INTRODUCTION

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UNDER PHYSIOLOGICAL CONDITIONS, a preload reserve is recruited to maintain ventricular ejection and regional wall excursion against an increase in afterload (17). Afterload mismatch occurs when the left ventricle is unable to recruit preload reserve sufficiently to maintain its normal volume displacement and regional wall excursion against the prevailing afterload, at a given level of myocardial inotropic state (17, 18). Afterload mismatch thus occurs either when preload is artificially kept constant while afterload is increased (12, 23, 24), or when venous return is adequate but myocardial inotropic state is reduced (17).

Acutely ischemic myocardium has increased afterload sensitivity, i.e., in anesthetized dogs, the inflation of an aortic balloon during a single cardiac cycle (20), aortic constriction (5, 10, 21), or infusion of phenylephrine (15) resulted in a larger decrease in mean circumferential fiber shortening (20), systolic wall thickening (5), systolic segment shortening (10, 15), or left ventricular (LV) pressure-segment length loop area (21) than in nonischemic control myocardium. In reperfused myocardium of anesthetized pigs, the reduction in systolic segment shortening and LV pressure-segment length loop area in response to increased afterload was also more pronounced than under control conditions (4), and stunned myocardium is "hypersensitive" for loading conditions in general (2).

The effects of increased afterload on regional myocardial function in short-term hibernating myocardium have not been studied so far. Short-term hibernating myocardium is characterized by reduced contractile function during persistent moderate ischemia, the recovery of metabolic parameters despite ongoing ischemia, and the absence of necrosis (for review see Ref. 7). In the present study, the effect of an acute aortic constriction on acutely ischemic, short-term hibernating, and reperfused myocardium was compared.

	MATERIALS AND METHODS

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The experimental protocols employed in this study were approved by the bioethical committee of the district of Düsseldorf, and they adhere to the guiding principles of the American Physiological Society.

The experimental model has been described previously (8); in brief, in 11 enflurane-anesthetized Göttinger miniswine, a micromanometer was placed in the left ventricle. The descending thoracic aorta was dissected, and a plastic tube was wrapped around it for later aortic constriction. Heart rate was controlled by left atrial pacing. Ultrasonic dimension gauges were implanted in the LV myocardium to measure the thickness of the anterior and posterior (control) walls. The proximal left anterior descending coronary artery (LAD) was cannulated and perfused from an extracorporeal circuit. Radiolabeled microspheres were injected to assess regional myocardial blood flow, and flow is reported for the myocardium with the dimension gauges. The large epicardial vein parallel to the LAD was cannulated for the withdrawal of blood samples to determine myocardial lactate consumption. Transmural myocardial biopsies were taken from the LAD perfusion bed for analysis of myocardial creatine phosphate content.

Regional Myocardial Function

The slope of the relationship between systolic wall thickening and LV end-systolic pressure during aortic constriction was calculated using the linear equation
where WT is systolic wall thickening, LVESP is left ventricular end-systolic pressure, m is slope of the regression line, and b is y-axis intercept.

Protocol

Statistics

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

In none of the animals was myocardial necrosis detected after 90 min of ischemia and 120 min of reperfusion.

Steady-State Data

The data demonstrate the successful development of short-term hibernating myocardium followed by myocardial stunning after reperfusion (Table 1). In brief, reducing coronary inflow decreased anterior transmural and subendocardial blood flows as well as anterior systolic wall thickening. At 5 min ischemia, creatine phosphate concentration was decreased, and the myocardium produced lactate. Prolonging ischemia to 90 min did not change transmural and subendocardial blood flows or anterior systolic wall thickening while metabolic parameters recovered toward control values. At 30 min reperfusion, anterior transmural and subendocardial blood flows had recovered, whereas anterior systolic wall thickening was still depressed.

Aortic Constriction Data

Hemodynamics. With aortic constriction at constant heart rate, LV peak pressure increased by ~30 mmHg during control conditions, at 5 and 90 min ischemia, as well as at 30 min reperfusion (Table 2). Maximum of LV dP/dt_max (LV dP/dt_max) did not change, whereas LV end-diastolic pressure increased during aortic constriction.

Regional myocardial dimensions. Anterior and posterior end-diastolic wall thickness tended to be decreased in the last cardiac cycle of the aortic constriction [not significant (NS)]. The relationships between anterior systolic wall thickening and LV end-systolic pressure had r values of 0.94 ± 0.04 under control conditions and 0.96 ± 0.03, 0.97 ± 0.06, and 0.96 ± 0.05 at 5 min and 90 min ischemia and 30 min reperfusion, respectively. The intercept decreased from 5.09 ± 1.33 mm under control conditions to 3.29 ± 1.04, 2.46 ± 0.98, and 3.22 ± 1.00 mm at 5 min and 90 min ischemia and 30 min reperfusion, respectively (all three P < 0.05 vs. control, NS vs. each other). Under control conditions, aortic constriction resulted in a slightly decreased anterior systolic wall thickening (Fig. 1); the slope of the relationship between anterior systolic wall thickening and LV end-systolic pressure averaged 11.2 ± 4.2 µm/mmHg (Fig. 2). At 5 min ischemia, aortic constriction markedly decreased anterior systolic wall thickening (slope: 26.5 ± 8.8 µm/mmHg, P < 0.05 vs. control). At 90 min ischemia, however, the slope of the relationship between anterior systolic wall thickening and LV end-systolic pressure had recovered toward control values (17.2 ± 6.6 µm/mmHg, P < 0.05 vs. 5 min ischemia, NS vs. control). At 30 min reperfusion, the slope was once more significantly decreased (27.8 ± 8.1 µm/mmHg, P < 0.05 vs. control).

View larger version (18K): [in this window] [in a new window]   Fig. 1.   Original tracing from one experiment demonstrating the load-dependent changes in systolic wall thickening.

View larger version (16K): [in this window] [in a new window]   Fig. 2.   Slopes of the relationships between anterior and posterior systolic wall thickening and left ventricular end-systolic pressure obtained during aortic constriction. Whereas the slopes of the relationships of the posterior wall did not change significantly throughout the protocol, the slope of the relationship of the anterior wall was significantly reduced at 5 min but recovered toward control at 90 min ischemia, to be reduced once more at 30 min reperfusion. n, Number of animals. *P < 0.05 vs. control. §P < 0.05 vs. preceding value.

	DISCUSSION

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Acutely ischemic myocardium had greater afterload sensitivity of regional wall excursion than control myocardium. After successful adaptation to ischemia, i.e., after short-term myocardial hibernation had developed, the afterload sensitivity was normalized again, indicating better inotropic competence of short-term hibernating than acutely ischemic myocardium. Such inotropic competence deteriorated again after reperfusion, i.e., in stunned myocardium.

Critique of Methods

Afterload Sensitivity in Ischemic and Reperfused Myocardium

Preload recruitment was not different in acutely ischemic, short-term hibernating, and stunned myocardium, as reflected by equivalent decreases in anterior end-diastolic wall thickness (Table 2), suggesting, in the concept of preload reserve and afterload mismatch (17, 19), that short-term hibernating myocardium is characterized by a better inotropic competence than acutely ischemic and stunned myocardium. Such better inotropic competence of short-term hibernating myocardium is primarily a descriptive finding, and we can only speculate about the underlying mechanism(s).

Such better inotropic competence of short-term hibernating myocardium is not related to an altered calcium responsiveness, as calcium responsiveness is comparable in acutely ischemic, short-term hibernating and stunned myocardium in this in situ heart model (8). Maximal calcium-activated work is decreased in ischemic and reperfused myocardium compared with control conditions; the reduction in maximal calcium-activated work, however, is not different among short-term hibernating myocardium, acutely ischemic and stunned myocardium (8).

The energetic situation of acutely ischemic, short-term hibernating and stunned myocardium differs significantly. Although the free energy change of ATP hydrolysis is reduced early during ischemia, it recovers to almost normal values in short-term hibernating myocardium (13). Therefore, part of the observed load dependence of acutely ischemic myocardium could have been related to an altered energetic situation. During reperfusion, however, there is no difference in the creatine phosphate content and ATP content compared with 85 min ischemia (11), and the free energy change of ATP hydrolysis is probably normalized at this time as well (6, 9), although the myocardium once again becomes load dependent to the same extent as seen during early ischemia. Therefore, it appears unlikely that alterations in the energy metabolism are the main determinant of the load dependence of acutely ischemic and reperfused myocardium.

Clearly, the functional characteristics of acutely ischemic, hibernating, and stunned myocardium differ, even at equivalent baseline dysfunction.