Microvascular Integrity and the Time Course of Myocardial Sodium Accumulation After Acute Infarction
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.
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
Materials and Methods
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 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=128×128×32, voxel size=3×3×3 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=128×128×32, voxel size=1.5×1.5×3 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.
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
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.
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 (88×55 to 116×92 and 111×78 to 127×95 mm Hg). However, blood pressure decreased in the infarct group after coronary reflow (108×83 mm Hg), which was not observed in the control group (130×90 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
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⇓).
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⇓).
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⇑).
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.
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.
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.
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.
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.
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).
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.
- © 2000 American Heart Association, Inc.
Kutchai HC. Cellular membranes and transmembrane transport of solutes and water. In: Berne RM, Levy MM, eds. Physiology. 3rd ed. St Louis, Mo: Mosby-Year Book, Inc; 1993:3–26.
Resar JR, Judd RM, Halperin HH, Chacko VP, Weiss RG, Yin FCP. Direct evidence that coronary perfusion affects diastolic myocardial mechanical properties in canine heart. Cardiovasc Res. 1993;27:403–410.
Gerber BL, Rochitte CE, Melin JA, McVeigh ER, Bluemke DA, Wu KC, Becker LC, Lima JAC. Microvascular obstruction and left ventricular remodeling early after acute myocardial infarction. Circulation. 2000;101:2734–2741.
Kim CB, Braunwald E. Potential benefits of late reperfusion of infarcted myocardium: the open artery hypothesis. Circulation. 1993;88:2426–2436.
Jennings RB, Sommers HM, Kaltenbach JP, West JJ. Electrolyte alterations in acute myocardial ischemic injury. Circ Res. 1964;14:260–269.
Lima JAC, Judd RM, Bazille A, Schulman SP, Atalar E, Zerhouni EA. Regional heterogeneity of human myocardial infarcts demonstrated by contrast-enhanced MRI: potential mechanisms. Circulation. 1995;92:1117–1125.
Kloner RA, Ganote CE, Jennings RB. The “no-reflow” phenomenon after temporary coronary occlusion in the dog. J Clin Invest. 1974;54:1496–1508.
Ambrosio G, Weisman HF, Mannisi JA, Becker LC. Progressive impairment of regional myocardial perfusion after initial restoration of postischemic blood flow. Circulation. 1989;80:1846–1861.
Ito H, Maruyama A, Iwakura K, Takiuchi S, Masuyama T, Hori M, Higashino Y, Fujii K, Minamino T. Clinical implications of the “no-reflow” phenomenon: a predictor of complications and left ventricular remodeling in reperfused anterior wall myocardial infarction. Circulation. 1996;93:223–228.
Wu KC, Zerhouni EA, Judd RM, Lugo-Olivieri CH, Barouch LA, Schulman SP, Blumenthal RS, Lima JAC. The prognostic significance of microvascular obstruction by magnetic resonance imaging in patients with acute myocardial infarction. Circulation. 1998;97:765–772.
Kim RJ, Lima JAC, Chen EL, Reeder SB, Klocke FJ, Zerhouni EA, Judd RM. Fast 23Na magnetic resonance imaging of acute reperfused myocardial infarction: potential to assess myocardial viability. Circulation. 1997;95:1877–1885.
Kim RJ, Judd RM, Chen E-L, Fieno DS, Parrish TB, Lima JAC. Relationship of elevated 23Na magnetic resonance image intensity to infarct size after acute reperfused myocardial infarction. Circulation. 1999;100:185–192.
Rochitte CE, Lima JAC, Bluemke DA, Reeder SB, McVeigh ER, Furuta T, Becker LC, Melin JA. Magnitude and time course of microvascular obstruction and tissue injury after acute myocardial infarction. Circulation. 1998;98:1006–1014.
Kim RJ, Chen E-L, Lima JAC, Judd RM. Myocardial Gd-DTPA kinetics determine MRI contrast enhancement and reflect the extent and severity of myocardial injury after acute reperfused infarction. Circulation. 1996;94:3318–3326.
Pike MM, Kitakaze M, Marbán E. 23Na-NMR measurements of intracellular sodium in intact perfused ferrets hearts during ischemia and reperfusion. Am J Physiol. 1990;259:H1767–H1773.
Askenasy N, Vivi A, Tassini M, Navon G. Cardiac energetics, cell volumes, sodium fluxes, and membrane permeability: NMR studies of cold ischemia. Am J Physiol. 1995;269:H1056–H1064.
Lotan C, Miller S, Simor T, Elgavish G. Cardiac staircase and NMR-determined intracellular sodium in beating rat hearts. Am J Physiol. 1995;269:H332–H340.
Pike MM, Luo C, Clark M, Kirk KA, Kitakaze M, Madden MC, Cragoe EJ Jr, Pohost G. NMR measurements of Na+ and cellular energy in ischemic rat heart: role of Na+-H+ exchange. Am J Physiol. 1993;256:H2017–H2026.
Kléber AG. Resting membrane potential, extracellular potassium activity, and intracellular sodium activity during acute global ischemia in isolated perfused guinea pig hearts. Circ Res. 1983;52:442–450.
Regan TJ, Broisman L, Haider B, Eaddy C, Oldewurtel HA. Dissociation of myocardial sodium and potassium alterations in mild versus severe ischemia. Am J Physiol. 1980;238:H575–H580.
Judd RM, Lugo-Olivieri CH, Arai M, Kondo T, Croisille P, Lima JAC, Mohan V, Becker LC, Zerhouni EA. Physiological basis of myocardial contrast enhancement in fast magnetic resonance images of 2-day-old reperfused canine infarcts. Circulation. 1995;92:1902–1910.
Wu KC, Kim RJ, Bluemke DA, Rochitte CE, Zerhouni EA, Becker LC, Lima JAC. Quantification and time course of microvascular obstruction by contrast-enhanced echocardiography and magnetic resonance imaging following acute myocardial infarction and reperfusion. J Am Coll Cardiol. 1998;32:1756–1764.
Mastro AM, Babich MA, Taylor WD, Keith AD. Diffusion of a small molecule in the cytoplasm of mammalian cells. Proc Natl Acad Sci U S A. 1984;81:3414–3418.
Latour LL, Svoboda K, Mitra PP, Sotak CH. Time-dependent diffusion of water in a biological model system. Proc Natl Acad Sci U S A. 1994;91:1229–1233.
DeLayre JL, Ingwall JS, Malloy C, Fossel ET. Gated sodium-23 nuclear magnetic resonance images of an isolated perfused working rat heart. Science. 1981;212:935–936.
Granot J. Sodium imaging by gradient reversal. J Magn Reson Imaging. 1986;68:575–581.
Reder SB. Development of High Speed, High Resolution Magnetic Resonance Imaging and Tagging Techniques [dissertation]. Baltimore, Md: Johns Hopkins University; 1993.
Searle J, Kerr JF, Bishop CJ. Necrosis and apoptosis: distinct modes of cell death with fundamentally different significance. Pathol Annu. 1982;17:229–259.
Matsumura K, Jeremy RW, Schaper J, Becker LC. Progression of myocardial necrosis during reperfusion of ischemic myocardium. Circulation. 1998;97:795–804.
Fishbein MC, Y-Rit J, Lando U, Kanmatsuse K, Mercier JC, Ganz W. The relationship of vascular injury and myocardial hemorrhage to necrosis after reperfusion. Circulation. 1980;62:1274–1279.