Effect of beta-adrenergic blockade with timolol on myocardial blood flow during exercise after myocardial infarction in the dog

The effect of beta-adrenergic blockade with timolol (40 micrograms/kg) on myocardial blood flow during rest and graded treadmill exercise was assessed in 12 chronically instrumented dogs 10 to 14 days after myocardial infarction was produced by acute left circumflex coronary artery occlusion. During exercise at comparable external work loads, the heart rate-systolic blood pressure product was significantly decreased after timilol, with concomitant reductions of myocardial blood flow in normal, border and central ischemic areas (p less than 0.001) and increases in subendocardial/subepicardial blood flow ratios (p less than 0.05). In addition to the blunted chronotropic response to exercise, timolol exerted an effect on myocardial blood flow that was not explained by changes in heart rate or blood pressure. At comparable rate-pressure products during exercise, total myocardial blood flow was 24% lower after timolol (p less than 0.02) and flow was redistributed from subepicardium to subendocardium in all myocardial regions. Thus, timolol altered myocardial blood flow during exercise by two separate mechanisms: a negative chronotropic effect, and a significant selective reduction of subepicardial perfusion independent of changes in heart rate or blood pressure with transmural redistribution of flow toward the subendocardium.     

Transmural heterogeneity of the left ventricular wall: subendocardial layer and subepicardial layer

The myocardium of the left ventricular wall is not homogeneous, but demonstrates transmural heterogeneity in myocardial blood flow, myocardial metabolism, and contraction and relaxation dynamics. Reimer and colleagues recognized that irreversible injury of the ischemic myocardium develops as a transmural wavefront, occurring first in the subendocardial myocardium, and with longer periods of ischemia, the wavefront of necrosis moves from the subendocardial zone across the wall to progressively involve more of the transmural thickness of the ventricular wall, ultimately becoming nearly transmural. This phenomenon was named the "wavefront phenomenon", and is the morphological counterpart of the transmural heterogeneity of the metabolism and blood flow. Autoregulation of myocardial blood flow is accomplished by changes in intramyocardial vascular resistance and intramyocardial pressure. It is more difficult to maintain the autoregulation in the subendocardial myocardium because contraction is greater, oxygen demand is greater, and myocardial pressure is higher in the subendocardium than in the subepicardial layer. In the normal myocardium, contraction is greater in the subendocardial layer, as is wall stress, accounting for the higher subendocardial energy requirements. Consistent with these findings, higher rates of metabolic activity and greater oxygen extraction are found in this region. As a consequence, ischemia becomes more severe and myocardial cells undergo necrosis first in the subendocardium. Under normal conditions, production and utilization of high-energy phosphates [adenosine triphosphate(ATP) and creatine phosphate] in the subendocardial myocardium are more active than in the subepicardial myocardium, but decline more easily in the subendocardium during ischemia, which induces the subendocardial ischemic injury. Lower production of Ca(2+)-ATPase in the subendocardium might also contribute to the subendocardial injury. Wavefront necrosis starts from the subendocardium, but the production of high-energy phosphates in the subepicardium is known to increase and compensate for the reduction in high-energy phosphate production in the subendocardium. Animal experiments have shown that systolic thickening of the endocardial half of the ventricular wall is double that in the epicardial half. Today, this can be confirmed in humans with the tissue Doppler tracking method which is completely noninvasive. Furthermore, the subepicardial half of the ventricular wall is known to compensate for the decreased systolic thickening of the subendocardial half in the case of subendocardial injury, which is called vertical compensation and is the mechanical counterpart of the concept of metabolic compensation. Many new technologies, including the tissue Doppler tracking method, magnetic resonance imaging tagging, and myocardial contrast echocardiography, will give more accurate information about the myocardial heterogeneity of layer-by-layer motion and blood flow, and will contribute to early detection and quantitative estimation of ischemia and other diseases of which the main lesion is in the subendocardium.     

Relation of intramyocardial and intracavitary pressure to regional myocardial asynergy in the canine left ventricle

The purpose of this study was to investigate the relation between abnormalities of left ventricular (LV) wall thickening during systole in ischemic regions and the interaction of LV pressure and regional intramyocardial pressure. Wall thickness was measured in 10 open-chest dogs with ultrasonic dimension gauges. LV pressure, aortic pressure, and intramyocardial pressure in the subendocardium were measured with catheter-tip micromanometers. Regional ischemia was produced by occlusion of the left anterior descending coronary artery. During the control period, peak subendocardial pressure exceeded LV pressure by 44 +/- 6 mm Hg. With hypokinesia, defined as a 50% to 89% reduction of systolic wall thickening, peak subendocardial pressure exceeded peak LV pressure but to a lesser extent (15 +/- 1 mm Hg). During akinesia, defined as a 90% to 100% reduction of systolic wall thickening, there was less than 1 mm Hg difference between peak subendocardial pressure and peak LV pressure. During dyskinesia, defined as systolic thinning of the ischemic wall, peak LV pressure exceeded peak subendocardial pressure by 29 +/- 6 mm Hg. These observations indicate that regional changes of LV wall thickness characterized by hypokinesia, akinesia, and dyskinesia are associated with pressure gradients between the LV cavity and the LV wall that are compatible with the abnormalities of wall motion.     

Comparison of the distribution of intramyocardial pressure across the canine left ventricular wall in the beating heart during diastole and in the arrested heart. Evidence of epicardial muscle tone during diastole

Computations of compliance of the left ventricle (LV) during diastole assume passive tissue characteristics. To evaluate this assumption, we measured diastolic LV intramyocardial pressure simultaneously in the subepicardium and subendocardium in 18 open-chest dogs, using 1-mm in diameter micromanometers. Subepicardial pressure, 26 +/- 1 mm Hg (mean +/- SEM) exceeded subendocardial pressure, 14 +/- 1 mm Hg (P less than 0.001), and it exceeded left ventricular end-diastolic pressure (LVEDP) (9 +/- 1 mm Hg) (P less than 0.001). After an infusion of dextran-40 (10 dogs), subepicardial diastolic pressure increased to 42 +/- 4 mm Hg which was higher than diastolic subendocardial pressure, 26 +/- 2 mm Hg (P less than 0.001) and LVEDP, 24 +/- 2 mm Hg (P less than 0.001). Following cardiac arrest (12 dogs) with the intramyocardial probes unchanged in position, LV intracavitary pressure, 9 +/- 1 mm Hg, and subendocardial pressure, 13 +/- 3 mm Hg, did not differ significantly from the pressures in the beating heart. Subepicardial pressure, 9 +/- 1 mm Hg, was lower than in the beating heart (P less than 0.001). Following distention of the arrested LV (12 dogs), subepicardial pressure, 31 +/- 7 mm Hg, was lower than both subendocardial pressure, 58 +/- 12 mm Hg (P less than 0.001) and LV intracavitary pressure, 54 +/- 11 mm Hg (P less than 0.001). These observations indicate that tone is maintained by the subepicardium during diastole. Furthermore, the LV wall does not appear to behave as a passive shell during ventricular filling.     

Microvascular pressures and resistances in the left ventricular subepicardium and subendocardium

These experiments tested the hypothesis that differences in the distribution of subepicardial and subendocardial microvascular resistances may alter the transmural distributions of microvascular pressures. Isolated blood- and physiological saline-perfused porcine hearts were surgically incised to enable exposure of the subendocardial and subepicardial microcirculations. Microvascular pressures were measured during cardiac arrest and maximal vasodilation at various perfusion pressures to formulate relations between perfusion pressure and microvascular pressure in the different subendocardial (both free wall and papillary muscle) and subepicardial segments. Measurements of arteriolar and venular pressures in both myocardial regions were performed in comparably sized vessels (80-120 microns in diameter). At a coronary perfusion pressure of 100 mm Hg, subendocardial arteriolar and venular pressures were 60 +/- 4 and 33 +/- 3 mm Hg, respectively. In contrast, at the same coronary perfusion pressure, arteriolar and venular pressures in the subepicardial microcirculation averaged 80 +/- 6 and 22 +/- 3 mm Hg, respectively (p less than 0.05 versus subendocardium). At all levels of coronary perfusion pressure, arteriolar pressures were significantly lower in the subendocardium than in the subepicardium (p less than 0.05). Venular pressures were also higher in the subendocardial microcirculation than in the subepicardial microcirculation at all but the lowest perfusion pressure (p less than 0.05). The relative distribution of resistances in arteries, microvessels, and veins was also different between the subepicardium and subendocardium. Specifically, in the subendocardium, arterial and venous resistances were higher, percentage-wise, but microvascular resistance was proportionately lower than that in the subepicardium (p less than 0.05). From these data, it is concluded that the distribution of microvascular resistances and pressures is different during maximal vasodilation in the subepicardial and subendocardial microcirculations of the left ventricle. It is also speculated that differences in autoregulatory capacity and vulnerability to ischemia may be partially related to unequal distribution of microvascular resistances across the wall of the left ventricle.     

Distribution of a neutral cardioplegic vehicle during the development of ischemic myocardial contracture

During prolonged ischemic cardiac arrest successful myocardial protection depends upon uniform delivery of cardioplegic solutions to all regions of the heart. Accordingly, we studied the regional and transmural distribution of a neutral crystalloid (dextran-saline) solution during normothermic (37 degrees C) ischemia in 18 isolated blood-perfused dog hearts (isovolumic left ventricle). In the baseline state, coronary perfusion pressure was 100 mmHg. At the onset of ischemia and every 15 min throughout ischemia, we infused 100 ml of crystalloid solution (37 degrees C) at a perfusion pressure of 100 mmHg and the distribution of crystalloid solution was assessed (radioactive microsphere technique). The hearts were reperfused after 60 min (n = 9) or 90 mins (n = 9) of ischemia. In the baseline pre-arrest state the left ventricle (LV) received 67 +/- 1.0% of the total coronary blood flow; the LV subendocardial to subepicardial flow ratio was 1.33 +/- 0.18, the LV end diastolic pressure was 7.5 +/- 0.4 mmHg, and mean transmural myocardial adenosine triphosphate (ATP) was 16.4 +/- 1.1 microM/g DW. At the onset and throughout the first 45 mins of ischemia (n = 9), regional and transmural distribution of the crystalloid solution was similar to that of coronary blood flow during the baseline state; there was no change in LV end diastolic pressure, but there was a moderate fall in ATP content (7.26 +/- 1.6 micron/g DW). After 75 mins of ischemia (n = 9), despite the development of ischemic contracture (LV end diastolic pressure exceeded 20 mmHg in all 9 hearts) and marked ATP depletion (2.76 +/- 0.5 microM/g DW), there was an increase in crystalloid solution delivery to the LV as a whole and the subendocardium in particular (the LV received 82 +/- 2.0% and the subendocardial to subepicardial flow ratio was 1.75 +/- 0.1). Even in a subgroup with severe contracture during ischemic arrest (LV end diastolic pressure greater than 60 mmHg, n = 4) there was no reduction in crystalloid solution delivery. Thus, the presence of ischemic contracture does not preclude delivery of crystalloid solution to the LV subendocardium.     

Effect of intracoronary nitroglycerin administration on phasic pattern and transmural distribution of flow during coronary artery stenosis.

BACKGROUND. Nitroglycerin is effective in relieving myocardial ischemia; however, intracoronary nitroglycerin often fails to relieve angina and has been reported to have deleterious effects on subendocardial blood flow. To understand the mechanisms involved, we evaluated the direct effect of nitroglycerin on coronary circulation of the ischemic hearts. METHODS AND RESULTS. We measured the phasic pattern of intramyocardial coronary arterial flow with an 80-channel, 20-MHz pulsed Doppler ultrasound flowmeter under moderate to severe coronary artery stenosis (distal perfusion pressure approximately 45 mm Hg group 1, n = 6) and transmyocardial blood flow distribution using radioactive microspheres while maintaining coronary pressure at a low constant level (40 mm Hg, group 2, n = 6). In anesthetized open-chest dogs, the left main coronary artery was perfused directly from the right carotid or femoral artery. In this bypass circuit, pressure was controlled with an occluder or a reservoir was connected to the circuit. In group 1, the systolic and diastolic pressures distal to the stenosis decreased significantly after intracoronary administration of nitroglycerin at maximal coronary flow from 66.5 +/- 18.5 to 56.5 +/- 13.8 mm Hg (p less than 0.01) and from 36.6 +/- 14.4 to 27.5 +/- 8.9 mm Hg (p less than 0.01), respectively. The phasic pattern of the septal artery flow was predominantly diastolic and was characterized by systolic reverse flow even in the absence of stenosis. Coronary stenosis increased systolic reverse flow. Nitroglycerin increased diastolic forward flow (p less than 0.05) but augmented systolic reverse flow markedly (p less than 0.001). In group 2, nitroglycerin increased subepicardial flow (p less than 0.05) but failed to increase subendocardial flow. With the administration of nitroglycerin, the subendocardial-to-subepicardial flow ratio decreased significantly from 0.73 +/- 0.19 to 0.32 +/- 0.14 (p less than 0.01). CONCLUSIONS. The increased systolic reverse flow after intracoronary administration of nitroglycerin may be closely related to failure of subendocardial blood flow to increase with increase subepicardial flow.     

Amlodipine, a long-acting calcium antagonist drug reduces ischemia-induced ventricular conduction delay in pig hearts

The effects of amlodipine, a novel, long-lasting calcium channel blocking agent, on ischemia-induced myocardial conduction delay was studied in anesthetized pigs paced at a constant heart rate. Acute coronary occlusion (3 minutes) significantly lengthened time to onset, time to peak and duration of bipolar electrograms recorded from both subendocardial and subepicardial left ventricular sites. After intravenous injection of amlodipine (0.3 mg/kg, n = 6), subsequent periods of ischemia greatly reduced (p less than 0.01) all indexes of subepicardial conduction delay. In the subendocardium, amlodipine decreased only time to onset (-25 +/- 4%, p less than 0.01) within the ischemic zone. Significant delays in all indexes were present during repeated ischemic periods in the placebo-treated control group (n = 5). Amlodipine also increased regional myocardial blood flow within the nonischemic myocardium by 25 +/- 10% and decreased mean aortic pressure by 7 +/- 2% without altering flow in the ischemic region. Left atrial pressure remained unchanged. Indexes of ischemia-induced conduction delay were more rapidly restored after reperfusion in amlodipine-pretreated than in control animals. In conclusion, amlodipine produced a beneficial blood flow-independent effect on ischemia-induced injury potentials. The effect may help to reduce the likelihood of development of lethal ventricular arrhythmias in the early stage of myocardial ischemia in the clinical setting.     

Beneficial effect of diltiazem on ischemia-reperfusion injury in the dog

We determined the effect of the calcium antagonistic agent, diltiazem hydrochloride upon ischemia-reperfusion injury in the dog. Ischemia was produced by occluding the left anterior descending artery for 40 min. Subsequent reperfusion was accomplished for 120 min by virtue of removal of the occlusion. Sixteen of the dogs studied were randomly assigned to diltiazem (D)-treated group (n = 8) and saline (S)-treated group (n = 8). D in saline was intravenously infused at a concentration of 3 mcq/kg/min starting 15 min after the occlusion. Myocardial blood flow (MBF) was measured using hydrogen gas clearance method. Infarct size was quantified as percent myocardium at risk by triphenyltetrazolium chloride staining. D administration caused a slight decline in mean aortic pressure, heart rate, and heart rate X systolic blood pressure throughout the periods of occlusion and reperfusion. However, there was no significant difference observed in both groups of dogs. MBF to ischemic myocardium was not significantly enhanced by D during ischemia. After 5 min of reperfusion subepicardial MBF was increased in group S, indicating a tendency towards reactive hyperemia. After 120 min of reperfusion there was a significant reduction in subendocardial MBF in group S and the transmural blood flow ratio was 1.23 +/- 0.59 in group D as compared with 0.53 +/- 0.39 in group S (p less than 0.05). The infarcted area as a percentage of the risk area was considerably smaller in group D than in group S (27.5 +/- 3.0 vs 47.0 +/- 6.5%, p less than 0.05). D markedly reduced the elevation of tissue calcium especially in the subendocardium. These findings suggest that D reduces the ultimate infarct size through the beneficial effect on ischemia-reperfusion injury.     

Non-elastic deformation of myocardium in low-flow ischemia and reperfusion: ultrastructure-function relations.

This study tested the hypothesis that regional low-flow ischemia and reperfusion alter myocardial material properties by causing non-elastic deformation. Twenty-two anesthetized, open-chest pigs were studied. Pigs underwent 90 min of regional low-flow ischemia (anterior LV subendocardial blood flow 29+/-7% of baseline) followed by 90 min reperfusion. LV pressure and regional subendocardial segment length were recorded to derive end-diastolic pressure vs segment length (EDP vs EDL) and preload-recruitable stroke work (PRSW) relations. In vivo, non-elastic myocardial deformation was inferred from increases in minimally loaded myocardial dimensions: the EDL at zero EDP (L0) and the EDL at which no regional external work was performed (Lw, the PRSW intercept). In 15 pigs, ultrastructural confirmation of non-elastic deformation was obtained from sarcomere dimensions measured by transmission electron microscopy after in situ perfusion fixation under non-ischemic conditions, after 90 min ischemia, or after 90 min ischemia plus 90 min reperfusion. Ischemia increased L0 and Lw to 1.17+/-0.05 and 1. 13+/-0.04 times baseline, respectively. After reperfusion, L0 and Lw remained increased to 1.09+/-0.03 and 1.15+/-0.02 times baseline (all P<0.05). After reperfusion, PRSW slope was not different from baseline, but regional external work remained depressed (0.38+/-0.03 times baseline) due to the persistent increase in Lw. Neither L0 nor Lw changed in the posterior (non-ischemic) region. In hearts fixed after ischemia or after ischemia plus reperfusion, sarcomere length was significantly greater and transverse distance between thick myofilaments was significantly smaller in the anterior (ischemic) subendocardium than in the posterior (non-ischemic) subendocardium (P<0.01). We conclude that regional low-flow ischemia and reperfusion cause non-elastic deformation of myocardium, manifest in vivo by increased minimally loaded myocardial dimensions (L0 and Lw) and ultrastructurally by increased sarcomere length and decreased transverse interfilament distance. Non-elastic deformation of myocardium may contribute to contractile dysfunction in low-flow ischemia and reperfusion.     

Effects of nontransmural ischemia on inner and outer wall thickening in the canine left ventricle

The effect of ischemic subendocardial dysfunction on contractile function in the normally perfused subepicardium remains controversial. Accordingly, regional wall thickening (WT) was measured directly in the left ventricle of 10 open-chest dogs using epicardial echocardiography. Two silk sutures, used as echocardiographic targets, were inserted beneath the transducer to a depth of 25.0 +/- 0.7% (subepicardium) and 48.0 +/- 2.7% (midmyocardium) of transmural thickness. A hydraulic cuff, placed around the left anterior descending coronary artery (LAD) was then inflated slowly until transmural WT was reduced to 62 +/- 2% of baseline. Myocardial blood flow (MBF) was not significantly altered in the subepicardial third of the wall; however, flow to the midwall and subendocardial thirds decreased by 39% (p less than 0.001) and 50% (p less than 0.001), respectively. Nontransmural ischemia produced a small but significant decrease in epicardial WT (baseline = 0.77 +/- 0.08 mm, ischemia = 0.69 +/- 0.08 mm; p less than 0.05) and substantially larger decreases in midwall (baseline = 1.66 +/- 0.14 mm, ischemia = 1.03 +/- 0.09 mm; p less than 0.001) and subendocardial WT (baseline = 3.39 +/- 0.34 mm, ischemia = 2.10 +/- 0.26 mm; p less than 0.001). The degree of regional dysfunction was linearly correlated with tissue depth (r = 0.88, p less than 0.001). Thus the degree of dysfunction produced by nontransmural ischemia increased progressively from the subepicardium to the subendocardium, paralleling the pattern of perfusion. We conclude that perfusion, rather than transmural tethering, largely determines subepicardial function in the setting of nontransmural ischemia.     

Exercise-induced subendocardial dysfunction in dogs with left ventricular hypertrophy

The effects of treadmill exercise on regional myocardial blood flow and function were examined in 10 adult, conscious dogs with left ventricular hypertrophy (LVH) induced by aortic banding in puppies, which resulted in a left ventricular (LV) weight/body weight ratio of 8.5 +/- 0.3. Data were compared with results from eight control dogs with an LV weight/body weight ratio of 4.9 +/- 0.2. At rest, LV systolic and end-diastolic pressures were significantly greater (p less than 0.01), and mean arterial pressure was significantly less (p less than 0.05) in LVH dogs. Mean myocardial blood flow (control dogs, 0.98 +/- 0.11 ml/min/g; LVH dogs, 1.16 +/- 0.06 ml/min/g) and the transmural blood flow distribution at baseline, as assessed by endocardial/epicardial blood flow ratio (control, 1.35 +/- 0.12; LVH, 1.21 +/- 0.09), were similar in the two groups. During exercise to a target heart rate (240 beats/min), LVH dogs demonstrated greater (p less than 0.01) increases in LV systolic and end-diastolic pressures. In control dogs, as expected, exercise augmented velocity of circumferential fiber shortening (16 +/- 9%) and shortening fraction (15 +/- 5%), but in LVH dogs, exercise reduced the velocity of circumferential fiber shortening (-14 +/- 6%) and shortening fraction (-17 +/- 5%). Exercise also increased full wall thickening (35 +/- 5%), subendocardial wall thickening (66 +/- 10%), and subepicardial wall thickening (44 +/- 9%) in control dogs. In LVH dogs, exercise increased subepicardial wall thickening (31 +/- 9%) and reduced subendocardial wall thickening (-40 +/- 7%); full wall thickening did not change (-11 +/- 9%). This was associated with a fall in endocardial/epicardial flow ratio to 0.72 +/- 0.05 (p less than 0.01) in LVH dogs. The subendocardial dysfunction persisted late into recovery, at a time when the transmural blood flow distribution had returned to baseline; this occurrence suggested myocardial stunning. Thus, in dogs with LVH, selective subendocardial hypoperfusion and profound selective depression in subendocardial wall thickening are observed during exercise. The subendocardial dysfunction persisted into recovery despite resolution of the perfusion abnormality.     

Serotonin selectively aggravates subendocardial ischemia distal to a coronary artery stenosis during exercise.

BACKGROUND. The coronary circulation has been shown to remain responsive to vasodilator and vasoconstrictor stimuli during myocardial ischemia. Because serotonin possesses both vasodilator and vasoconstrictor properties, we examined its effect in the coronary circulation distal to an arterial stenosis that resulted in myocardial hypoperfusion during exercise. METHODS AND RESULTS. Seven chronically instrumented dogs were studied during treadmill exercise in the presence of a stenosis that reduced distal left circumflex coronary artery perfusion pressure to 42 +/- 1 mm Hg. Myocardial blood flow was assessed with radioactive microspheres during exercise before and during intracoronary infusion of 0.4 and 2.0 micrograms/kg-1.min-1 serotonin. The stenosis was adjusted to maintain distal coronary pressure constant during control exercise and with the two doses of serotonin. In seven dogs, the effect of serotonin (2.0 micrograms/kg-1.min-1) was also studied during exercise with normal arterial inflow. During control exercise, the stenosis decreased mean myocardial blood flow to 45% of flow in the normally perfused region. This decrease was most pronounced in the subendocardium (endocardial/epicardial ratio 0.36 +/- 0.06 versus 1.46 +/- 0.14 in the control region; p < 0.01). With no change in pressure distal to the stenosis, serotonin decreased subendocardial flow from 0.51 +/- 0.09 ml/min-1.g-1 to 0.41 +/- 0.12 (p < 0.05) and then to 0.35 +/- 0.08 ml/min-1.g-1 (p < 0.05) and tended to increase subepicardial flow from 1.47 +/- 0.17 to 1.91 +/- 0.23 and 1.85 +/- 0.21 ml/min-1.g-1 (p = 0.08) during infusions of 0.5 and 2.0 micrograms/kg-1.min-1, respectively, with no change in total arterial inflow. In contrast, in the absence of a stenosis, serotonin (2.0 micrograms/kg-1.min-1) increased subendocardial flow from 2.43 +/- 0.25 to 3.73 +/- 0.25 ml/min-1.g-1 (p < 0.01) and subepicardial flow from 1.88 +/- 0.20 to 5.29 +/- 0.38 ml/min-1.g-1 (p < 0.01). CONCLUSIONS. During normal arterial inflow, serotonin dilated coronary resistance vessels and increased flow to all myocardial layers. During hypoperfusion, a vasodilator response was still present in the subepicardium, but vasoconstriction was then observed in the subendocardium. Our data suggest that serotonin constricts the intramural penetrating arteries, thereby selectively increasing resistance to subendocardial blood flow.     

Effect of inosine on ventricular regional perfusion and infarct size after coronary occlusion.

In 16 dogs inosine was infused at 0.5 mmol/min i.v. for 5 min beginning 15 min after coronary occlusion. Tracer microspheres were used to estimate flow in subepicardium and subendocardium of nonischemic, central ischemic, and borderline ischemic muscle. Estimates of flow before occlusion, 5 min after occlusion, during inosine infusion, 30 min after infusion and 60 min after infusion were obtained. Coronary occlusion reduced flow in the central ischemic regions by 75-95%. The reduction in flow was greatest in subendocardium. In the borderline regions subendocardial flow was reduced by 30% while subepicardial flow was unaffected. The major effects of inosine were seen in nonischemic and borderline ischemic regions. Flow in borderline subendocardium returned to its pre-occlusion value, and flow in nonischemic myocardium increased by approximately 60-80%. However, only in the ischemic regions was the increase in flow sustained for the entire 60 min. In 20 dogs infarct size was determined using nitro blue tetrazolium stain. In 10 controls infarct size was 20.1%, while in 10 inosine-treated dogs infarct size was 15.2% of left ventricular weight (p less than 0.01). Thus, following coronary occlusion inosine infusion was associated with an increase in perfusion of ischemic myocardium and a reduction in infarct size.     

Effects of atrial natriuretic peptide on transmural blood flow and reactive hyperemia in the presence of flow-limiting coronary stenosis in the awake dog: evidence for dilation of the intramural vasculature

The effects of atrial natriuretic peptide (ANP) on transmural myocardial blood flow distribution and the reactive hyperemic response in the presence and absence of flow-limiting coronary stenosis were examined in chronically instrumented conscious dogs. Ten-second coronary occlusion without subsequent flow restriction resulted in marked reactive hyperemic responses (Doppler flow probes), mean flow debt repayment was 481 +/- 55%. When the 10-second coronary occlusions were followed by a 20-second partial restriction that allowed normal preocclusion coronary inflow, the subsequent reactive hyperemia was significantly augmented, mean flow debt repayment was 938 +/- 91% (p less than 0.05). Pretreatment with ANP (3 micrograms/kg) did not alter the flow debt repayment after a 10-second occlusion without restriction (474 +/- 30%, NS) but attenuated the augmentation of reactive hyperemia resulting from the 20-second inflow restriction, flow debt repayment (613 +/- 66%, NS). Regional myocardial blood flow to the ischemic region was measured during restricted inflow after a 10-second coronary occlusion before and after ANP pretreatment. Before ANP, subendocardial flow decreased (0.54 +/- 0.04 ml/min/g) and subepicardial flow significantly increased (1.03 +/- 0.12 ml/min/g) when compared with the nonischemic zone (subendocardial, 1.03 +/- 0.09 ml/min/g; subepicardial, 0.87 +/- 0.09 ml/min/g, p less than 0.05), indicating maldistribution of the restricted inflow. The resultant subendocardial-to-subepicardial ratio in the ischemic region was significantly decreased when compared with the nonischemic region (0.56 +/- 0.03 vs. 1.18 +/- 0.04, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Subendocardial and subepicardial segmental function changes in the dog heart due to gradual coronary flow reduction by an acutely developing thrombus

Regional myocardial dynamics were assessed during continuous, gradual coronary flow reductions caused by spontaneous thrombus formation in the stenosed left circumflex coronary artery of eight open chest dogs. Contractile changes in the subendocardial and subepicardial layers were measured by ultrasonic crystal techniques. Segment length shortening was continuously measured as coronary flow reductions occurred. Contractile dysfunction in the subendocardium preceded that in the subepicardium. At lowest flow levels the subendocardial function degenerated to severe holosystolic bulging whereas some systolic shortening was maintained in the subepicardium. Exponential equations derived to express changes in end diastolic segment length and end systolic length as a function of coronary blood flow for both subendocardium and subepicardium indicated that increases in end systolic length were a more sensitive index of ischaemia than increases in end diastolic length for both the subendocardium and subepicardium during coronary flow reduction. Comparison of exponential curves of end diastolic segment length vs coronary blood flow in subendocardium and subepicardium showed a small but significant difference (p less than 0.02). Comparison of exponential curves of end systolic length vs coronary blood flow in subendocardium and subepicardium showed a large difference in changes at end systole occurring between subendocardium and subepicardium (p less than 0.001). Active contraction of the subepicardium may serve to limit the extent of paradoxical systolic segment lengthening in the underlying ischaemic myocardium and thus help to preserve ventricular function during acute gradual coronary flow limitation.     

Mechanisms of subendocardial dysfunction in response to exercise in dogs with severe left ventricular hypertrophy.

The effects of exercise on regional myocardial blood flow and function were examined in the presence and absence of beta-adrenergic receptor blockade in 10 adult conscious dogs with severe left ventricular (LV) hypertrophy induced by aortic banding in puppies, which increased the LV weight/body weight ratio by 87%. Exercise at the most intense level studied increased LV systolic (+87 +/- 8 mm Hg) and end-diastolic (+28 +/- 5 mm Hg) pressures, systolic (+85 +/- 12 g/cm2) and diastolic (+49 +/- 11 g/cm2) wall stresses, and subepicardial wall thickening (+0.18 +/- 0.05 mm) but reduced subendocardial wall thickening (-0.45 +/- 0.12 mm) and full wall thickening (-0.42 +/- 0.13 mm). This was associated with a fall in the subendocardial/subepicardial (endo/epi) blood flow ratio to 0.87 +/- 0.06 from 1.24 +/- 0.08. Subendocardial dysfunction persisted during recovery, at a time when transmural blood flow distribution returned to baseline, suggesting myocardial stunning. At the least intense level of exercise studied, the endo/epi blood flow ratio did not fall (1.27 +/- 0.14), but increases in heart rate (+73 +/- 8 beats per minute) and LV systolic (+35 +/- 8 g/cm2) and diastolic (+27 +/- 3 g/cm2) wall stresses were observed, and subendocardial wall thickening fell significantly (-0.21 +/- 0.08 mm, p less than 0.05). With anticipation of exercise, subendocardial wall thickening was not changed. However, subendocardial dysfunction was even evident after 10 beats, i.e., the first 3 seconds of exercise, at a time when LV pressures and stresses had not increased. After beta-adrenergic receptor blockade with propranolol, the most intense level of exercise was associated with lesser increases in systolic and diastolic LV wall stresses, heart rate, and LV dP/dt, and the endo/epi blood flow ratio was no longer reduced below unity (1.17 +/- 0.09). In addition, there were no decreases in subendocardial or full wall thickening, and myocardial stunning was no longer observed. Thus, the subendocardial hypoperfusion and depression in subendocardial wall thickening observed during exercise in dogs with LV hypertrophy was prevented by pretreatment with beta-adrenergic receptor blockade. Furthermore, the subendocardial dysfunction occurred rapidly, before alterations in LV systolic or diastolic wall stress or an alteration in the endo/epi blood flow ratio.(ABSTRACT TRUNCATED AT 400 WORDS)     

Three-dimensional distribution of collateral blood flow within the anatomic area at risk after circumflex coronary artery occlusion in dogs

Summary It is generally accepted that occlusion of a major coronary artery in the dog results in a transmural gradient of collateral blood flow, with the subepicardial region receiving the greatest perfusion. The lateral and base to apex distribution of collateral blood flow and of metabolic and functional consequences of ischemia have been more difficult to define. One reason for such difficulties has been the failure to define the anatomic boundarics of the ischemic vascular bed so that uncontaminated samples of ischemic and non-ischemic tissue could be selected for study. In the present study, the three dimensional distribution of myocardial blood flow during occlusion of the circumflex artery was mapped in seven dogs. At the end of the study, the boundaries of previously ischemic and non-ischemic regions were identified by simultaneous coronary perfusion with red and blue dyes. Left ventricular slices were separated into ischemic and non-ischemic vascular beds based on the dye boundarics, with 1–2 mm of tissue trimmed from this interface to eliminate visually apparent admixture. The ischemic vascular bed of each cross sectional slice then was cut into five transmural wedges, each 3–5 mm wide; each wedge was further subdivided into subendocardial, middle, and subepicardial thirds. The results of blood flow measurements in these samples indicate that the dye injection technique identifies a real interface with a sharp lateral transition in blood flow between ischemic and non-ischemic vascular beds. Within the ischemic vascular bed, there is a transmural gradient of collateral blood flow, but within a given mural layer, there is no consistent gradient from the center to lateral edge or from base to apex of the ischemic region. Thus, in studies designed to characterize the properties of myocardium on either side of the ischemic/non-ischemic interface, reasonable resolution can be achieved by coronary dye infusions to permit visual identification of this interface. On the other hand, in studies in which collateral blood flow is measured as a baseline predictor of infarct size, measurements can be made in a central ischemic block which will be representative of most or all of the ischemic region. Borderzone samples can be excluded to avoid contamination of ischemic samples with non-ischemic tissue.Supported in part by NIH grants 27416 and 23138.     

Phasic mitral blood flow and regional left ventricular dimensions: possible mechanism of active assist to ventricular filling

Postsystolic myocardial segment shortening (PSS) has been observed in dogs and humans by means of ultrasonic crystals but has never been studied specifically. In this study, both subendocardial and subepicardial regional function in the basal circumflex and midventricular anterior myocardium (LAD) was studied during late systole and early diastole with ultrasonic crystals. Fifteen open-chest dogs were instrumented with electrocardiographic leads; Millar catheters for measurement of left ventricular pressure, left ventricular dP/dt, and aortic blood pressure; flow probes for determination of aortic and mitral blood flow; and subendocardial and subepicardial crystal pairs to measure subendocardial segment length shortening velocity (dL/dt). Crystal pairs were placed in the subendocardial left oblique mode and the extreme subendocardial right oblique mode (-50 and +50 degrees from equator) in the lateral basal (circumflex, n = 9) and anterior midventricular myocardium (LAD, n = 6). Subendocardial segments showed PSS averaging 34 +/- 7% of the total shortening distance in the circumflex bed and 21 +/- 2% in the LAD bed (p = NS). The rate of subendocardial segment shortening during PSS increased 273 +/- 42.6% (p less than .05) relative to the rate of segment shortening during ejection in the circumflex bed and 126 +/- 40% (p less than .05) in the LAD bed (p = NS). The most rapid diastolic increase in subendocardial length (peak +dL/dt) occurred immediately after subendocardial PSS. Subendocardial diastolic peak +dL/dt occurred after the onset of mitral inflow during the acceleration limb of the rapid ventricular filling phase. Overlying subepicardial segments began lengthening 82 +/- 12 msec before onset of subendocardial segment lengthening in the circumflex bed and 63 +/- 9 msec before subendocardial lengthening in the LAD bed (p less than .05), indicating that the subepicardial segment had begun to lengthen while subendocardial segment shortening continued after end-systole. Onset of early segmental subepicardial lengthening varied with respect to the point of end-systole. Early segmental subepicardial lengthening with subendocardial PSS may be a mechanism by which the rapid filling phase of the left ventricle is actively potentiated by storing potential energy released as early diastolic elastic recoil.     

Effect of alpha-adrenergic stimulation on regional contractile function and myocardial blood flow with and without ischemia.

BACKGROUND. The effect of alpha-adrenergic receptor activation on regional contractile function and transmural myocardial blood flow is controversial. Accordingly, the effects of selective alpha 1-(methoxamine) and alpha 2-(BHT 933) receptor stimulation on regional contractile function and transmural myocardial blood flow distribution were studied in 15 anesthetized open-chest dogs. METHODS AND RESULTS. The alpha-adrenergic agonists were separately infused into the cannulated left circumflex coronary artery during control and ischemic conditions in the same animal. Mean coronary perfusion pressure was held constant by a servocontrolled pump in an extracorporeal circuit. Ischemia was created by reducing coronary perfusion pressure to the level at which percent systolic wall thickening (%WT) decreased by 54%. Contractile function during control conditions was unchanged, whereas under ischemic conditions a further significant decrease in %WT of 27% occurred with either alpha 1- or alpha 2-receptor stimulation without any change in the anterior (control) wall function. Both alpha 1- and alpha 2-receptor stimulations during control conditions resulted in a relatively uniform transmural decrease in blood flow with no change in the subendocardial-to-subepicardial blood flow ratio. With alpha 1-stimulation during ischemia (n = 13), there was a tendency toward decreased subepicardial blood flow with no change in subendocardial flow, resulting in an increased subendocardial-to-subepicardial blood flow ratio (0.61 +/- 0.23 to 0.82 +/- 0.40, p less than 0.05). alpha 2-Receptor stimulation during ischemia (n = 12) produced a significant decrease in subepicardial blood flow (0.45 +/- 0.20 to 0.35 +/- 0.12 ml/min/g, p less than 0.01) with no change in subendocardial blood flow, also resulting in an increased subendocardial-to-subepicardial blood flow ratio. CONCLUSIONS. These results indicate the selective vasoconstriction in outer wall layers during ischemia mediated by either alpha 1- or alpha 2-receptors can cause a decrease in regional contractile function despite unchanged subendocardial blood flow and improved subendocardial-to-subepicardial flow ratio. This suggests an adverse effect of alpha-adrenergic vasoconstriction during ischemia in this coronary perfusion pressure-controlled canine model.