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(Circulation. 1996;94:2210-2215.)
© 1996 American Heart Association, Inc.

Articles

Spatial Heterogeneity of Myocardial Blood Flow Presages Salvage Versus Necrosis With Coronary Artery Reperfusion in Conscious Baboons

Bijan Ghaleh, PhD; You-Tang Shen, MD; Stephen F. Vatner, MD

the Departments of Medicine, Harvard Medical School, Brigham & Women's Hospital, Boston, Mass; and the New England Regional Primate Research Center, Southborough, Mass.

Correspondence to Stephen F. Vatner, MD, New England Regional Primate Research Center, One Pine Hill Dr, PO Box 9102, Southborough, MA 01772-9102 or to You-Tang Shen, MD, Merck Research Laboratories, Pharmacology Department, West Point, PA 19486.

	Abstract

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Background Myocardial blood flow distribution is known to be heterogeneous. It is also known that not all of the area at risk (AAR) infarcts with coronary artery occlusion (CAO) and coronary artery reperfusion (CAR). The goal of the present study was to determine whether the proportion of AAR that is salvaged or infarcted can be predicted by the pre-CAO level of myocardial blood flow, which varies considerably in individual samples as a result of natural heterogeneity.

Methods and Results The effects of 90-minute CAO followed by 5- to 7-day CAR were examined in six conscious baboons instrumented with aortic and left atrial catheters and coronary artery occluders. AAR was determined by dual perfusion. Myocardial blood flow was measured by radioactive microspheres before and after CAO and CAR. The AAR was cut into small pieces (0.21±0.01 g) and separated into two categories: salvaged (n=252) or infarcted (n=133). Analysis of myocardial blood flow distribution revealed two distinct populations (P<.01); infarcted tissues demonstrated higher pre-CAO myocardial blood flow than salvaged tissues. Importantly, 50% of the salvaged tissue samples were characterized by pre-CAO myocardial blood flows of <0.90 mL·min^-1·g^-1 compared with 29% for infarcted samples, whereas 51% of infarcted samples were characterized by pre-CAO myocardial blood flows of >1.12 mL·min^-1·g^-1 compared with 22% of salvaged samples. Endocardial analyses were qualitatively similar to transmural analyses.

Conclusions This study suggests that heterogeneity of pre-CAO myocardial blood flows can predict the proportion of myocardium salvaged by CAR and can further explain the spatial heterogeneity of infarction that occurs after CAR, potentially independent of CAR injury.

Key Words: myocardial infarction • microspheres • coronary blood flow

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
It is now well established that myocardial blood flow in the heart is not homogeneous but rather that myocardial blood flow demonstrates considerable spatial heterogeneity in the dog,^{1 2} rabbit,³ and baboon.⁴ In anesthetized dogs, measurement of myocardial blood flow, even in the absence of coronary vascular tone, revealed that the distribution of maximal blood flow is also heterogeneous¹ but does not correlate with the spatial heterogeneity observed under baseline conditions. Our hypothesis was that the marked differences in baseline myocardial blood flow reflected areas within the heart that would be more susceptible or resistant to myocardial ischemia.

The goal of the present study was to determine whether the proportion of AAR that is salvaged or infarcted can be predicted by the level of pre-CAO myocardial blood flow measured with radioactive microspheres. Because general anesthesia can affect the control of arterial pressure, myocardial contractility, and, in particular, autonomic control,⁵ all of which are important determinants of myocardial blood flow, this investigation was performed in conscious baboons, which are phylogenetically close to humans and characterized by sparse collateral development.⁶ The baboon was particularly suited for this study because the infarct that developed after 90-minute CAO and 1-week CAR is relatively small for the AAR (16.8±3.7%) and, more importantly, does not involve the entire subendocardium.⁶ Accordingly, we examined the distribution of myocardial blood flows in the entire heart from six baboons (a total of 5290 individual measurements from 1058 samples) before and after 90 minutes of CAO and analyzed the spatial heterogeneity of pre-CAO baseline blood flows in both salvaged and infarcted tissues.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
The data in the present study were derived from six chronically instrumented baboons that underwent 90-minute CAO and 5- to 7-day CAR. The hemodynamic and gross pathological data have been reported previously.⁶ The AAR of the left ventricle rendered ischemic was 25.3±6.7%.⁶ After 5- to 7-day CAR, infarct size averaged 16.8±3.7% of the AAR.⁶ Therefore, the methodology for the physiological experiments is reported only briefly.

Six baboons (Papio anubis), weighing 25±4 kg, were premedicated with ketamine hydrochloride (5 to 10 mg/kg IM). General anesthesia was induced with sodium thiamylal (10 to 20 mg/kg IV), and then the animals were intubated and maintained with halothane (0.5 to 1.5 vol%). With sterile surgical technique, the thoracotomy was performed at the fifth intercostal space. Tygon catheters (Norton Plastics) were implanted in the descending aorta and in the left atrium for arterial blood withdrawal and radioactive microsphere injection. Either the left circumflex (n=3) or the left anterior descending (n=3) coronary artery was isolated, and a hydraulic occluder, made of polyethylene tubing, was implanted. The catheters were externalized between the scapulae and buried in subcutaneous pouches, the incision was closed in layers, and the chest was evacuated. Each baboon was treated with 20 mg/kg cephalothin sodium BID (Keflin) starting after surgery and continuing for 3 days.

Regional myocardial blood flows were measured with the radioactive microsphere technique. From 2 to 3 million microspheres (15±1 µm) labeled with ⁹⁵Nb, ⁸⁵Sr, ¹⁴¹Ce, ⁴⁶Sc, ¹¹³Sn, ⁵¹Cr, ¹¹⁴In, and ¹⁰³Ru were suspended in 0.01% Tween 80 solution (10% dextran) and placed in an ultrasonic bath for 30 to 60 minutes. Before the first injection of microspheres, 1 mL of Tween 80 solution was injected to test for the potential adverse cardiovascular effects. Microspheres were injected and flushed with saline over a 20-second period via the left atrial catheter. Arterial blood reference samples were withdrawn at a rate of 7.75 mL/min for a total of 120 seconds.

A single 90-minute CAO followed by 5- to 7-day CAR was performed in conscious baboons 2 to 4 weeks after surgery. On the day of the experiment, the animal was sedated with ketamine hydrochloride (4 to 6 mg/kg IM) and then placed in a chair, with supplemental small doses (0.1 to 0.2 mg/kg IV) being given before CAO and during CAR if necessary. When the effects of ketamine hydrochloride had worn off and the baboon was awake in the chair, the protocol was started. After the first microspheres were injected at baseline, the coronary artery was occluded by inflation of the hydraulic occluder. At 5 minutes after CAO, a second injection of microspheres was given. During CAO, multiple ventricular premature contractions were treated with bolus injections of lidocaine through the left atrial catheter. Lidocaine was also injected, immediately before CAR. All animals received 10 to 15 mg/kg lidocaine. The microspheres were given again at 5 minutes before CAR and at 3 and 24 hours after CAR. To examine whether alteration in spatial distribution of myocardial blood flow is affected by allowing 5 to 7 days to elapse between CAR and tissue analysis, one monkey (Macacca rhesus) weighing 21 kg was instrumented similarly to the baboons. The monkey underwent a similar protocol but received the last microspheres at 6-hour CAR instead of 24-hour CAR, after which the heart was retrieved for tissue analysis.

At the end of the experiment (5- to 7-day CAR for the baboons, 6-hour CAR for the monkey), the animals were anesthetized with sodium pentobarbital (50 mg/kg IV), and the heart was excised and placed on a perfusion apparatus. The ascending aorta was cannulated (distal to the sinus of Valsalva) and perfused retrogradely with Evans blue dye (0.1% solution). The coronary artery was cannulated at the site of occlusion and perfused with saline. The driving pressure for the perfusion apparatus was maintained at 120 to 150 mm Hg for both cannulas. After completion of perfusion, the heart was fixed in 5% formalin for 1 day and then was sectioned at the atrioventricular junction; the monkey heart was treated with tetrazolium tetrachloride. The left ventricle was cut into six to nine slices, which were weighed. Both sides of the individual rings were photographed. The previously occluded vascular bed was identified and traced from enlarged projections of photographic slides of each ventricular slice. Planimetry of the tracings was performed to measure the AAR, which was calculated as a percentage of the total area for each slice. The infarct area was determined by pathological analysis. Each slice was then cut into subendocardial, midmyocardial, and subepicardial layers. Each layer was further subdivided into small regions (Fig 1) with a mean piece weight of 0.21±0.01 g. For each of the samples, a value of myocardial blood flow was determined after measurement of the radioactivity. In all, there were a total of 5290 measurements in 1058 regions from six hearts, including the nonischemic and ischemic zones. Samples from the AAR were separated into two categories: salvaged (n=252) or infarcted (n=133). Samples originating from border zones were discarded.

View larger version (21K): [in this window] [in a new window]   Figure 1. Schematic of the method used to section the hearts. After the heart was sliced transversely, each slice was further subdivided. Infarcted tissues were separated from the salvaged tissues. Each sample was numbered, and a map was drawn to identify the samples for the analysis.

Statistical Analysis
The myocardial blood flows measured in infarcted and salvaged samples were analyzed with histogram distribution analysis. Distributions of salvaged and infarcted samples were described by mean values. The dispersions were evaluated by calculating the coefficient of variation, defined as the ratio of the SD of the distribution of measurements to its mean. The normality of the distributions was tested by calculating and plotting the normal probabilities, allowing us to test the null hypothesis of no difference between the two populations of samples by using the Student's t test. A value of P<.05 was considered significant.

	Results

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Examination of the different slices showed that the necrosis was preferentially located in the subendocardium. Almost all of the subepicardium and most of the subendocardium near the cavity were spared by infarct. Most of the slices were characterized by patchy localization of the infarcts rather than confluent transmural necrosis.

Myocardial Blood Flows
In the baboons studied, baseline pre-CAO myocardial blood flow was characterized by its heterogeneous distribution (Fig 2). In the entire left ventricle, the flows ranged from 0.1 to 2.2 mL·min^-1·g^-1, averaging 1.03±0.01 mL·min^-1·g^-1 with a coefficient of variation of 28.9% and a skewness value of 0.087. In the AAR, the flows ranged from 0.2 to 2.0 mL·min^-1·g^-1. The myocardial blood flows in the AAR averaged 0.98±0.01 mL·min^-1·g^-1, with a coefficient of variation of 28.6% and a skewness value of -0.017. In the subendocardium AAR, the flows ranged from 0.2 to 2.0 mL·min^-1·g^-1, with a mean value of 1.06±0.02 mL·min^-1·g^-1, a coefficient of variation of 23.8%, and a skewness value of -0.156.

View larger version (20K): [in this window] [in a new window]   Figure 2. Spatial distribution of pre-CAO myocardial blood flow from the six baboons. In the entire left ventricle (top), flows ranged from 0.1 to 2.2 mL·min-1·g-1 (n=1058). In the AAR (bottom), flows ranged from 0.2 to 2.0 mL·min-1·g-1 (n=385).

The final analysis on the six baboons was performed by separating the samples located in the AAR into two categories: salvaged (n=252) or infarcted (n=133). As illustrated in Fig 3, the analysis of the spatial flow distribution revealed the presence of two distinct populations (P<.01). Infarcted tissues averaged 1.12±0.02 mL·min^-1·g^-1, with a coefficient of variation of 21.5% and a skewness value of -0.127. Salvaged tissue samples elicited lower levels (P<.05) of resting myocardial blood flows, 0.91±0.02 mL·min^-1·g^-1, with a coefficient of variation of 29.9% and a skewness value of 0.153. The distribution of salvaged samples was shifted to the left, whereas the distribution of infarcted samples was shifted to the right. In other words, samples that ultimately infarcted were characterized by higher pre-CAO blood flows than were samples salvaged by CAR. This type of heterogeneity of myocardial blood flows was not simply related to transmural differences. Indeed, when the analysis was limited to the subendocardium, the same pattern of heterogeneity of myocardial blood flow for salvage versus necrosis was observed (Fig 4). Salvaged samples were characterized by lower levels (P<.05) of pre-CAO blood flows (1.00±0.02 mL·min^-1·g^-1), whereas infarcted samples were characterized by higher levels of resting myocardial blood flows (1.12±0.02 mL·min^-1·g^-1). The coefficients of variation were 21.0% and 25.7% and the skewness values were -0.188 and -0.046 for the infarcted and salvaged samples, respectively. The distribution of blood flows and relationship between infarction and salvage were qualitatively similar in the one animal studied with the truncated protocol. To determine whether regional anatomical differences could account for these patterns of blood flow distribution, samples in the AAR were split by regional criterion, ie, septal and lateral wall location. Again, the same patterns of heterogeneity of myocardial blood flow for salvage versus necrosis were observed.

View larger version (15K): [in this window] [in a new window]   Figure 3. Spatial distribution of pre-CAO myocardial blood flows in the AAR in the six baboons compared for salvaged samples (open bars) and infarcted samples (shaded bars). The distribution of the salvaged samples is shifted to the left, whereas the distribution of infarcted samples is shifted to the right, ie, to higher pre-CAO myocardial blood flows.

View larger version (25K): [in this window] [in a new window]   Figure 4. Spatial distribution of pre-CAO myocardial blood flows only in the subendocardium. Samples with infarct (shaded bars) were characterized by higher pre-CAO myocardial blood flows than salvaged samples (open bars).

During CAO, the myocardial blood flows decreased by 95.1±0.3% in the AAR and averaged 0.05±0.004 and 0.03±0.004 mL·min^-1·g^-1 in salvaged and infarcted samples, respectively. At the end of the CAO period, ie, 5 minutes before reperfusion, the blood flows were still depressed by 94.4±0.4% and averaged 0.06±0.004 and 0.03±0.004 mL·min^-1·g^-1 in salvaged and infarcted samples, respectively. The myocardial blood flows measured at 3 and 24 hours were not correlated with resting pre-CAO blood flows for infarcted and salvaged regions, respectively (Fig 5), but myocardial blood flows were still characterized by heterogeneity during reperfusion.

View larger version (22K): [in this window] [in a new window]   Figure 5. Plots comparing myocardial blood flows before CAO with those at 3 and 24 hours after CAR for salvaged samples (left) and infarcted samples (right). The levels of myocardial blood flows measured during the reperfusion period do not correlate with pre-CAO blood flows.

In the nonischemic zone, CAO and reperfusion did not shift the spatial heterogeneity of blood flow (Fig 6).

View larger version (16K): [in this window] [in a new window]   Figure 6. Spatial distribution of myocardial blood flows measured before CAO and after 3 hours' reperfusion (CAR 3h) in the nonischemic zone (n=673).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The concept of spatial heterogeneity in the myocardium has been described in different species,^{1 2 3} including baboons.⁴ Prior studies have demonstrated that the heterogeneous regional myocardial flow is not distributed randomly but that in each layer of the ventricle, regional flows in adjacent segments tend to change gradually.^{1 7} The spatial heterogeneity of myocardial perfusion is not an artifact of the microsphere technique.^{1 2 4 8} Prior studies have demonstrated the validity of this technique for spatial distribution of myocardial flow.^{1 2 4 8} In our study, we used the same methodology. Flow heterogeneity has also been assessed without the use of microspheres, ie, by indicator/dilution studies with diffusible tracers.⁹ The finding in the present study of myocardial blood flows ranging from 0.2 to 2.2 mL·min^-1·g^-1, ie, 10-fold in its extremes, confirms these previous reports of spatial heterogeneity.^{1 2 3 4 7} There also is variability of blood flow over time, ie, temporal heterogeneity.^{10 11 12} However, temporal heterogeneity appears to be quantitatively less important than spatial heterogeneity.⁴

The present investigation extends the concept of spatial heterogeneity in the distribution of myocardial blood flows by demonstrating its utility in determining myocardium at risk before CAO and CAR. The analysis of the blood flow distribution after an episode of 90-minute CAO followed by 5- to 7-day CAR shows clearly that salvaged and infarcted tissues elicit two different pre-CAO blood flow patterns. The resting myocardial blood flows of the infarcted samples were significantly higher than those observed in salvaged tissues. Importantly, 50% of the salvaged tissue samples were characterized by pre-CAO myocardial blood flows of <0.90 mL·min^-1·g^-1 compared with 29% for infarcted samples, whereas 51% of infarcted samples were characterized by pre-CAO myocardial blood flows of >1.12 mL·min^-1·g^-1 compared with 22% of salvaged samples. Thus, spatial heterogeneity of myocardial blood flow can be used to predict salvage versus necrosis with CAO followed by CAR in conscious baboons. The same flow patterns were revealed when the analysis was limited to the subendocardium, demonstrating that our conclusion is not biased by the fact that the first analysis also took into account the subepicardium, which tends to exhibit lower resting levels of myocardial blood flows and less infarct development than the subendocardium.

Classically, infarct size is determined by the size of the AAR and the transmural distribution of blood flow within the ischemic bed.¹³ The recruitment of collateral vessels is of major importance in the development of infarction, especially in dogs, in which an inverse relationship between collateral blood flow and infarct size has been described.¹⁴ However, the baboon is characterized by sparse collateral development, eliminating this factor. Taking this into consideration, it is surprising that the infarcts in the baboon hearts with 90-minute CAO and 5- to 7-day CAR were not more homogeneous.⁶ It is thus difficult to reconcile the absence of collateral blood flow during CAO, resulting in homogeneously near-zero blood flows in both subendocardium and subepicardium and the patchy nature of necrosis that developed after CAR. These observations suggest that events either pre-CAO or post-CAR influenced the spatial distribution of the infarct and serve in part as the basis for the concept of CAR damage. The major findings of the present investigation are that in the conscious baboon, some regions of the heart are more vulnerable to ischemia than others and that these regions, characterized by statistically higher levels of resting pre-CAO myocardial blood flows than salvaged samples, are determined before CAO rather than after CAR—ie, inconsistent with the concept of CAR damage.

The resting distribution of regional myocardial blood flow is of particular interest because there is evidence that under most conditions, regional perfusion closely reflects local metabolic needs. For example, it is well known that alteration in baseline global MVO₂ will affect the response to ischemia.¹⁵ In fact, it is also known that resting coronary arteriovenous oxygen difference is near maximal and does not widen substantially with changes in myocardial metabolic demands.¹⁶ Reductions in regional contractility secondary to reduction in coronary blood flow also suggest that regional perfusion is coupled to metabolic demand.^{17 18 19 20} Consequently heterogeneous metabolic distribution of regional flow probably reflects an equally heterogeneous metabolic demand, perhaps due to differences in local geometric factors and regional function.^{4 21} Both ischemia and hypoxia result in spatial heterogeneity of anoxic tissue, which is consistent with differences in regional metabolic demand or baseline myocardial blood flow.^{22 23} Franzen et al²¹ showed a relationship between myocardial blood flow and metabolic markers in small segments of the heart, supporting the idea that regulation of blood flow and metabolism at a microvascular level may occur as independent units and behave differently from neighboring units. Interestingly, some units of myocardium demonstrate less coronary reserve than others.²³ On the other hand, spatial heterogeneity of blood flow has also been demonstrated in the nonbeating heart,⁸ an observation that tends to diminish the importance of differences in regional contractility.

The results of the present investigation also have implications for understanding the concept of CAR damage. This concept proposes that events after CAR are critical for determining the extent of infarction, which is internally inconsistent with the present results. The present data support a different concept, ie, that events before coronary artery occlusion are critical in predetermining the extent of infarction. Although the two concepts are not mutually exclusive, one might have to postulate that CAR damage is a minor independent function in the baboon or is somehow linked to the pre-CAO resting blood flow and metabolism. Our study ruled out the possibility that the infarct process was related to blood flows after CAR but did not rule out the possibility that other events occurring after CAR did not play a role. Interestingly, some previous reports did not find any evidence of lethal reperfusion injury after reperfusion,^{24 25} suggesting that reperfusion may accelerate necrosis of irreversibly injured myocytes but does not add substantially to the area of myocardium ultimately damaged.

There are potential limitations to the methodology used in the present study that must be addressed. Pre-CAO myocardial blood flow measurements, with use of the microsphere technique, are known to be affected by the change in the volume of tissue after reperfusion. It is well recognized that early in the infarct process (the first week), "microsphere loss" is observed, with its mechanism the result of tissue swelling.^{26 27} Conversely, 1 month later, "microsphere gain" occurs due to scar formation and tissue contraction in the infarcted tissue.²⁷ If the infarcted samples in the present study were characterized by scar formation and tissue contraction, the results could be accounted for in part on that basis. However, this is not likely, because prior studies have shown that at 5 to 7 days after CAO and CAR, scar formation has not occurred.²⁸ Nevertheless, we tested this possibility in one experiment, which was terminated 6 hours after CAR. At this time, ischemic tissue swelling should have occurred, yet we still observed a similar pattern of blood flow distribution, with the preponderance of salvaged tissues demonstrating lower pre-CAO blood flows and the preponderance of infarcted samples demonstrating higher pre-CAO blood flows. Second, chronic instrumentation may affect the coronary circulation. For example, if the instrumentation is applied inappropriately to the coronary artery, denervation or coronary stenosis might be induced. Previous studies from our laboratory have addressed this issue and found that these problems are not significant if the surgical procedures are performed correctly.^{29 30}

One final point deserves mention. Measurements of regional myocardial blood flow of <0.6 mL·min^-1·g^-131 may be taken to indicate myocardial ischemia or, in the chronic setting, myocardial hibernation. The results of the present study demonstrate that in the normal baboon heart, without ischemia, many segments of normal myocardium demonstrate flows of <0.6 mL·min^-1·g^-1 (Fig 2). This normal distribution of myocardial blood flow must be recognized before a diagnosis of ischemia can be rendered. Interestingly, this point has already been alluded to in studies of myocardial blood flow distribution in normal human subjects without coronary artery disease.³¹

In conclusion, the heterogeneity of myocardial blood flows in the AAR of baboons with CAO followed by CAR can predict the proportion of myocardium salvaged by CAR and can further explain the patchy nature of infarcts, independent of later events—eg, CAR injury. Regions in the left ventricle characterized by high levels of resting myocardial blood flows are more susceptible to infarction than are regions with low resting myocardial blood flows. It is interesting to speculate that shifting the spatial heterogeneity of myocardial blood flow to the left (lower blood flows) under baseline conditions will result in less damage inflicted with ischemia and consequently enhance salvage elicited by CAR.

	Selected Abbreviations and Acronyms

 

AAR = area at risk CAO = coronary artery occlusion CAR = coronary artery reperfusion

	Acknowledgments

 
This work was supported in part by USPHS grants HL-33065, HL-38070, and HL-33107. Dr Ghaleh was a recipient of the Association Francaise pour la Recherche Therapeutique.

Received February 5, 1996; revision received May 10, 1996; accepted May 21, 1996.

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