina (VSA).6 Given that Rho-kinase levels and
activity in circulating leucocytes are central mediators of coronary
spasm,5,7,8 the authors measured Rho-kinase activity in circulating
leucocytes in patients with non-obstructive coronary artery disease
(CAD) and assessed coronary vasospasm. VSA was defined by > 90%
stenosis of the epicardial coronary artery along with ECG changes
and/or symptoms and microvascular dysfunction, defined as an
increase in lactate production without demonstrable epicardial
stenosis, resulting from acetylcholine provocation testing. Of 233
patients, 178 had a positive acetylcholine provocation test
(4 excluded in the final analysis) and 55 did not have VSA (5 excluded
in the final analysis). Interestingly, only 7% of patients in the entire
cohort of 768 patients did not have endothelial dysfunction—assum-
ing those with obstructive CAD had concomitant endothelial
dysfunction.
Among baseline characteristics, only Rho-kinase activity in circulat-
ing leucocytes was found to be significantly higher in patients with
VSA. When evaluated in a receiver operating characteristic (ROC)
analysis, a median Rho-kinase activity, expressed as the ratio of phos-
phorylated myosin-binding subunit (p-MBS) to the total MBS
.. (t-MBS), a value of 1.24 p-MBS/t-MBS was used to differentiate high
..
.. from low Rho-kinase activity, with a sensitivity of 90% and specificity
.. of 64%. Importantly, those with high Rho-kinase activity were found
..
.. to be at greater risk of a cardiac event [predominantly hospitalization
.. for unstable angina (UA)], whereas no events were observed in the
..
.. non-VSA patients. Finally, when combined with the Japanese
.. Coronary Spasm Association (JCSA) score, the prognostic impact in
..
.. VSA patients significantly increased towards cardiac events.
.. Seemingly a quick verification of the JCSA score2 in Western popula-
..
.. tions would go a long way towards expanding the generalizability of
.. this work.
..
.. The authors observed an association between Rho-kinase activity
..
.. and angina frequency, and, when added to nearly any metric, Rho-
.. kinase levels appeared to enhance the prediction of events in patients
..
.. with VSA. Interestingly, the authors found no correlation between
.. inflammatory markers and Rho-kinase activity, and presumably no dif-
..
.. ference in circulating leucocytes between the two groups. Although
.. there appeared to be no inflammatory connection, Rho-kinase is well
..
.. known to be a mediator in the inflammatory cascade,9 has been asso-
.. ciated with smoking,10 and is reduced with statin use.11 One potential

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
†
doi:10.1093/eurheartj/ehx657.
* Corresponing author. Division of Cardiovascular Diseases, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA. Tel: þ1 507 255 4152, Fax: þ1 507 255 2550,
Email: lerman.amir@mayo.edu
Published on behalf of the European Society of Cardiology. All rights reserved. V
C The Author(s) 2017. For permissions, please email: journals.permissions@oup.com.
Editorial 961

Chest Pain/Ischemia

Coronary
angiography
Obstructive No Obstructive
CAD CAD

Vasoreactivity Study
(Acetylcholine challenge)

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Revascularization

Positive Negative*

Biomarkers
+ -

Individualized treatment Treatment

guided by biomarker CCB, Statin, NTG

©2017 MFMER | 3697842-1

Figure 1 Proposed algorithm for detecting, diagnosing, and treating vasospastic angina (VSA). If chest pain and/or ischaemia is documented, and
obstructive coronary artery disease (CAD) is excluded, then the patient undergoes physiological assessment of the coronary circulation. If negative
(*), then non-cardiac causes of chest pain should be pursued. A positive acetylcholine test should then prompt biomarker evaluation to treat the
underlying cause of the VSA specifically. If the patient continues to have chest pain or ischaemia after revascularization, then one should proceed
back through the algorithm for non-obstructive CAD.

explanation is the different mechanism underlying endothelial dys-

..
..
function and VSA. It could be postulated that inflammation may play a ..
..
more significant role in the mechanism of endothelial dysfunction ..
than in vascular spasm. However, work will be needed to elucidate ..
..
the potential role, or lack thereof, of Rho-kinase in the inflammatory ..
milieu of VSA. Specifically, it would be interesting to determine
..
..
whether any inhibitors of Rho-kinase could be used as a potential ..
..
therapy to ameliorate symptoms and improve coronary epicardial ..
and/or microvascular blood flow in patients with VSA. One specific ..
..
inhibitor of Rho-kinase (SAR40789912) has been found to reduce ..
endothelial end-organ damage in the heart and kidneys of animal
..
..
models of hypertension.13 An ongoing clinical trial intends to test this
hypothesis using SAR407899 in patients with microvascular angina
and/or persistent angina despite angiographically successful elective
percutaneous coronary intervention.14
The findings of Nihei et al. are intriguing and potentially paradigm
altering—particularly if the data can be extrapolated and confirmed
in larger cohorts of the general population, including non-Asian
patients. The conceivable implications for individualized diagnosis and
treatment of VSA are exciting, and could change the existing clinical
approach to patients with VSA (Figure 1). Currently, patients with
non-obstructive disease are either treated empirically medically or
undergo coronary physiology testing.15 The patients are medically
managed based on the results of the physiological assessment.
However, in a model using a more individualized and molecularly spe-
cific approach, one could envisage patients evaluated by undergoing
both coronary physiology as well as biomarker testing, using assays
such as Rho-kinase activity, to tailor the medical approach further, to
treat symptoms, and improve coronary blood flow. Other potential
targets for precision treatment may include C-reactive protein, which
could be targeted with high-dose statins similar to the Justification for
the Use of Statins in Prevention: an Intervention Trial Evaluating
Rosuvastatin (JUPITER) study.16 Furthermore, the inflammatory
agent uric acid has recently been implicated in microvascular dis-
ease,17 and administration of colchicine has been found to be benefi-
.. cial at reducing plaque volume and high sensitivity C-reactive protein
... in patients with recent acute coronary syndromes.18 Finally, with the
..
.. recent Canakinumab Anti-inflammatory Thrombosis Outcomes
.. Study (CANTOS) trial,19 a renewed and undeniable link between
..
.. CAD—both obstructive and non-obstructive—and the inflamma-
.. tory cascade has refocused the field, and should drive the study of
..
.. other inflammatory mediators and their association with CAD and/
..
.. or microvascular disease.
.. Altogether, the results of this initial and preliminary study might
..
.. not only be promising to those patients who suffer from VSA, but
.. may also offer a potential game-changing approach to treating
..
.. patients with non-obstructive CAD. Further confirmation of these
.. data in larger populations, and potential exploration of other
962 Editorial

biomarkers specific to non-obstructive CAD, will be important next ... concomitant coronary and peripheral arterial disease. Clin Cardiol 2013;36:
.. 347–351.
steps in designing treatment strategies for patients with VSA. .. 10. Noma K, Higashi Y, Jitsuiki D, Hara K, Kimura M, Nakagawa K, Goto C, Oshima
.. T, Yoshizumi M, Chayama K. Smoking activates rho-kinase in smooth muscle
Conflict of interest: none declared. ..
.. cells of forearm vasculature in humans. Hypertension 2003;41:1102–1105.
.. 11. Nohria A, Prsic A, Liu P-Y, Okamoto R, Creager MA, Selwyn A, Liao JK, Ganz P.
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