Microvascular function, is there a link to myocardial viability: Is this another piece to the puzzle?
Microvascular function, is there a link to myocardial viability: Is this another piece to the puzzle?
Fernanda Erthal 0 1
Natasha Aleksova 0 1
Aun Yeong Chong 0 1
Robert A. de Kemp 0 1
Rob S. B. Beanlands 0
FRCPC 0 1
0 Fernanda Erthal and Natasha Aleksova are co-lead authors. Reprint requests: Rob Beanlands, FRCPC, National Cardiac PET Centre and the CAPITAL Interventional investigator group, Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute , 40 Ruskin Street, Ottawa, ON, K1Y 4W7 , Canada; J Nucl Cardiol 1071-3581/$34.00 Copyright 2016 American Society of Nuclear Cardiology
1 National Cardiac PET Centre and the CAPITAL Interventional investigator group, Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute , Ottawa, ON , Canada
‘‘It’s always the small pieces that make the big
The coronary microvasculature regulates flow
resistance and perfusion pressure, and is capable of adapting
to different conditions of metabolic demand. Our
increasing ability to measure absolute myocardial flow
both invasively and noninvasively, has led to greater
understanding and some misunderstanding of the
microvasculature and its role in the pathogenesis of
myocardial disease states.
In this issue, Fukuoka et al.1 investigated
microvascular function following revascularization for acute
myocardial infarction (AMI). They studied 18 patients
who were 14 ± 5 days post-AMI, and had undergone
successful revascularization. Using 13N-ammonia-FDG
PET imaging, they observed an interesting phenomenon
that myocardial flow reserve was reduced in
flowmetabolism mismatch segments. Specifically, they note
that ‘‘in successfully revascularized AMI, microvascular
function is impaired despite preserved myocardial
glucose metabolism in mismatch segments,’’ and that the
recovery in these segments was incomplete.1 The
authors speculate that the latter reflects microvascular
dysfunction. This is a reasonable hypothesis, but there
are several considerations when interpreting flow
reserve measurements in the post-MI,
Several important questions arise from these
findings: 1. Is microvascular dysfunction the reason for
impaired MFR measurements in this setting? 2. Is there
any other evidence for microvascular dysfunction after
revascularization post-MI? 3. What is the metabolic
state of the myocardium after revascularization post-MI?
4. What is the clinical relevance of the observations?
PET AND MICROVASCULAR DYSFUNCTION
There are no direct methods for visualizing the
microvasculature of the myocardium in-vivo.2
Currently, information about coronary microvascular
function is obtained invasively with flow-wire
measurements and/or noninvasively via PET imaging.2,3
PET measurements of myocardial blood flow
(MBF) and myocardial flow reserve (MFR) assess the
combined effects of microcirculatory dysfunction and
epicardial stenosis.4 Although it is not currently possible
to directly distinguish between them, MFR measurement
adds prognostic information in the context of both
ischemic and nonischemic cardiomyopathies.5-7
Microvascular dysfunction may be due to several
mechanisms, including endothelial and smooth muscle
dysfunction, microvascular spasm, sympathetic
dysfunction, and altered microvascular remodeling8, and is
recognized as one cause of impaired flow reserve.4 In
the circumstance where the myocardium supplied by the
infarct-related artery has been fully reperfused following
PCI, as in the study by Fukuoka et al., any impairment in
flow reserve may represent microvascular dysfunction
(with a few caveats noted below), although it is not
possible to determine which mechanism may be at play.
There are now several studies that demonstrate the
value of MFR in populations of patients with suspected
myocardial ischemia, showing that impaired MFR is
associated with worse prognosis, and can be used to
distinguish patients at high risk of having major adverse
cardiovascular events (MACE).5-7 Also, the prognostic
information of MBF is additive to standard perfusion
imaging results, and can impact reclassification of
risks.5-7 More recently, Majmudar et al.9 studied 510
patients with nonischemic and ischemic
cardiomyopathy, and found that MFR B 1.65 was related to
increased risk of MACE regardless of the
cardiomyopathy etiology.9 MFR impairment as a marker of
microvascular dysfunction was also studied in
hypertrophic and idiopathic dilated cardiomyopathies, and
again was able to stratify patients at higher risk of
having an unfavorable outcome.10,11
Even in the setting of normal coronaries, MFR may
be impaired. Van den Heuvel et al.12 observed that MFR
had an inverse correlation with left ventricular systolic
wall stress (r = -0.61, p = 0.01) and a positive
correlation between the extent of mismatch (decreased flow/
increased FDG uptake) and wall stress (r = 0.64,
p = 0.02) in patients with idiopathic dilated
cardiomyopathy.12 They also identified abnormal oxygen
consumption in the mismatch areas, with a
predominance of anaerobic over aerobic metabolism.12 The
abnormal oxygen consumption in these mismatch areas
may reflect hibernation or chronic ischemia in idiopathic
dilated cardiomyopathies, and is a reminder of how
complex and multifaceted the mismatch of flow and
metabolism can be.
Fallavollita et al.13 showed that while there is
reduced flow at rest, the hibernating myocardium
reduces both function and oxygen metabolisms as part
of an adaptive response to avoid supply-demand
imbalance and at least partially protect against the
development of ischemic injury. These downregulations
of oxygen consumption,13 flow, and flow responsiveness
suggest that flow-metabolism mismatch in the context of
AMI may be more a ‘‘physiologic response’’ to the state
of the myocardium than secondary to microvascular
dysfunction per se. An alternate explanation for reduced
MFR observed by Fukuoka et al. may be that this
physiological down regulation persists for hibernating
myocardium even after restoration of perfusion. It is also
possible that the microvasculature itself is part of the
PET imaging and flow quantification post-AMI and
in chronic remodeled myocardial infarction can be
challenging.4 PET scans have limited spatial resolution,
therefore, the 13N-ammonia tracer concentration can be
under- or overestimated in very thin myocardial walls
due to the blurring effects of partial volume averaging
and/or spillover contamination of activity from adjacent
regions such as the blood pool, liver, and lungs.14
In the tracer kinetic model (Patlak) used by the
authors, MBF estimation using 13N-ammonia is based
on the initial tracer uptake and retention rates. After
13Nammonia enters into the myocardium by passive
diffusion and active transport, its retention is predominantly
via the conversion of 13N-ammonia and glutamic acid to
13N-glutamine, which is mediated by glutamine
synthetase and is an adenosine triphosphate-dependent
process. Both transport and retention kinetics may be
affected in the context of AMI, since reduced flow and
ischemia can modify cell membrane permeability,
energetics, and metabolism, changing the ‘apparent’
perfusion measured using 13N-ammonia-PET. It has
not been well studied whether such potential changes to
13N-ammonia kinetics may bias MBF measurements
during the 14 days post-MI, post-revascularized
myocardium. Nonetheless, the effects of tracer kinetic
changes must be considered when measuring flow using
PET in injured myocardium.
MICROVASCULAR OBSTRUCTION AND NO
REFLOW EFFECTS ON MYOCARDIAL FLOW
Following effective percutaneous coronary
intervention (PCI), a considerable number of patients who
present with ST-segment elevation myocardial
infarction (STEMI) will have evidence of microvascular
dysfunction or even microvascular obstruction (MVO)
(ranges from 5% to 50% according to modality).15
‘‘MVO’’ is multifactorial, including distal embolization,
ischemia-reperfusion injury, capillary compression due
to myocardial cell and interstitial edema, and obstruction
formed by neutrophils and platelets. It is a very
heterogeneous mixture of complete occlusion
(no-reflow) and peripheral layers of less severe damage
(lowflow) with dynamic evolving changes following the
Cuculi et al. studied 82 patients with STEMI who
underwent PCI and measured coronary flow reserve as
well as the index of microcirculatory resistance 24 h and
6 months after the event.16 They observed that MVO
detected by MRI was present in 47% of the patients and
demonstrated that microvascular blood flow is not
always restored immediately after revascularization with
PCI, but does begin to recover within 24 h and continues
to do so up to 6 months (especially in the group with
MVO), showing the relationship between MVO and
reduced flow.16 Patients with MVO also had
significantly more fibrosis detected by late gadolinium
enhancement sequence at 6 months. While the presence
of more scars in those who develop microvascular
dysfunction post-revascularization may be an important
finding, no targeted therapies for microvascular
dysfunction are currently available, and further research is
required.8,16 Thus, reduced flow with maintained
metabolism associated with impaired flow reserve observed
by Fukuoka et al., may reflect some level of MVO
reducing perfusion but still viable metabolically active
tissue, hence the perfusion-metabolism mismatch they
Beygui et al. studied 41 patients with single vessel
disease after AMI followed by successful primary PCI
and described that coronary flow reserve (CFR) was
correlated with the extent of the infarcted
myocardiumat-risk but was not able to predict viability.17
Meanwhile, Montisci et al. also studied 24 patients after
primary PCI following AMI and found an inverse
correlation between CFR and no-reflow (similar to
Cuculi et al.), but that both CFR and no-reflow were
correlated with myocardial viability.18 Normal CFR 48 h
after the event was a predictor of regional wall motion
recovery.18 Correlation between CFR and wall motion
recovery was also described by other groups,19,20 but the
techniques and times of measurement after the acute
event differ in the literature.
FLOW-METABOLISM PATTERNS POST
INFARCTION IN PET
Dysfunctional myocardium in patients with
ischemic heart disease can be classified as either viable
or nonviable. In the latter, the organized myocyte tissue
is replaced by fibrosis, and no improvement with
revascularization is expected. On the other hand, viable
myocardium is characterized by a spectrum of
mismatches between function, perfusion, and metabolism.21
Stunning is used to describe post-ischemic dysfunction
that has delayed recovery, despite the return of resting
perfusion to normal. The duration of the function
impairment may vary, but myocardium typically will
recover over time.22-24 In myocardial hibernation, on the
other hand, the dysfunction is believed to be the result of
downregulation after chronic or repeated ischemic
events or repeated stunning.13,21 Hibernating
myocardium may recover contractile function after adequate
revascularization and time.21,25,26
Perfusion-metabolism imaging can define states of
myocardium as viable or nonviable prior to
consideration of revascularization, and has been used to predict
recovery of function and clinical outcomes with and
There are four flow-metabolism patterns described
in perfusion/FDG PET myocardial viability studies: (i)
preserved perfusion and glucose metabolism (viable but
not ischemic at rest), (ii) reduced perfusion with
preserved metabolism (viable mismatch = hibernating
myocardium), (iii) reduced perfusion and metabolism
(nonviable match = fibrotic scar), and (iv) preserved
perfusion with reduced metabolism (reverse mismatch).
The first 3 patterns are well known and common.
Less common is the reverse mismatch pattern, which
may be seen in patients with left bundle branch block
(LBBB) with altered septal metabolism in ischemic or
nonischemic cardiomyopathy, in repetitive stunning or
post-myocardial infarction.21,31,32 This pattern has been
observed early post-revascularization following AMI.31
Anselm et al. described that the reverse mismatch
pattern was seen in 48% of patients who underwent early
PCI, with perfusion-FDG PET performed in the first 10
days following revascularization.31 They observed that
reverse mismatch was more associated to regional wall
motion abnormalities and was associated with shorter
time to PCI. These authors hypothesized that there was
‘‘myocardial metabolic shift during the sub-acute phase
of recovery,’’ but further studies were needed.31
Fukuoka and colleagues represent such a study, but it
is unclear why they did not report reverse mismatch.
This may be because these segments were considered
among those with normal perfusion. Taken together,
these studies demonstrate that the post-MI myocardium
undergoes complex metabolic changes that are less well
understood than the typical perfusion-metabolism match
and mismatch patterns observed in patients with
ischemic heart disease and LV dysfunction before
A wealth of literature has accumulated to support the
application of perfusion-FDG PET viability imaging to
guide decision making in patients with LV dysfunction
being considered for revascularization.21,25,27,28,30,33,34
Although one recent trial called these observations into
question,35 we and others have shown that in selected
populations and experienced hands there appears to be
good clinical value.27,34,36,37 Less is known regarding the
role of perfusion-metabolism imaging to understand the
pathophysiology of the post-infarct myocardium that has
already been revascularized and whether this yields
information that is of clinical or prognostic value.
Furthermore, FDG uptake has been observed in
association with inflammation including the post-MI
myocardium, but with suboptimal relationships with
radiolabelled white blood cells due to myocardial activity
and different levels of microvascular function which may
further impact inflammatory uptake.38,39 It is for this
reason that many studies do not use FDG for viability
detection in the first 2-4 weeks after large MIs.27
CLINICAL RELEVANCE OF FINDINGS
Fukuoka et al. described that nonviable segments
had reduced rest MBF and MFR when compared to
viable segments. Also, these mismatch segments
(normal FDG uptake but low rest MBF) had reduced MFR
and incomplete wall motion recovery, suggesting that
the measurement of flow reserve after acute myocardial
infarction may be a stronger tool than metabolic imaging
to predict viability in this context. Despite these
intriguing results, the study has some limitations and
should be interpreted with caution. The post-MI
myocardium is a complex state with vascular and myocardial
changes that are in a state of flux, making it difficult to
draw conclusions on the role of flow and FDG imaging
in this context. Downregulation, MVO, inflammation as
well as technical factors including altered tracer kinetics
and partial volume effects may all contribute to this
complexity. Furthermore, the clinical relevance of
viability imaging after full revascularization is unclear,
since there is currently no additional therapy to offer.
It is provocative to consider microvascular
dysfunction as a mechanism for mismatch in post-MI
dysfunction. Fukuoka et al. have shed some light on
post-MI recovery, but further studies are needed. This
study reminds us of the challenges of viability imaging
post-MI. Given the complexity, it remains prudent to
avoid FDG PET in the first 2-4 weeks following large
transmural MI. Likewise, it remains prudent to exercise
caution when interpreting flow and flow reserve studies
in the infarct zone, until we have a better understanding
of the evolving flow-metabolism patterns and their
relationship in this setting. In the meantime, another
piece has been placed into the puzzle.
RSB is a career investigator supported by the Heart and
Stroke Foundation of Ontario, a Tier 1 Research Chair
supported by the University of Ottawa, and the University of
Ottawa Heart Institute Vered Chair in Cardiology. FE is
Cardiac Imaging Fellow at the University of Ottawa Heart
Institute supported by the UOHI Associates in Cardiology.
RSB is or has been a consultant for and receives grant
funding from GE Healthcare, Lantheus Medical Imaging, and
Jubilant DraxImage. RdK is a consultant for and receives
grant funding and royalty revenues from Jubilant DraxImage.
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