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Editorial
Myocardial Hypoxia in Dilated Cardiomyopathy:
Is it Just a Matter of Supply and Demand?
Jie Zheng, PhD; Robert J. Gropler, MD
E
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ighty years ago Tennant and Wiggers1 made the seminal
observation that coronary artery occlusion lead to systolic
left ventricular (LV) dysfunction laying the foundation for the
current well-accepted physiological paradigm of tight coupling
between myocardial blood flow (MBF) and systolic function.
The link between MBF and function is oxygen, which serves
as the final electron acceptor in oxidative phosphorylation, the
primary process for generating cellular ATP. Consequently,
myocardial health and thus normal LV function is dependent
on a balance between oxygen supply and demand. In contrast
to other vascular beds, the resting myocardial extraction of
oxygen is high, ≈75% of the arterial oxygen content. Thus, the
ability of the myocardium to further increase oxygen extraction is limited. As a consequence, the demands for increased
myocardial oxygen are met via increases in oxygen delivery,
which is determined by MBF and arterial oxygen content. The
major determinants of the myocardial oxygen demand or consumption are heart rate, wall stress, and LV contractility with
wall stress being directly related to systolic blood pressure
and LV diameter and inversely related to wall thickness. Thus,
under normal conditions where oxygen supply and demand
are balanced, oxygen extraction will not change, whereas
during ischemia where oxygen supply is inadequate to meet
demand, oxygen extraction will increase, albeit modestly.
oxygenation have provided conflicting results. For example,
coronary sinus blood content is reduced in patients with DCM
consistent with ischemia and is a marker of poor prognosis.6
Yet, studies where positron emission tomography was used to
measure myocardial oxygen consumption, a putative index of
oxygenation, demonstrated either similar or reduced levels at
rest in patients with DCM when compared with controls.7–10
Determining whether myocardial oxygenation is reduced or
preserved in patients with DCM is of relevance as this information would help direct whether therapeutic strategies should
target increasing MBF and thus oxygen delivery or focus on
more downstream processes reflecting altered metabolism,
impaired energy transduction, or increased fibrosis.
In this issue of Circulation: Heart Failure, Dass et al11
describe an elegant study designed to address this conundrum.
In 14 patients with well-characterized DCM and 12 age- and
sex-matched controls, magnetic resonance imaging was performed to measure the MBF and myocardial oxygenation
responses to vasodilator stress induced with adenosine. In addition, magnetic resonance imaging measurements of LV mass,
volume and ejection, and phosphorous-31 magnetic resonance
spectroscopy measurements myocardial energetics (PCr/ATP
ratio) were performed at rest and after oxygen supplementation. Measurements of MBF in response to vasodilator stress
or the myocardial perfusion index (MPRI) were determined
from the ratio of the slope of the myocardial signal intensity
curve post contrast obtained at stress divided by the slope of the
curve obtained at rest. Myocardial oxygenation was based on
the blood oxygen level dependent (BOLD) effect on magnetic
resonance imaging. This techniques exploit the fundamental
difference in the paramagnetic properties of deoxyhemoglobin and oxyhemoglobin. Deoxyhemoglobin is paramagnetic,
whereas oxyhemoglobin is diamagnetic. As a consequence,
deoxyhemoglobin causes local dephasing of water protons
and hence signal reduction on T2- or T2*-weighted imaging,
whereas oxyhemoglobin does not. Thus, conditions that either
increase deoxyhemoglobin in the venous blood or increase the
venous blood volume will lead to signal loss, whereas conditions that decrease deoxyhemoglobin content or blood volume will lead to signal gain. Implicit in this measurement is
that only changes in blood oxygen content in response to an
intervention (eg, change from rest to stress) can be detected as
opposed to absolute levels for a given state (eg, rest or stress).
In the normal heart, the induction of stress by exercise or dobutamine should lead to a balanced increase in oxygen supply
and demand with no change in oxygen extraction or deoxyhemoglobin levels and as a consequence to no change in BOLD
signal. In contrast, with vasodilator stress, MBF blood flow
or oxygen supply exceeds oxygen demand leading to reduced
myocardial oxygen extraction, decreased deoxyhemoglobin
Article see p 1088
The LV dysfunction of idiopathic dilated cardiomyopathy
(DCM) is characterized by abnormalities in resting MBF, vasodilator function as evidenced by impaired MBF reserve (peak
MBF/rest MBF in response to vasodilator stress) and impaired
energetics.2–4 On the basis of the aforementioned discussion
on the tight linkage of MBF and LV function, it would be reasonable to surmise that in DCM myocardial oxygenation must
be inadequate resulting in tissue hypoxia. Indeed, the induction hypoxia-inducible factor 1α, which functions as a master
regulator of oxygen homeostasis by controlling both the delivery and the utilization of oxygen, by hypoxia, further supports
this notion.5 However, studies examining the level of tissue
The opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
From the Division of Radiological Sciences, Mallinckrodt Institute of
Radiology, Washington University School of Medicine, St. Louis, MO.
Correspondence to Robert J. Gropler, MD, Cardiovascular Imaging
Laboratory, Mallinckrodt Institute of Radiology, 510 S Kingshighway, St.
Louis, MO 63110. E-mail [email protected]
(Circ Heart Fail. 2015;8:1011-1013.
DOI: 10.1161/CIRCHEARTFAILURE.115.002677.)
© 2015 American Heart Association, Inc.
Circ Heart Fail is available at http://circheartfailure.ahajournals.org
DOI: 10.1161/CIRCHEARTFAILURE.115.002677
1011
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levels, and an increased BOLD signal. In the case of the stressinduced ischemia, oxygen supply does not meet demand
resulting in increased myocardial oxygen extraction, increased
deoxyhemoglobin levels, and decreased BOLD signal.
Consistent with the known impairment in myocardial
vasodilator capacity with DCM, the authors observed that
MPRI was reduced by ≈19% in patients when compared with
controls. However, changes in oxygenation were equivalent
between the groups. Of note, both groups exhibited a similar
response in the rate-pressure product, suggesting equivalent
increases in oxygen demand. As anticipated, PCr/ATP levels at
rest were lower in the patients with DCM than in the controls
consistent with impaired energetics. However, supplemental
oxygen in the patients had no effect on either PCr/ATP levels
or LV function. On the basis of these results, the authors concluded that myocardial oxygenation is not impaired in patients
with DCM and thus as a corollary, it seems that myocardial
hypoxia does not contribute to the impaired energetics and LV
dysfunction in these patients.
So what can the readers make of these results? First, given
that the patients with DCM had normal hemoglobin levels
and were stable New York Heart Association class II–III (and
thus not likely to be hypoxemic), it is not surprising that supplemental oxygen failed to improve myocardial energetics
and LV function. Consequently, these results neither confirm
nor repudiate the presence of tissue hypoxia. The presence
of changes in oxygenation between patients with DCM and
controls despite impaired vasodilator capacity in the patients
with DCM is harder to explain. When reviewing Figure 2,
one cannot help but be struck by the marked variability in
the oxygenation responses in both patients with DCM and
normal controls, particularly when compared the MPRI measurements. The MR method used to measure oxygenation is
sensitive to heart rate variability, so increased arrhythmias
during adenosine might have contributed to the variability. In
addition, the pulse sequence to measure BOLD signals is also
sensitive to B0 and B1 inhomogeneity.12 However, it should
be noted that using similar methods with similar amounts
of measurement variability, these investigators have demonstrated reduced levels of myocardial oxygenation commensurate with reduced levels in MPRI in patients with diabetes
mellitus and aortic stenosis.13,14 So why does the dissociation
between oxygenation and MPRI occur in patients with DCM?
A potential explanation is the likely greater heterogeneity
in cause and disease presentation in the patients with DCM
compared with the diabetic and aortic stenosis cohorts. The
definition of DCM was made based on echocardiographic
measurements of LV size and function and the absence of
flow-limiting lesions on coronary angiography. Thus, the
presence of other causes for DCM such familial-genetic,
autoimmune, postviral, or alcohol-induced that might show
variable oxygenation patterns is unknown. Moreover, prevalence of comorbidities that can impair vasodilator function
and oxygenation, such as hypertension and diabetes mellitus,
is unclear. As mentioned previously, augmentation in the oxygenation signal is inversely related to blood volume. In ischemic myocardium subjected to vasodilator stress, significant
capillary derecruitment can occur that will lead to decrease
in myocardial blood volume.15 Thus, in patients with DCM,
if adenosine induces significant ischemia because of microvascular disease, myocardial oxygenation will be uncoupled
from blood flow.
Ultimately how does one reconcile this study and put it
into context with the current literature? Perhaps 1 way is to
view the question from the perspective of whether the level
of myocardial oxygenation is adequate to meet the oxygen
demands of the myocardium under the conditions studied. At rest, the LV myocardial oxygen demand in DCM
typically exceed those of normal hearts because of a higher
rate-pressure product and the increased LV cavity size and
thinner myocardial wall that results in increased LV wall
stress. Consequently, similar levels of oxygenation between
patients with DCM and controls would imply ischemia, and
thus hypoxia, would be more likely in patients with DCM .
Indeed, the magnitude coronary sinus blood deoxygenation
as biomarker of poor prognosis would support this notion.6
Moreover, this disparity in oxygen supply and demand should
become more pronounced with forms of stress where increase
in oxygen demand drives the increase in MBF, and thus oxygen delivery, such as with exercise, pacing, or adrenergic
stimulation, as opposed to vasodilator stress where increases
in MBF are uncoupled to myocardial oxygen demand. Indeed,
in response to 20 µg/kg per minute of dobutamine, patients
with DCM exhibit a blunted response in oxygen consumption (measured with positron emission tomography) compared with controls. Moreover, in these same patients, there
was evidence of accelerated glucose metabolism relative to
flow during dobutamine further, suggesting the induction of
ischemia with adrenergic stimulation.16 So as we continue to
study the relationship between MBF, oxygenation, and LV
function in CV health and disease, it may be useful to keep as
a reference the law of supply and demand.
Disclosures
None.
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Key Words: Editorials ■ arrhythmias, cardiac ■ cardiomyopathy, dilated
■ hypoxia-inducible factor 1 ■ oxygen consumption ■ positron emission
tomography
Myocardial Hypoxia in Dilated Cardiomyopathy: Is it Just a Matter of Supply and
Demand?
Jie Zheng and Robert J. Gropler
Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 5, 2017
Circ Heart Fail. 2015;8:1011-1013
doi: 10.1161/CIRCHEARTFAILURE.115.002677
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