World Journal of Cardiovascular Diseases, 2013, 3, 8-16 WJCD Published Online August 2013 (
The myocardial microcirculation: A key target for
salvaging ischemic myocardium?
John G. Kingma
Département de Médecine, Pavillon Ferdinand-Vandry 1050, Université Laval Québec, Québec, Canada
Received 27 June 2013; revised 27 July 2013; accepted 30 July 2013
Copyright © 2013 John G. Kingma. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Clinical management of patients with acute myocar-
dial infarction for the most part involves re-opening
of an infarct-related coronary vessel by the use of
clot-busting pharmacologic treatment or percutane-
ous coronary interventions. While blood flow in the
epicardial coronary vessel is restored downstream, ef-
fects remain largely unexplored; progressive injury at
the microvessel level has significant repercussions on
restoration of cardiocyte viability and the ventricular
blood flow and contractile function relationship. This
review focuses on the cardiac microcirculation and
the fact that it should be a principle target of future
studies to permit improvement of clinical outcomes in
patients presenting with evolving myocardial infarc-
Keywords: Microcirculation; Ischemia; Reperfusion;
Blood Flow; Cardioprotection
Cardiovascular disease currently generates billions of dol-
lars in healthcare costs globally and accounts for the ma-
jority of deaths and disability worldwide. Principle com-
plications of cardiovascular diseases include myocardial
infarction and subsequent ventricular contractile failure.
Acute myocardial infarction occurs subsequent to sudden
obstruction of coronary blood flow (i.e. ischemia due to
coronary thrombus or embolus) to a specific region of
the heart muscle. The duration of blood flow deficit ul-
timately determines the overall level of cellular injury
and the potential for recovery of function of affected my-
ocardium. With prolonged ischemia a “wavefront” of cell
death, commencing from the innermost (endocardium) to
the outermost (epicardium) layer of the ventricular wall
develops until a fully transmural infarct is produced [1].
Irreversible damage also occurs to components of the
myocardial microvasculature but it is not clear that da-
mage at this level occurs prior to onset of cardiocyte ne-
crosis [2]. Finally, damage also occurs at the level of in-
tramyocardial nerves [3]; however, few studies have fo-
cused on this aspect of post -i s c hemic myocardial injury.
For patients presenting with an acute myocardial in-
farction, various reperfusion strategies have been devel-
oped in an attempt to delay progression of or to reduce
ultimate infarct size, improve recovery of ventricular con-
tractile function, limit onset of heart failure and improve
clinical outcomes. Paradoxically, restoration of blood flow
to the infarct-related coronary artery, though critical for
myocardial salvage, could produce further injury to al-
ready damaged (and even previously undamaged) cardio-
cytes and thereby mitigate the potential benefits of “re-
perfusion therapy”; this phenomenon is more widely re-
ferred to as myocardial reperfusion injury [4-7]. Within
this context various phenomenon including, reperfusion-
induced arrhythmias, myocardial stunning, microvessel
obstruction and lethal reperfusion injury are currently ac-
knowledged [8]. Compro mised blood flow at the level of
the microvasculature is generally associated with larger
infarcts, reduced cardiac contractile performance, adverse
LV remodelling and poor clinical outcomes [9,10]. This
review focuses on the cardiac microcirculation and whe-
ther it should be targeted to permit improvement of cli-
nical outcomes in patients presenting with evolving myo-
cardial infarction.
Delivery of oxygen and nutrients to tissues in each organ
is the ultimate function of th e card iovascu lar syste m. The
architecture of the microcirculation includes arterioles,
capillaries and venules [11,12]. Crucial exchange proc-
esses for oxygen, nutrients and hormones all occur at the
level of the microcirculation; metabolic catabolites are
also removed here. In addition, during inflammation an-
J. G. Kingma / World Journal of Cardiovascular Diseases 3 (2013) 8-16 9
tibodies, fibrinogen, elements of the complement system
and inflammatory cells all enter injured tissues at the
level of the microcirculation. Chemical and physical
factors that regulate microvessel functions have been
widely investigated; a specific focal point has been the
production of endogenously produced compounds that
could affect endothelial cells or underlying smooth mus-
cle cells in different disease processes [13-15].
In the heart, the microcirculation comprises a dense in-
tramyocardia l network of micro vessels that originat e from
a proximal arterial system [16]. The latter is divided into
three compartments: 1) epicardial coronary (conductive)
arteries, 2) pre-arterioles and 3) intramural arterioles;
each of these compartments has the capacity to modulate
capacitance and tone so that blood flow is matched to
oxygen requirements [17,18]. Krogh first described the
regulation of the capillary circulation in relation to tissue
oxygen supply [19], and showed in the heart that during
exercise (with an increase in oxygen demand) capillary
vessels could be recruited to enable adequate distribution
of blood flow. A small number of coronary capillaries
are open under resting conditions in the heart; when oxy-
gen demand is higher additional cap illaries are recruited.
In the setting of coronary artery disease vasodilatory ca-
pacity of the microvasculature is reduced and aerobic
threshold (i.e. critical equilibrium between oxygen sup-
ply and demand) of ischemic myocardium is reached
much sooner. Metabolic, neural and myogenic mechani-
sms regulate blood flow within the vascular network;
higher blood flows require a corresponding increase in
vessel diameter particularly at the level of the microvas-
Cardiocyte viability post-ischemia is integrally linked
to the ability of the microvasculature to deliver oxygen
and nutrients either via pre-existing coronary or collat-
eral networks or promotion of new vessel growth (arteri-
ogenesis). Transmural distribution of coronary collaterals
varies considerably between species and is genetically
determined [20,21]; consequently, post-ischemic devel-
opment of cardiocyte injury is directly dependent on the
location of functional collateral vessels across the ven-
tricular wall. Development of functional collateral ves-
sels cannot be predicted in advance of an acute corona-
ry event; neither can we predict which patients have the
ability to develop collateral vessels after an acute insult
[22]. However, an extended time frame is necessary for
new vessel growth [23,24]. Existing small vessels may
also undergo a process of endogenous remodeling via sti-
mulation of molecular and cellular processes [25]. There
is ample reference in the scientific literature regarding
recruitment of coronary collateral vessels at the onset of
ischemia. It would seem more reasonable to use the ter-
minology of microvessel recruitment as initially suggest-
ed by Krogh [19]; questions as to whether arterial vessels
recruited during the acute ischemic event are true collat-
eral vessels or pre-existing arterioles/capillaries that op en
because of local changes in external influences on the
myocardial wall independent of the vessels themselves is
not trivial and should be addressed. External factors such
as intramyocardial tissue pressure, coronary perfusion
pressure and location within the ventricular wall all in-
fluence coronary collateral circulation. The functional ef-
ficacy of coronary collaterals remains controversial; cli-
nical evidence of improved ventricular function post-is-
chemia remains anecdotal. On a similar note reduced
infarct size, incidence of arrhythmias and mortality due
to the presence of functional coronary collateral circula-
tion remains speculative.
Acute obstruction of a coronary vessel initiates profound
pathological changes in cardiocytes (within the area of
no blood flow or anatomic area at risk) due to abrupt
stoppage of biochemical and metabolic pathways. Re-
duced oxygen delivery halts oxidative phosphorylation at
the mitochondrial level and lead s to mitochondrial mem-
brane depolarization, depletion of intracellular energy
phosphate stores and inhibition of myocyte contractile
function. Ultrastructural changes at the level of cardio-
cytes include cellular swelling, sub sarcolemmal blebbing,
cytoplasmic membrane-bound vacuoles, swollen mito-
chondria, nuclear chromatin clumping and margination
[26]. Within the coronary vessels vascular endothelial
cells become swollen and deformed with small intralu-
minal protrusions; these cells also demonstrate nuclear
chromatin clumping and margination, fewer pinocytotic
vesicles and intercellular separation [27]. The described
cellular injury represents a small portion of the ultra-
structure changes that occur briefly after onset of coro-
nary occlusion. Reversibility of these ultrastructure al-
terations is possible but entirely dependent on duration of
the ischemic insult. Mechanisms responsible for abnor-
mal blood flow to damaged myocardium have not been
clearly established; capillary damage and external capil-
lary compression due to edema, micro-embolization of
microthrombi from atherosclerotic plaque or platelet
aggregation and neutrophil plugging remain potential can-
didates for poor transmural distribution of blood flow
For patients presenting with cardiac symptoms reduc-
ing the time from chest pain onset to arriv al at the hospi-
tal coronary intervention unit remains the first p riority. In
the pre-hospital phase different ambulatory therapeutic
strategies have been shown with varying degrees of suc-
cess to delay development of cardiocyt e injury. M ost phar-
macologic compounds have not yet shown consistent
benefit with respect to reduction of ischemic injury, pre-
serving cardiac function and improving patient outcomes;
Copyright © 2013 SciRes. OPEN ACCESS
J. G. Kingma / World Journal of Cardiovascular Diseases 3 (2013) 8-16
the reasons for the poor performance are currently the
subject of debate and ongoing research [31,32]. Timely
restoration of blood flow to an infarct-related artery may
be the most effective strategy to limit ischemic injury
and cardiocyte necrosis. While a host of experimental
and clinical studies have reported that it is possible to
limit development of post-ischemic myocardial injury
[32-35], for the most part a delay and not a reduction of
ultimate infarct size has been demonstrated. No pharma-
cologic treatment has been shown to sufficiently limit
infarct size; potential reasons being; 1) timing of admini-
stration and dosage of potentially cardioprotective treat-
ments, and 2) heterogeneity of comorbidities within the
patient populations [36].
Myocardial infarction produces a persistent reduction
in contractile function due to loss of cardiocytes and re-
placement by fibrotic tissue [33]. Even when ischemia is
alleviated by restoration of blood flow to the infarct-
related artery before the onset of irreversible cardiocyte
death contractile dysfunction can persist—this is more
commonly referred to as “myocardial stunning” [37,38].
When myocardium is subjected to repetitive reversible
ischemia over an extended period card iocyte remodelling
can occur at both the cellular and molecular levels [39].
Within the ischemic zone viable chronically dysfunctio-
nal myocardium has also been reported in the absence of
persistent perfusion abn ormalities—this is commonly re-
ferred to as “myocardial hibernation” [40-42]. While loss
of cardiocytes and cellular hypertrophy play a role in
persistent ventricular contractile dysfunction pathologic
fibrosis to replace necrotic cardiocytes within the ische-
mic zone is also important [43]. The extent of patho-
physiological remodeling that occurs is partly dependent
on the degree of coronary perfusion to the ischemic vas-
cular bed [44]; reductions in blood flow could result in
activation of endogenous metabolic pathways that could
result in a down-regulation of myocardial oxygen require-
ments [39,45,46]. Cellular adaptive mechanisms such as
down-regulation of mitochondrial proteins or up-regula-
tion of stress and cytoskeletal proteins all impact the abi-
lity of the failing heart to adjust to changes in cardiac
workload [47,48]. Additional studies are needed to un-
derstand cardiocyte as well as vascular remodeling after
restoration of blood flow to an infarct-related coronary
Transient ischemia produces persistent regional car-
diac contractile dysfunction even in the absence of cardi-
ocyte necrosis [49-53]. A direct relation has been repor-
ted between blood flow and contractile function [50];
this relation is superimposable at rest and during ex ercise
under normal conditions (i.e. no underlying coronary ar-
tery disease) [53,54]. We recently documented, in ca-
nine hearts subjected to transient ischemia, that the flow-
function relation was influenced by nitric oxide bioavai-
lability resulting in a perfusion-function mismatch [55].
Timely opening of an infarctrelated artery is essential for
the salvage of viable cardiocytes within the anatomic
area at risk; however, on reperfusion vessel injury could
occur resulting in local or downstream obstruction of the
vessel lumen. Endothelial injury and obstruction of cap-
illaries therefore remains a primary consideration for the
success of potential reperfusion therapies. Restoration of
blood flow within an infarct-related artery (i.e. conduit
vessel) is generally accomplished by pharmacologic
thrombolytic therapy or percutaneous angioplasty [32,
34]. While restoration of blood flow in the conduit vessel
is readily observed it do es not assure transmural distribu-
tion of blood flow at the level of the microvasculature.
This is probably due to the transmural heterogeneity for
distribution of microvascular resistance where resistance
is higher in the endocardial tissue layer compared to the
epicardium [56]; however, this gradient is reversed
within the microcirculation [57]. Circulation to the
deeper myocardial layers may remain abnormal and
would probably be insufficient to maintain normal car-
diocyte function and ventricular contraction [58]. We
raise the question as to whether more attention should be
paid in both pre-clinical and clin ical studies to the role of
the coronary microcirculation and its distribution across
the ventricular wall on development of ischemic injury
and post-ischemic ventricular remodeling. While restora-
tion of blood flow to the vascular bed of an infarct-re-
lated artery clearly delays development of tissu e necrosis
this may also be a mixed blessing since additional cardi-
ocyte damage may occur to a population of reversibly
injured myocytes within the area at risk. Thus, myocar-
dial reperfusion is often viewed in the context of being a
“double-e dged sword” [4].
After successful reperfusion of an infarct-related artery
further cellular necrosis could be induced in cardiocytes
that were believed to be viable at the end of the ischemic
event; this phenomenon is commonly referred to as lethal
myocardial reperfusion injury [8]. Potential pathways
responsible for lethal myocardial reperfusion injury in-
clude oxidative stress, intracellular calcium overload,
rapid restoration of physiological pH to ischemic myo-
cardium, dysfunctional mitochondrial permeability tran-
sition pore and inflammation. These mechanisms and
their contribution to lethal myocardial reperfusion injury
have recently been reviewed [8]. Whether lethal myocar-
dial reperfusion injuries actually occur remains contro-
versial; several studies suggest it may account for up to
50 percent of final infarct size [6,59]. The choice of
Copyright © 2013 SciRes. OPEN ACCESS
J. G. Kingma / World Journal of Cardiovascular Diseases 3 (2013) 8-16 11
reperfusion strategy may therefore impact on the overall
severity of lethal reperfusion injury inasmuch as one
adheres to the dogma that reperfusion can actually be
detrimental to post-ischemia cardiocyte survival.
More attention is being paid in the clinical setting to the
phenomenon of “no-reflow” which results from endothe-
lial cell injury during ischemia and develops within the
ischemic vascular bed after opening an infarct-related
artery. Interacting factors that contribute to no-reflow
include ischemic injury, reperfusion injury, distal vessel
embolization and microvessel susceptibility to injury
[60]; all of these elements are associated with profound
disturbances of vasoregulatory pathways [61]. Ischemia-
reperfusion damage is central to the physiopathology of
no-reflow which results in impaired LV remodeling, ven-
tricular dysfunction and clearly impacts survival. After
opening of the infarct-related vessel regional blood flow
is initially hyperemic and then progressively declines
[27,62-66]; the area of no-reflow progresses across the
LV wall from the endocardium, is constrained to the
ischemic area [2,26,58], and may depend on degree of
collateral blood flow to ischemic region during coronary
occlusion [66]. The causal link between microvascular
and myocardial damage remains to be established [62,63,
67]; reduction of no-reflow and tissue necrosis has been
documented with pharmacologic interventions given at
the time of reperfusion [68]. Mechanisms responsible for
no-reflow are probably quite similar across species in-
cluding humans and include endothelial injury, accumu-
lation of inflammatory cells, reactive oxygen intermedi-
ates and the coagulation cascade. While no-reflow may
not produce cardiocyte necrosis the overall consensus is
that improvements in coronary collateral flow to the
ischemic vascular bed will produce less ventricular re-
modeling; in a retrospective clinical study of cardiovas-
cular disease Rezkalla et al. reported no-reflow in more
than a third of patients [69]. Intracoronary pharmaco-
logic treatment in these patients resulted in normalization
of flow to ischemic myocardium and, more importantly,
reduced mortality.
Cardiac conditioning represents a potential breakthrough
for protection of the ischemic heart. Murry et al. initially
described “ischemic preconditioning” in dogs exposed to
intermittent cycles of nonlethal coronary occlusion and
reperfusion prior to a period of sustained coronary occlu-
sion [70]. In this study infarct size was consistently
smaller in hearts pretreated by the conditioning stimulus
prior to index ischemia; however, cardioprotection was
not sustained when the duration of coronary occlusion
was extended to 3 hours. Since the publication of this
landmark paper a host of studies have attempted to eluci-
date underlying mechanisms responsible for this endo-
genous cellular protective phenomenon with the hope of
identifying mediators amenable to pharmacologic ma-
nipulation for clinical utilisation [71-73]. In the current
paradigm the conditioning stimulus generates endoge-
nous ligands including adenosine, opioids and catecho-
lamines that trigger cellular transduction pathways and
mediate protective signals from the cell membrane to mi-
tochondria where end-effectors induce protection [72,
74]. Although most studies have focused on pro tection in
the heart conditioning pre-treatment protection has been
reported for all organs studied [75-78]. To date, cardiac
conditioning has been achieved using anesthetic, phar-
macological and even remote interventions; the similar-
ity of mechanisms forwarded for the different condition-
ing stimuli suggest the existence of a cross-tolerance
phenomenon [79,80]. Even though significant progress
has been made in the identification of innate protective
pathways involved translation of the overall benefits of
conditioning into clinical practice remains a challenge.
The key requirement for organ conditioning is reper-
fusion of the ischemic tissues. In humans, protection of
the coronary vasculature by various conditioning mano-
euvers has not been clearly established but in several
reports better myocardial perfusion (higher TIMI score
or myocardial blush grade and coronary flow reserve)
has been reported [81,82]. Prevention of vessel dysfunc-
tion by cardiac conditioning remains controversial; in
animal models cardiac conditioning has been shown to
conserve endothelial function and increase regional myo-
cardial blood flow [62,83-87]. Vascular injury produced
by myocardial ischemia-reperfusion ranges from mild
functional impairment of endothelium-dependent vasodi-
latation, to increased permeability and severe structural
alterations to no-reflow. A recent elegant study by Sky-
schally et al. examined the impact of microembolization
at the onset of coronary reperfusion on myocardial in-
farction in a porcine experimental preparation of ische-
mia-reperfusion [88]. They showed that no-reflow and
tissue necrosis were significantly attenuated in post-con-
ditioned animals and suggested that embolization of mi-
crovessels located primarily at the border zone (i.e. be-
tween ischemic and non-ischemic myocardium) prevent-
ed an increase in cardiocyte necrosis. Whittaker and Pr-
zyklenk previously hypothesized that the border zone
was most susceptible to further damage during post-is-
chemic reperfusion of the infarct-related artery [89]. On
the other hand, several recent clinical studies using post-
conditioning failed to show cardioprotection thus confir-
ming the need for further study [90,91].
Copyright © 2013 SciRes. OPEN ACCESS
J. G. Kingma / World Journal of Cardiovascular Diseases 3 (2013) 8-16
Progress has been substantial over the past several dec-
ades regarding angioplasty technologies for rapid resto-
ration of blood flow in infarct-related conduit vessels in
humans. Keeping afflicted vessels open by implantation
of a coronary stent is also effective; however, consider-
able efforts are ongoing to limit problems associated
with their use. While it is clear that these interventions
are successful in the majority of patients to restore/main-
tain patency of conductive arteries and trigger myocar-
dial salvage much less is known about the recovery of
cardiocyte viability and distribu tion of blood flow within
the infarct core (i.e. deeper myocardial tissue layers). In
the clinical setting direct anatomical quantification of
blood flow in the myocardial microcirculation remains
elusive. However, coronary microvascular abnormalities
could explain clinical signs of myocardial isch emia often
observed in patients with normal coronary angiograms
(cf. Herrmann et al. for recent review [92]). Microvessel
dysfunction in patients is generally estimated by the use
of vasodilator agents in conjunction with positron emis-
sion tomography or cardiovascular magnetic resonance
techniques [16]. Myocardial contrast echocardiography
is also used to assess microvessel perfusion [93,94]; us-
ing this technique it has been reported that microvessel
obstruction occurs in 30 - 40 percent of patients with re-
perfused ST-elevation acute myocardial infarction in
which optimal TIMI (Thrombolysis in Myocardial In-
farction) flow was achieved [10]. The consensus of clini-
cal findings with myocardial contrast echocardiography
is that poor perfusion of the deeper myocardium with
adequate restoration of epicardial blood flow is a primary
risk factor for ventricular remodelling and major adverse
cardia c ev en ts [95 ,96 ]. In ad ditio n , co ron a r y flow re se rv e
can be directly measured the catheterisation laboratory;
Posa et al. recently documented the occurrence of mi-
crovessel obstruction immediately post-opening of the
infarct-related artery in a collateral circulation poor por-
cine model of ischemia-reperfusion [97]. Coronary re-
serve is spatially variable [98-101]; myocardial regions
with reduced intrinsic coronary reserve could be most
vulnerable to transient, repetitive ischemic events that
culminate in microareas of cardiocyte necrosis. In pre-
clinical studies organ blood flow under diverse experi-
mental conditions can be more readily evaluated by the
use of microspher es [102]. Marked pro gressive r eduction
of blood flow and capillary filling in the canine heart
following acute myocardial ischemia has been reported
even after initial demonstration of adequate blood flow
in epicardial coronary arteries [66,103]. Poor blood flow
at the level of the microvessels could be due to increased
microcirculatory resistance distal to the site of conduit
vessel occlusion [104]; clinical studies have not ye t ev a lu -
ated microvessel responses or ultrastructural changes in
viable but dysfunctional myocardium. It is suggested that
progressive vascular remodeling of coronary resistance
vessels could adversely influence acute metabolic and
autoregulatory adjustments and thereby contribute to
poor ventric ul ar function.
In conclusion, protection against post-ischemic injury
remains an important goal in patients with coronary ar-
tery disease. The majority of pharmacologic compounds
developed to date to delay progression of ischemic injury
have not shown great promise against no-flow and its
consequences—this is probably due to progressive loss
of microvessel function post-ischemia. Therefore apprai-
sal of changes in the coronary microcirculation within
the ischemic vascular bed is absolutely central to the
maintenance of cellular viability (including cardiocytes,
coronary vascular cells and cardiac nerves) and restora-
tion of ventricular contractile function. Future pre-clini-
cal and clinical studies must take into account post-ische-
mic changes occurring at the level of the myocardial mi-
crovessel network and probably most-importantly within
the deeper layers of the ventricular wall. Failure to do so
will undoubtedly reduce th e therapeutic potential that fu-
ture interventions might have for patients with acute my-
ocardial infarction.
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