Ridker, Paul M.

Taqueti, Viviany R.

PubMed

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Inflammation, Coronary Flow Reserve, and Microvascular Dysfunction Moving Beyond Cardiac Syndrome X∗

J A C C : C A R D I O V A S C U L A R I M A G I N G V O L . 6 , N O . 6 , 2 0 1 3
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P U B L I S H E D B Y E L S E V I E R I N C . h t t p : / / d x . d o i . o r g / 1 0 . 1 0 1 6 / j . j c m g . 2 0 1 3 . 0 2 . 0 0 5E D I T O R I A L C OMM E N T
Inﬂammation, Coronary Flow Reserve,
and Microvascular Dysfunction
Moving Beyond Cardiac Syndrome X*Viviany R. Taqueti, MD,y Paul M. Ridker, MD, MPHyz
Boston, MassachusettsConventional approaches to risk assessment in pa-
tients with coronary artery disease (CAD), including
assessment of systolic left ventricular function,
inducible myocardial perfusion defects, and angio-
graphic appearance of epicardial stenoses, have been
unable to account fully for risk of future cardiovas-
cular events (1). Part of this unexplained risk may be
attributable to low-grade systemic inﬂammation that
contributes to lesion progression, vascular dysfunc-
tion, insufﬁciency, and plaque rupture (2). In clinical
practice, biomarkers of inﬂammation such as high-See page 660sensitivity C-reactive protein (hsCRP), identify
higher risk individuals, even in the apparent absence
of other conventional risk factors (3). In a recent
meta-analysis of 54 prospective cohort studies, the
magnitude of independent risk associated with a
1 SD change in hsCRP was equal to or greater than
that of a comparable 1 SD change in blood pressure
or cholesterol (4). Nonetheless, the complex biology*Editorials published in JACC: Cardiovascular Imaging reﬂect the views
of the authors and do not necessarily represent the views of JACC:
Cardiovascular Imaging or the American College of Cardiology.
From the yDivision of Cardiovascular Medicine, Noninvasive Cardiovas-
cular Imaging Program, Departments of Medicine and Radiology,
Brigham and Women’s Hospital, Harvard Medical School, Boston,
Massachusetts; and the zCenter for Cardiovascular Disease Prevention,
Department of Medicine, Brigham and Women’s Hospital, Harvard
Medical School, Boston, Massachusetts. Dr. Taqueti is supported by
National Institutes of Health (Grant T32HL094301-02). Dr. Ridker is
listed as a co-inventor on patents held by the Brigham and Women’s
Hospital that relate to the use of inﬂammatory biomarkers in cardiovascular
disease and diabetes that have been licensed to Siemens and AstraZeneca;
and he receives investigator initiated research support from the National
Heart, Lung, and Blood Institute, Amgen, and Novartis.linking inﬂammation to atherothrombotic risk has
not been fully elucidated.
Coronary ﬂow reserve (CFR) is emerging as an
additional noninvasive quantitative imaging marker
of vascular age and clinical risk (5–7). Signiﬁcant
progress has been made in the development of dy-
namic positron emission tomography (PET) perfu-
sion imaging to accurately quantifyCFRas the ratio of
absolute global myocardial blood ﬂow (MBF)
measured at peak stress (i.e., during vasodilator-
induced hyperemia) over that at rest (which is
corrected for rate-pressure product as an index of
baseline cardiac work). From a pathophysiologic per-
spective, CFR provides a measure of the integrated
effects of epicardial CAD, diffuse atherosclerosis,
vessel remodeling, and microvascular dysfunction on
myocardial tissue perfusion (1) (Fig. 1).
CFR quantiﬁed using vasodilator PET can predict
cardiac death and myocardial infarction, even in the
absence of overt obstructive disease, independently of
perfusion score (5–7). These associations are espe-
cially evident among high, but heterogeneous, risk
cohorts, including patients with diabetes (8) and
chronic renal impairment (9). In diabetics, diffuse
coronary vascular dysfunction precedes overt athero-
sclerosis (10), and absence of myocardial ischemia on
noninvasive testing does not necessarily identify a
lower risk cohort (11). Diabetic patients without
known CAD with impaired CFR show a risk of
cardiac death comparable to, and possibly higher than,
that for nondiabetic patients with known CAD (8).
There is growing evidence that microvascular
dysfunction is associated with increased systemic
inﬂammation, and may precede or coexist with high-
risk coronary atherosclerosis. In a previous work,
Recio-Mayoral et al. (12) showed that, compared with
a healthy control group, patients with systemic lupus
AB
Figure 1. Coronary Function Versus Anatomy With Diffuse Coronary Artery Disease and Remodeling
(A) Limitations of anatomic measures of stenosis severity by arteriogram (Artgm) or intravascular ultrasound (IVUS) due to diffuse disease with
and without remodeling compared with coronary ﬂow reserve (CFR). (B) For the arteries illustrated in A, a scatterplot of CFR versus percent
diameter stenosis (%DS) by arteriogram (brown diamonds) and by IVUS (yellow circles). The numbers beside each point of the scattergram
correspond to the numbered schematic examples of A. Reprinted, with permission, from Gould (1).
J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 6 , N O . 6 , 2 0 1 3 Taqueti and Ridker
J U N E 2 0 1 3 : 6 6 8 – 7 1 Inﬂammation and Coronary Flow Reserve
669erythematosus or rheumatoid arthritis, who had no
signiﬁcant CAD on invasive angiography, demon-
strated impaired CFR in a manner that was directly
related to disease duration. Recently, in patients
presenting with acute coronary syndrome who were
found to have nonobstructive CAD by angiography,
those demonstrating coronary microvascular dysfunc-
tion (as assessed by coronary ﬂow velocity reserve
using invasive Doppler ﬂow velocity monitoring)
also showed higher frequency of thin-cap ﬁbroa-
theroma, greater plaque burden, and higher levels of
hsCRP, despite similar amounts of epicardial dis-
ease by luminal area and fractional ﬂow reserve
measurements (13).
In this issue of iJACC, Recio-Mayoral et al. (14)
extend this work, showing that in a cohort of
patients with cardiac syndromeX (CSX), elevation inhsCRP correlates with reduced CFR (Spearman
r ¼ 0.49, p ¼ 0.02). In brief, 21 nonsmokers who
met a strict clinical deﬁnition for CSX, including
exertional angina, ST-segment depression on exer-
cise stress testing, and normal coronary angiography
but without rest or Prinzmetal’s variant angina, dia-
betes mellitus, hypertension, obesity, or hyperlipid-
emia, underwent PET imaging following intravenous
injection of adenosine andwater labeledwith oxygen-
15. These 21 cases of CSX, none taking statins, were
then compared with 21 well-matched asymptomatic
controls. The cases differed, however, in 1 important
risk factor. Eight of the 21 patients with CSX, but
none of the control group, had elevated levels of
hsCRP (>3 mg/l) at baseline. Only the 38% of
CSX patients who had elevated baseline hsCRP
demonstrated lower peakMBF and correspondingly,
Taqueti and Ridker J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 6 , N O . 6 , 2 0 1 3
Inﬂammation and Coronary Flow Reserve J U N E 2 0 1 3 : 6 6 8 – 7 1
670decreased CFR. Of note, those patients with CSX
who did not have elevated levels of hsCRP showed no
difference in corrected CFR compared with the
control group, despite an incidence of ST-segment
depression during adenosine infusion that was not
signiﬁcantly different from that of high hsCRP CSX
patients. These results thus reinforce previous ob-
servations (15–17) that inﬂammation is associated
with impaired coronary vasoreactivity, and in the
appropriate patient population, may be a better
marker for poor outcomes associated with diffuse
and/or microvascular CAD than conventional as-
sessments for ischemia.
To date, no clinical trial has yet proven that
directly reducing inﬂammation lowers cardiovas-
cular event rates. However, 2 large-scale hard
outcome trials have now been launched to address
this issue. In the ﬁrst, the CANTOS (Canakinu-
mab Anti-inﬂammatory Thrombosis Outcomes
Study) trial, post-myocardial infarction patients
with elevated CRP are being randomly allocated to
placebo or to the interleukin (IL)-1b inhibitor
canakinumab (18). In the second, the CIRT
(Cardiovascular Inﬂammation Reduction Trial)
study, funded by the National Heart, Lung, and
Blood Institute, similar post-myocardial infarction
patients with either diabetes or metabolic syndrome
are being randomly allocated to placebo or to low-
dose methotrexate (19). Both trials provide a
unique opportunity to assess whether CFR might
provide a simple noninvasive method to predict
which patients best respond to targeted anti-
inﬂammatory interventions. For example, withregard to IL-1b, previous work has suggested that
the ability of statins to improve measures of coro-
nary blood ﬂow and endothelial dysfunction
(20,21) is modiﬁed among carriers of a speciﬁc
genetic polymorphism that reduces IL-1b expres-
sion (22). Further, short-term inhibition of IL-1
activity with the IL-1 receptor antagonist ana-
kinra in rheumatoid arthritis patients without
perfusion abnormalities has been shown to improve
echocardiographic measures of left ventricular
myocardial deformation (by speckle tracking) and
CFR (by Doppler ﬂow velocity in the left anterior
descending artery [LAD]) (23). With regard to
low-dose methotrexate, the use of this common
systemic anti-inﬂammatory agent in early rheu-
matoid arthritis has been found to reduce clinical
scores of disease severity and improve CFR (as
measured by echo Doppler ﬂow velocity in the
LAD), without effect on common carotid intima-
medial thickness (24). As such, PET imaging
substudies embedded in CANTOS and CIRT
would provide not only an opportunity to investi-
gate the clinical utility of CFR as a marker of
subsequent vascular risk, but would also allow for
a direct evaluation of 2 anti-inﬂammatory thera-
pies on changes in coronary vascular function
over time.
Reprint requests and correspondence: Dr. Paul Ridker,
Center for Cardiovascular Disease Prevention, Brigham
and Women’s Hospital, 900 Commonwealth Avenue
East, Boston, Massachusetts 02215. E-mail: pridker@
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- coronary ﬂow reserve -
inﬂammation - microvascular
dysfunction.


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Inflammation, Coronary Flow Reserve, and Microvascular Dysfunction Moving Beyond Cardiac Syndrome X∗

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