© 2000 American Heart Association, Inc.
Integrative Physiology |
Microvascular Integrity and the Time Course of Myocardial Sodium Accumulation After Acute Infarction
From the Cardiology Division, Department of Medicine (C.E.R., J.A.C.L.), and Department of Radiology (H.B.H., J.A.C.L.), Johns Hopkins University, Baltimore, Md, and Division of Cardiology, Department of Medicine (R.J.K., E.-l.C.), Northwestern University Medical School, Chicago, Ill. Carlos E. Rochitte’s present address is Heart Institute (InCor), University of São Paulo Medical School, Brazil.
Correspondence to João A.C. Lima, MD, The Johns Hopkins Hospital, Cardiology Division, Blalock 569, 600 N Wolfe St, Baltimore, MD 21287-6568. E-mail jlima{at}mri.jhu.edu
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Abstract |
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Abstract—Loss of membrane permeability caused by ischemia leads to cellular sodium accumulation and myocardial edema. This phenomenon has important implications to left ventricular structure and function in the first hours after myocardial infarction. We hypothesized that during this period of time, after prolonged coronary occlusion and complete reflow, the rate of myocardial sodium accumulation is governed by microvascular integrity. We used 3-dimensional 23Na MRI to monitor myocardial sodium content changes over time in an in vivo closed-chest canine model (n=13) of myocardial infarction and reperfusion. Infarcts with microvascular obstruction (MO) defined by both radioactive microspheres and contrast-enhanced 1H MRI showed a slower rate of sodium accumulation as well as lower blood flow at 20 minutes and 6 hours after reperfusion. Conversely, the absence of MO was associated with faster rates of sodium accumulation and greater blood flow restoration. In addition, infarct size by 23Na MRI correlated best with infarct size by triphenyltetrazolium chloride and contrast-enhanced 1H MRI at 9 hours after reperfusion. We conclude that in reperfused myocardial infarction, sodium accumulation is dependent on microvascular integrity and is slower in regions of MO compared with those with patent microvasculature. Finally, 23Na MRI can be a useful tool for monitoring in vivo myocardial sodium content in acute myocardial infarction.
Key Words: magnetic resonance imaging • sodium • myocardial infarction • microcirculation • reperfusion
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Introduction |
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The ability to control electrochemical gradients across the cell membrane is a unique characteristic of the living cell.1 In patients with acute myocardial infarction, the precise delineation of regions containing viable versus nonviable myocytes represents a crucial parameter in the decision-making process. Moreover, the development of novel treatment strategies for patients with acute infarction depends on an in-depth understanding of the mechanisms involved in cellular injury and death after coronary occlusion and reperfusion. Among these, cellular edema caused by sodium accumulation not only represents a marker of cell injury, but it may also play an important role in altering cardiac mechanical function in response to myocardial infarction.2 3 4
Previous studies5 have suggested that the time course of myocardial sodium accumulation after an acute ischemic insult depends on sodium delivery to the injured territory. However, those studies were based on postmortem pathologic examinations performed at different time points and were therefore unable to monitor the process of myocardial sodium accumulation continuously. Moreover, those studies examined the influence of epicardial coronary artery patency and did not investigate the process at the level of the myocardial microvasculature. This is particularly important given that recent clinical studies6 have demonstrated the failure to achieve complete reperfusion of the infarcted territory even after the infarct-related artery has been successfully opened. This failure results from microvessel occlusion at the level of the myocardium, a process known from basic studies as the "no-reflow phenomenon."7 8 Moreover, microvascular obstruction (MO) has been identified as a marker of greater ventricular remodeling and worse prognosis in patients with acute myocardial infarction9 and experimentally.3 10
In this study, we sought to investigate the influence of microvascular integrity on the time course of changes in myocardial sodium content. For this purpose, we used methodology previously developed to measure myocardial sodium concentration in vivo.11 12 We performed magnetic resonance sodium imaging of the heart in 3 dimensions with sufficient spatial and temporal resolution to monitor myocardial sodium concentration before, during, and up to 9 hours after coronary occlusion and reperfusion. We compared myocardial sodium accumulation in areas with and without MO defined by myocardial blood flow (MBF) measured with radioactive microspheres8 and in vivo by contrast-enhanced proton MRI.6 10
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Materials and Methods |
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Experimental Protocol
Thirteen mongrel dogs underwent a closed-chest myocardial infarction protocol consisting of 90-minute coronary occlusion followed by 8 to 9 hours of reperfusion performed inside a 4.7-T MRI magnet. After thiopental (25 mg/kg IV) induction, animals were intubated; mechanically ventilated; and kept under halothane anesthesia until completion of the protocol, which lasted 14 hours.
Microspheres were administrated by a 7F pigtail catheter placed into the left ventricle (LV) cavity. The femoral artery blood pressure wave from the catheter sheath was the trigger for the ECG-gated MRI pulse sequence. Through the right carotid artery under fluoroscopic guidance, a 3.0-mm angioplasty balloon catheter was positioned into the proximal left anterior descending artery (LAD).
The animals were then transferred to the MRI magnet and placed in left
lateral decubitus with the precordium over a 15-cm-diameter
double-resonant (23Na-1H)
surface coil. A baseline 23Na magnetic resonance
image was acquired with the balloon deflated. The balloon was then
inflated (5 atm) for 90 minutes to induce myocardial infarction. During
the coronary occlusion period, 3 sets of images were acquired
sequentially. After the 90-minute occlusion, the angioplasty balloon
was deflated and removed from the coronary artery to allow
myocardial reperfusion. After coronary reflow, 
10 serial
sets of 23Na images were acquired up to 8 hours
after reperfusion. Between 6 and 7 hours after reperfusion,
contrast-enhanced 1H MRI was acquired before and
after gadolinium–diethylenetriaminepenta-acetic acid (Gd-DTPA) bolus
injection (0.3 mmol/kg). At 8 to 9 hours after reperfusion, the
last 23Na image set was acquired.
The heart was then excised and the LV sectioned into 5 equal-thickness short-axis (SA) slices from apex to base. The slices were submerged into 1% triphenyltetrazolium chloride (TTC) solution at 37°C for 20 minutes and immediately photographed.
Regional blood flow was measured 4 times during the experimental
protocol. For each flow measurement, 2 million radioactive
microspheres (15 to 16 µm in diameter, Dupont) labeled
with 153Gd, 113Sn,
103Ru, 95Nb, or
46Sc were injected into the LV. MBF measurements
were performed at baseline, during occlusion, and 20 minutes and 6
hours after reperfusion in the following 4 regions of interest (ROI):
risk region (MBF <50% of the remote region during occlusion),
infarcted region (TTC negative), TTC+/risk region (risk region subset
that did not become infarcted), and no-reflow region (infarcted region
subset with MBF <50% of the remote region after coronary
reflow).
Myocardial slices were sectioned in radial segments and then into the following 3 equal transmural pieces: subendocardial, subepicardial, and midwall. Pieces were weighted and counted in a gamma-emission spectrometer (Packard) at appropriated energy windows. The radioactive counting and relative flow calculations were performed by standard methods. Relative blood flow was calculated as the radioactive counting ratio for a given myocardial segment and the average counting for segments at the same level and transmural position in the remote nonischemic LV wall opposite the infarcted region.
From the 13 experiments that completed the above protocol, 8 animals underwent prolonged myocardial ischemia and reperfusion (infarct group) confirmed by microspheres, TTC, and contrast-enhanced MRI. In 4 experiments (control group), myocardial ischemia was never generated because of collateral flow, as documented by radioactive microspheres, no TTC-negative regions at postmortem examination, and no evidence of myocardial infarction by in vivo contrast-enhanced 1H MRI. In 1 animal, total coronary occlusion was sustained up to protocol completion to examine myocardial sodium accumulation in a nonreperfused coronary territory.
MRI Protocol
MRI methods used in this study have been described in detail
elsewhere.11 12 In brief, a cardiac-gated, segmented
k-space, 3-dimensional GRASS was used on a GE/Bruker 4.7-T Omega
system. At 4.7 T the Lamor frequencies for 23Na
and 1H are 52.9 and 200 MHz, respectively. The
imaging parameters for 23Na MRI were
the following: TR=12.6 ms, TE=4.3 ms, number of excitations=16, number
of views per segment=32, field of view=384 mm, matrix
size=128x128x32, voxel size=3x3x3 mm, and imaging acquisition
time=20 minutes. Proton imaging parameters were the
following: TR=8.6 ms, TE=2.7 ms, number of excitations=1, number of
views per segment=16, field of view=192 mm, matrix
size=128x128x32, voxel size=1.5x1.5x3 mm, and imaging
acquisition time=3 minutes.
The short 23Na T1 (30 ms) allows large flip-angle excitations even for fast gradient-echo pulse sequences with extremely short TR. Specifically, the GRASS sequence used in this study (Ernst angle of 59° for 23Na and 16° for 1H11 and the peak signal 6-fold higher for 23Na) is more efficient for 23Na than for 1H imaging.
To provide the best possible cross-registration between 23Na and 1H magnetic resonance images and histological data, we used 3-dimensional volume acquisition of magnetic resonance signal and a double-resonant RF coil able to tune at 23Na and 1H Lamor frequencies without changing coils or animal position.11 12
MRI Data Analysis
Raw myocardial slices were double oblique images of the heart,
which were rotated and resliced offline using NIH Image software to
obtain "true" SA image planes perpendicular to the major axis of
the LV. Typically, 15 slices 3 mm each covered the whole LV.
To compare images over time, the endocardial and epicardial contours of
the LV were defined on the baseline image (LV ROI), thereby isolating
LV myocardium from both ventricular cavities
and the surrounding structures of the heart (Figure 1
). LV ROI was pasted on the subsequent
images over time. An operator corrected cardiac translations. The
baseline LV ROI was then subtracted from the LV ROI for the last image
(9 hours after reperfusion). On this subtraction image, an infarct ROI
was defined by the operator as the bright region using a threshold of 2
SDs of signal intensity (SI) above that measured in normal
myocardium. The time course of SI in infarcted
myocardium was measured as changes in mean SI over time
within this fixed-infarct ROI.
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Additionally, 1 infarct ROI was defined for each image obtained during occlusion and after reperfusion, and their extent was measured to evaluate the changes in 23Na MRI and contrast-enhanced 1H MRI infarct size over time.
For experiments in the control group, with no regions of increased myocardial SI, measurements were obtained from septal, anteroseptal, and anterior LV walls (LAD territory) of 70 different LV slices from apex to base.
MO was defined by radioactive microsphere MBF measurements (<50% relative to flow in remote noninfarcted myocardium)13 and confirmed by contrast-enhanced 1H MRI as a hypoenhanced region in the first 3 minutes after contrast injection as previously described.6 13 14
Statistical Methods
Values are expressed as mean±SEM. We used paired t
test for comparison of extent of the regions (risk, infarcted, and MO
regions) and simple linear regression to assess correlation among the
different imaging and histopathologic methods. Repeated-measures ANOVA
and Bonferroni tests were performed for comparisons of
hemodynamic parameters, MBF, and myocardial
SI (time-intensity curves) over time.
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Results |
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Hemodynamics
Heart rate and systolic and diastolic blood pressure values were measured at baseline, occlusion, and 20 minutes and 6 hours after reperfusion. Mean values for both control and infarct groups showed an increase in blood pressure from baseline to occlusion (88x55 to 116x92 and 111x78 to 127x95 mm Hg). However, blood pressure decreased in the infarct group after coronary reflow (108x83 mm Hg), which was not observed in the control group (130x90 mm Hg). The heart rate decreased slightly during the protocol (86 to 71 and 103 to 97 bpm), which was likely related to prolonged anesthesia.
Myocardial Blood Flow
Relative MBF decreased in all infarcted animals to 9.9±3.1%
relative to the remote region during occlusion. It recovered to
baseline levels shortly after reperfusion (79.6±7.9%) but decreased
progressively toward the end of the experiment (42.7±2.8%) as a
result of the development of MO in a subset of animals as described
below (ANOVA; P<0.001).
Two subgroups of infarcts were identified on the basis of the presence
or absence of MO in the infarct core. MO was defined retrospectively by
radioactive microspheres as a >50% decline in MBF after
coronary reflow. Restoration of MBF was severely impaired
(<50% MBF relative to remote) both early (44.4±4.9%) and late
(28.3±2.1%) after reperfusion in the subset with MO. Conversely, in
the absence of MO, MBF within the infarcted region showed
hyperemic reperfusion 20 minutes after coronary reflow
(106.1±6.3%). At 6 hours after coronary reflow, MBF
measurements demonstrated that reperfusion was still maintained well
above blood flow levels in the group with MO (Figure 2A). Additionally, contrast-enhanced
1H MRI confirmed radioactive microsphere
findings by demonstrating in vivo the presence of MO only in animals
with >50% MBF reduction in the infarcted regions after
coronary reflow, as previously described.5 13
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Time Course of Myocardial SI by 23Na MRI
Sequential measurements of 23Na myocardial
SI over time revealed distinct time-intensity curves as depicted in
Figure 2B
. The control group showed no changes in myocardial SI
during 9 hours of image acquisition (Figure 2B).
Two different patterns of 23Na MRI SI changes
over time were observed in the infarct group on the basis of the
presence or absence of MO by radioactive microsphere and
contrast-enhanced 1H MRI. Infarcts without
regions of MO showed a steeper increase in SI immediately after
reperfusion. 23Na MRI SI rose up to 60.6±5.5%
(P<0.001 versus baseline) in the first image after
reperfusion (20 minutes) and continued to increase up to 103.6±9.0%
(P<0.001 versus baseline) 1 hour after reperfusion. From
this point on, myocardial SI increased at a much slower rate until the
end of the protocol, reaching 133.2±7.1% (P<0.001 versus
baseline) 9 hours after reperfusion (Figures 2B and 3).
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Conversely, the subgroup of experiments with MO showed a much slower
myocardial 23Na SI increase after reperfusion. In
the first image after reperfusion, 23Na SI
increased only 20.9±1.9% over baseline SI, and at 1 hour the mean SI
was only 29.8±3.0% greater than baseline. Thereafter, a progressive
but slow myocardial SI increase was noted, reaching a lower plateau
(72.8±6.9%) than the subgroup with complete reperfusion at 6 hours
after reperfusion. Maximal SI was 85.6±7.1% at 9 hours after
reperfusion, which represented a level similar to the
40-minute SI level observed in the group without MO (Figures 2B and 4).
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Finally, in 1 animal, total coronary occlusion was maintained
up to the end of the protocol. Microsphere MBF measurements
indicated that myocardial perfusion was not reestablished within the
territory at risk during occlusion (relative MBF was 1.0±0.5% during
occlusion and 0.8±0.5% after coronary reflow,
P=NS). Five hours after reperfusion,
23Na SI in the LAD territory was only 47.4±3.4%
higher than baseline, whereas in reperfused infarcts containing regions
of MO it was 76.9±7.0%, and 119.4±8.3 in infarcts without MO (Figure 2B).
Transmural Myocardial Sodium Accumulation After
Reperfusion
Transmural differences in SI in the subgroup with MO produced a
dark subendocardial region where 23Na SI was
reduced between 50 minutes and 6 hours after reperfusion (Figure 4). These dark regions reflect slower local
myocardium sodium accumulation when compared with the
correspondent subepicardial regions (Figure 4) or when compared
with infarcted regions from animals without MO (Figure 3). The
dark regions were also characterized by lower restoration of local
myocardial perfusion relative to the subepicardium (Figure 5). In the subgroup with MO, the
subendocardial layer had significantly lower blood flow compared with
the subgroup without MO both during occlusion (3.3±0.7% versus
8.4±1.2%, P<0.01) and early (35.8±7.1% versus
161.3±7.8%, P<0.001) and late (23.4±4.3% versus
62.7±3.1%, P<0.001) after reperfusion (Figure 5).
Moreover, infarcts without MO showed a hyperemic flow pattern
in the subendocardium immediately after coronary reflow, which
did not occur in infarcts with MO (Figure 5). These differences
in MBF correlated well with myocardial sodium accumulation as indexed
by 23Na MRI. Infarcts without MO showed a rapid
and homogeneous increase in SI across the entire infarcted
region as early as 20 minutes after coronary reflow (Figure 3).
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Whereas differences in subendocardial blood flow between the 2
subgroups of experiments correlated with differences in SI by both
sodium and proton MRI, differences in subepicardial blood flow did not
correspond to subepicardial differences in SI by either imaging
modality (Figure 5). This probably indicates a threshold effect
above which microvascular injury is not reflected by either imaging
method.
Infarct Size
The extent and location of myocardial regions with increased SI by
23Na MRI 8 to 9 hours after reperfusion
correlated well with infarct size defined as TTC-negative regions at
postmortem examination (Figures 6 and 8A, r=0.95, P<0.001) and as regions of
myocardial hyperenhancement by contrast-enhanced
1H MRI (Figures 7 and 8B, r=0.98,
P<0.001). Mean infarct size by contrast-enhanced
1H MRI (19.1±3.5% of LV mass), TTC (18.1±4.2%
of LV mass), and 23Na MRI (18.8±3.6% of LV
mass) were similar at 8 to 9 hours after reperfusion (P=NS).
Similarly, infarct size by contrast-enhanced 1H
MRI at completion of the imaging protocol (8 to 9 hours after
reperfusion) correlated well with infarct size by TTC
(r=0.95, P<0.001). However, the extent of
myocardial regions with increased 23Na SI
augmented over time from 11.7±2.7% at 2 hours to 16.5±3.9% at 8 to
9 hours after reperfusion relative to LV mass and from 31.3±6.5% at 2
hours to 41.5±8.1% at 8 to 9 hours relative to the risk region
(P<0.03 for both comparisons). This augmentation was caused
by progressive myocardial 23Na accumulation
within injured territory (Figures 1, 3 and 4), as
discussed below.
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Discussion |
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This is the first study to demonstrate protracted myocardial sodium accumulation in regions of MO after acute myocardial infarction. In addition, this is also the first study to measure the rate of local myocardial sodium accumulation in situ during acute coronary occlusion and reperfusion.
We used image SI as an index of total myocardial sodium concentration on the basis of previous work, which validated such an approach in the same animal model.11 12 15 Data on ischemia-induced changes in myocardial sodium concentration have been derived from isolated perfused heart models using NMR spectroscopy with shift reagents,16 17 18 19 20 21 22 23 24 25 ion-sensitive electrodes,16 18 21 26 and patch-clamp cell studies.27 These studies have provided knowledge on intracellular versus extracellular sodium concentrations by probing Na+/K+ ATPase, Na+/H+, and Na+/Ca2+ membrane pump activities during ischemia and reperfusion. However, none of these previous studies addresses differences in local sodium accumulation in injured myocardial tissue in vivo. Furthermore, most previous work investigated ionic changes during brief periods of ischemia in the isolated heart or in in vitro settings.5 In the present report, severe and prolonged myocardial ischemia followed by reperfusion was produced, causing extensive myocardial necrosis with large areas of myocyte membrane rupture and, in some cases, sizable areas of MO.8
Total myocardial sodium content augmentation seen in our study agrees with previous in vitro studies performed up to 26 hours after infarction.5 A question raised by our work is whether this augmentation in sodium content is mostly due to increased intracellular or extracellular sodium accumulation. Although it is obvious that at one point in the acute infarction scenario intracellular and extracellular compartments will no longer have pathophysiological meaning, it may still apply to the early phases of studies reported here. In this regard, Regan et al28 have demonstrated that alterations in myocardial sodium concentration differ significantly in severe versus mild ischemia. In that study, intracellular sodium concentration increased 5 times during severe ischemia and just 2-fold during mild ischemia. Significant changes in the extracellular space during either mild or severe ischemia were not found. Indeed, analyses of cation distribution indicated that significant increments of sodium and water in ischemic tissue were predominantly intracellular.28 Therefore, the increase in total myocardial sodium content reported in this study parallels these previous observations and is probably secondary to intracellular sodium accumulation in the early phases of the ischemic injury (see Pathophysiologic Implications, below).
No-Reflow Phenomenon and Myocardial Sodium Concentration
Our study also shows for the first time that myocardial sodium
accumulation is delayed in regions of MO. In reperfused
myocardium with patent microvasculature, sodium
concentration rises steeply, reaching 2-fold its baseline concentration
in 2 hours. Conversely, in regions of MO, a similar increase in
myocardial sodium concentration requires 6 hours. These findings
demonstrate that sodium accumulation rate within infarcted territory is
dependent on regional blood flow in the first hours after
coronary occlusion and reflow. Therefore, even after reflow,
infarcted regions with impaired microcirculatory function will have
delayed sodium accumulation.
MO in this study was documented by radioactive microsphere MBF (gold standard) but also monitored by contrast-enhanced 1H MRI used as a secondary index for MO in situ.13 14 29 30 In these regions, diffusion would constitute the most important mechanism for sodium content increase. This diffusion process may be further slowed by long distances between the source of sodium (open capillaries) and by myocytes within the center of MO regions, in which myocardial samples (300 to 500 mg) with near-0 MBF are frequently found. In addition, the effective diffusion constant for sodium in necrotic myocardial tissue should be much lower than in free water. As proposed by numerous previous studies,31 32 33 factors such as increased viscosity, molecular crowding, increased tortuosity, electrostatic interactions, sodium binding to soluble proteins, cytoplasmic organelles, and/or membrane fragments could contribute to the delayed sodium transport observed in the no-reflow regions at the infarct core.31 32 33
Methodological Considerations and Clinical Significance
In this study, we obtained high-resolution 3-dimensional images of
the heart by 23Na MRI in a 4.7-T magnet, which
permitted the analysis of transmural myocardial sodium
accumulation over time. These methods evolved from previous
studies.11 15 34 35 However, several methodological
characteristics of the present study represent important
improvements over previous work.11 12 The pulse-sequence
features used in this study were adapted from fast-imaging techniques
originally developed for proton imaging (gradient and fractional
echoes, extremely short TRs, and imaging at the Ernst angle).
Furthermore, inherent 3-dimensional volume imaging advantages provided
faster volume imaging of thin contiguous slices without crosstalk,
increased signal-to-noise ratio, and reformation capabilities, which
allowed an easier and more precise definition of LV cross-sectional
images for comparisons with histology and MBF. The sequence high
temporal resolution (20 minutes for the entire sodium 3-dimensional
segmented k-space) and continuous data acquisition (dedicated
scanner workstation console) allowed a high sampling rate during the
several hours of continuous 23Na image
acquisition. Simultaneous raw data processing and
visualization were performed in another workstation (using a customized
software in IDL).
The 15-cm-diameter double-resonant 23Na-1H RF coil, especially designed,11 12 and the advantageous usage of the short sodium T1,11 coupled with recent developments of fast MRI techniques described above,36 enabled the development of methods with sufficient spatial and temporal resolution to perform the studies reported here.
The advantage of sodium over proton MRI in this study is the ability to measure ongoing myocardial sodium accumulation over a long period of time. Conversely, contrast-enhanced 1H MRI represents a snapshot of the entire process. Repeated gadolinium proton MRI studies would require long intervals (hours) for contrast agent washout. Recent studies linking the development of MO to impaired LV remodeling after infarct3 and worse prognosis10 suggest that the rate of myocardial sodium accumulation may constitute a crucial parameter in postinfarction patients. In the clinical setting, a clear advantage of sodium MRI would be the lack of contrast agent use.
Recent studies on the feasibility of performing sodium imaging at 1.5 T in humans37 38 have opened the possibility of enabling this technique to be used clinically. In this regard, the present contribution highlights the value of monitoring myocardial injury noninvasively, which in the future could be performed in humans using commercially available 1.5-T magnetic resonance scanners.
Pathophysiological Implications
In this study, elevated myocardial sodium SI has been shown to
correspond to irreversibly injured myocardial regions. The available
evidence strongly supports the notion that, after reperfused myocardial
infarction, elevated 23Na magnetic resonance SI
is due to intracellular sodium accumulation secondary to loss of
myocyte ionic homeostasis.11 12 15 This conclusion comes
from the observation that myocardial tissue volume is primarily
intracellular and that after acute myocardial reperfusion, the
extracellular space shows only a minor increase.12 28
Previous studies have shown that after myocardial reperfusion, intense
intracellular edema happens and precedes cell membrane rupture.
Therefore, initial elevation of sodium SI is likely secondary to
intracellular edema after reperfusion as a result of Na/K ATPase pump
failure, which at the same time represents a marker of
irreversible cell damage. At later phases there will be increased
sodium content within infarcted myocardium as a result of
cell membrane rupture and equilibration with plasma sodium
concentration.
However, the increase in tissue sodium concentration in nonviable myocardial regions requires sodium delivery by the microcirculation. Our study demonstrates that myocardial regions with low flow due to MO or permanent coronary occlusion have a slower increase in sodium content. Our observation has several pathophysiologic implications. For instance, differences in myocardial sodium accumulation between open- and closed-artery infarcts could partially underlie the well-known prognostic differences between these 2 groups of patients.4 In this regard, myocardial edema could theoretically preserve myofilament integrity and prevent infarct expansion, reducing ventricular remodeling. On the other hand, although the presence of no-reflow regions has been linked to the development of ventricular remodeling and postinfarct complications,9 10 the mechanisms underlying these relationships remain unclear. Recently, we have reported significant alterations of mechanical properties in large areas of MO consisting of increased stiffness with reduced distensibility during passive systolic stretch.3 This could theoretically lead to myofilament rupture and/or impose abnormally high levels of afterload on the remaining noninfarcted ventricle, leading to greater ventricular remodeling.
Another thought-provoking finding is a significant increase in the extent of the region with increased myocardial SI by 23Na MRI at its periphery. This progressive cell swelling after the onset of reperfusion is unlikely to be secondary to extracellular edema as discussed above. Moreover, these cell deaths, which are associated with an increase in intracellular sodium content, are unlikely secondary to apoptosis.39 This phenomenon either could represent additional cell death due to reperfusion injury8 40 41 or could reflect the final manifestations of cell swelling and rupture after irreversible damage during occlusion.7 42 Our work was not designed to directly differentiate between these 2 possibilities, which are also not mutually exclusive. In any case, the progression of myocardial sodium accumulation within infarcted territory deserves further investigation as a phenomenon theoretically amenable to modulation in the future treatment of patients with acute infarction.
Conclusions
We conclude that fast 3-dimensional 23Na MRI
is a useful tool to monitor in vivo dynamic changes in sodium
myocardial content over time after prolonged coronary occlusion
and reflow. Sodium myocardial accumulation occurs progressively within
injured territory up to 8 hours after reperfusion. More importantly,
the rate of sodium myocardial accumulation is dependent on its delivery
through the microcirculation and is directly related to regional MBF.
Therefore, in the first hours after prolonged coronary
occlusion and reperfusion, myocardial sodium accumulation is greater in
reperfused myocardial tissue where the microvasculature has remained
patent, and it is reduced in regions with MO.
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Acknowledgments |
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This work was supported by Grant-in-Aid 92-10-26-01 from the American Heart Association, Dallas, Tex; and National Heart, Lung, and Blood Institute Grant HL-45090. C.E.R. was supported in part by Fellowship Grant 200247/95-6 from CNPq (Brazilian National Research Council).
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Footnotes |
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This manuscript was sent to Eugene Braunwald, Consulting Editor, for review by expert referees, editorial decision, and final disposition.
Received July 21, 2000; revision received August 22, 2000; accepted August 22, 2000.
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