European Heart Journal (2015) 36, 3125–3127
doi:10.1093/eurheartj/ehv629
The coronary circulation: plaques,
collaterals, and the microcirculation
Thomas F. Lüscher, MD, FESC
Editor-in-Chief, Zurich Heart House, Careum Campus, Moussonstrasse 4, 8091 Zurich, Switzerland
A functionally and structurally normal coronary circulation is essen-
tial for a physiologically adequate oxygen supply of the myocardium.
Indeed, an adequate relationship of myocardial oxygen demand and
supply is normally maintained through active and continuous adjust-
ments of epicardial coronary arteries and the microcirculation. Epi-
cardial coronary arteries increase the conductance during exercise
in response to shear stress,1 mainly by an increased release of nitric
oxide,2 an effect that is impaired with endothelial dysfunction and
plaque development.
For the prevention of acute coronary syndromes, early identifica-
tion of vulnerable, rupture-prone atherosclerotic plaques3 in epicar-
dial coronary arteries is of utmost clinical relevance. Despite the
advances in imaging modalities4 and the in vivo identification of
many characteristics of vulnerability, few of these plaques actually
rupture and even fewer lead to clinical events,5 casting doubt on
the predictive value of such techniques. Indeed, factors leading to
an increased vulnerability of plaques within a prothrombotic6 and
inflamed environment7 are generally unknown. However, microcal-
cifications8 and biomechanical factors9 may contribute. In a Clinical
Review ‘Vulnerable plaque imaging: updates on new patho-
biological mechanisms’, Konstantinos Toutouzas and colleagues
from the Athens School of Medicine in Greece10 discuss new fea-
tures implicated in vulnerable plaque formation and rupture, analys-
ing their potential clinical value.
Coronary microvessels acutely respond to signals arising from lo-
cal intra- and extravascular conditions and tissue metabolic require-
ments via changes in the release of endothelial factors and vascular
smooth muscle tone.11 These adaptive responses control vascular
resistance, the distribution of blood flow, and oxygen delivery to
the myocardium. Changes in vascular tone and structure, so-called
remodelling, play critical roles during growth and exercise as well as
in hypertension, microvascular dysfunction,12,13 and collateral de-
velopment. The dynamics and plasticity of the coronary circulation
are the basis for many diagnostic and therapeutic concepts, including
coronary flow reserve,14 microcirculatory resistance,15 therapeutic
angiogenesis,16 or regenerative therapy.17 However, studies of cor-
onary remodelling and collateralization are relatively sparse, limiting
the options to exploit the potential of vascular dynamics for treat-
ment and prevention. These aspects are thoroughly discussed in a
Position Paper entitled ‘Coronary vascular regulation, remodel-
ling, and collateralization: mechanisms and clinical
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: journals.permissions@oup.com.
ISSUE @ A GLANCE
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implications on behalf of the working group on coronary
pathophysiology and microcirculation’ by Axel Pries from
the Charité in Berlin and colleagues from the working group.18 Spe-
cifically, mechanisms of coronary vasomotor regulation, remodel-
ling, and collateralization, as well as their translational potential
are presented, and their dysfunction is discussed in the context of
coronary artery disease. Finally, areas of future research are
identified.
Coronary artery disease is a leading global cause of morbidity and
mortality,19 and improvements in its diagnosis and treatment are
crucial to reduce the health and economic burden of this condition.
In patients with stable coronary artery disease, culprit lesions are
commonly visually assessed angiographically in several projections.
As plaques have a three-dimensional structure, such an assessment
is often inappropriate. To overcome these limitations, pressure
measurements in the coronary circulation have been developed.20
In another Clinical Review ‘Fractional flow reserve-guided man-
agement in stable coronary disease and acute myocardial
infarction: recent developments’, Colin Berry from the Univer-
sity of Glasgow in Scotland21 reminds us that fractional flow reserve
is a pressure-derived index of the maximal achievable myocardial
blood flow in the presence of an epicardial coronary stenosis as a
ratio to maximum achievable flow. When compared with standard
angiography-guided management, fractional flow reserve provides
crucial information on the haemodynamic relevance of a stenosis
as a basis for decision-making for revascularization. Importantly,
such an approach also improves clinical outcomes. In this review art-
icle, Berry and colleagues discuss novel developments in our under-
standing of coronary pathophysiology, diagnostic applications,
prognostic studies, clinical trials, and clinical guidelines.
Primary percutaneous coronary intervention (PCI) is the optimal
treatment for ST-elevation myocardial infarction (STEMI) and is re-
commended by current guidelines.22 An elevated index of microcir-
culatory resistance reflects microvascular function23 and, when
measured after primary PCI, it is predictive of an adverse clinical
outcome.24
In the first clinical research paper, entitled ‘How does coronary
stent implantation impact upon the status of the microcir-
culation during primary percutaneous coronary interven-
tion in patients with ST-elevation myocardial infarction?’,
Adrian Banning from the John Radcliffe Hospital in Oxford
3126
measured coronary microvascular function using fractional flow re-
serve, coronary flow reserve, and the index of microcirculatory re-
sistance in 85 STEMI patients and compared sequential changes
before and after stent implantation.25 Stenting significantly improved
all parameters. However, after stenting, the index of microcircula-
tory resistance remained elevated in about a third of the patients.
In 18% only a partial reduction of the index occurred, and these pa-
tients were more likely to present after .6 h. The extent of jeopar-
dized myocardium and the pre-stenting index of microcirculatory
resistance predicted a reduction in microcirculatory resistance after
stenting, while thrombotic burden and deployed stent volume were
associated with a potentially deleterious increase of the index.
The authors conclude that improved perfusion of the myocar-
dium after stent deployment during primary PCI is not universal.
The causes of impaired microvascular function at completion of a
technically successful treatment are heterogeneous, but reflect later
clinical symptoms and/or the location and extent of the thrombotic
burden. The manuscript is accompanied by an Editorial by Carl
J. Pepine from the University of Florida in Gainesville.26
In a second clinical research paper, ‘Deferral vs. performance
of percutaneous coronary intervention of functionally non-
significant coronary stenosis: 15-year follow-up of the
DEFER trial’, Nico Pijls and colleagues from the Catharina Hos-
pital in Eindhoven in the Netherlands note that stenting an angiogra-
phically intermediate but functionally non-significant stenosis is
controversial.27 As such, it has been questioned whether deferral
of a functionally non-significant lesion on the basis of fractional
flow reserve is safe, especially in the long term. To address this ques-
tion, Pijls et al. present the 5-year follow-up of the DEFER trial that
enrolled 325 patients scheduled for PCI of an intermediate stenosis
in which fractional flow reserve was measured immediately before-
hand. Only patients with values of 0.75 or higher were randomly as-
signed to deferral or PCI and followed-up for 15 years, which was
attainable in 92%. Death was not different between groups. How-
ever, the rate of myocardial infarction was 2.2% and significantly
lower in the deferred group compared with the stented group,
where it was 10.0%. Pijls et al. therefore conclude that deferral of
PCI of a functionally non-significant stenosis is associated with a fa-
vourable very long-term follow-up without signs of a late ‘catch-up’
phenomenon.
The optimal strategy for coronary chronic total occlusions is con-
troversial.28 Marouane Boukhris and colleagues from the Canniz-
zaro Hospital in Catania, Italy therefore provide data on
prevalence, characteristics, and outcome of patients with chronic
total occlusions according to the management strategy in their clin-
ical research paper ‘Management strategies in patients af-
fected by chronic total occlusions: results from the Italian
Registry of Chronic Total Occlusions (IRCTO)’.29 The IRC-
TO is a prospective real-world multicentre registry enrolling pa-
tients with at least one chronic total occlusion. Clinical and
angiographic data were collected irrespective of the therapeutic
strategy, i.e. optimal medical therapy, PCI, or coronary artery bypass
grafting (CABG), and a 1-year clinical follow-up was obtained. A to-
tal of 1777 patients were enrolled. Medical therapy was used in 46%,
PCI in 44%, and CABG in 10%. At 1 year, patients undergoing PCI
showed a lower rate of major adverse cardiac and cerebrovascular
events and cardiac death compared with those treated medically or
Issue @ a Glance
with bypass surgery, respectively. After propensity score matching
analysis, patients treated with PCI showed a lower incidence of car-
diac death, infarction, and re-hospitalization compared with those
managed medically. The authors therefore conclude that PCI of
chronic total occlusions might improve survival and decrease
cardiovascular events at 1 year compared with medical therapy
or bypass surgery. The manuscript is accompanied by an
interesting Editorial by Bradley Strauss from the Sunnybrook
Health Sciences Centre in Toronto, Canada.30
Platelets and their reactivity play a crucial role in acute coronary
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syndromes, and pharmacological inhibition of P2Y12 receptors im-
proves outcome in such patients.31 The level of young or reticulated
platelets reflects the rate of thrombopoiesis in an analogous fashion
to the red cell reticulocyte count.32 However, their influence on
platelet inhibition by ticagrelor or prasugrel is unknown. In their
manuscript entitled ‘Impact of immature platelets on platelet
response to ticagrelor and prasugrel in patients with acute
coronary syndrome’, Isabell Bernlochner and colleagues from
Munich, Germany determined the influence of reticulate platelets
on ADP-induced platelet aggregation in 124 patients with acute cor-
onary syndrome randomized to either ticagrelor or prasugrel.33
Platelet aggregation significantly correlated with the immature plate-
let fraction in patients receiving prasugrel, but not in those receiving
ticagrelor. Within the thiazole orange-positive reticulate platelet
fraction, P-selectin expression was significantly higher in prasugrel-
as compared with ticagrelor-treated individuals. A time-dependent
P-selectin expression was observed in prasugrel-, but not in
ticagrelor-treated patients. The authors conclude that reticulated
platelets show a greater impact on platelet reactivity in response
to prasugrel as compared with ticagrelor. The manuscript is accom-
panied by a critical Editorial by Carlo Patrono and Bianca Rocca
from the Catholic University in Rome, Italy.34
The editors hope that the readers of this issue of the European
Heart Journal find it of interest.
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