Subendocardial Flow Research Articles

Coronary patency and its relation to contractile reserve in hibernating myocardium.

Recent clinical studies suggest that contractile reserve may occur in a minority of viable, chronically dysfunctional segments with reduced resting flow (hibernating myocardium). We hypothesized that epicardial artery patency might predict which segments have critically reduced subendocardial flow reserve and limited contractile reserve. Pigs were chronically instrumented with a fixed stenosis on the left anterior descending coronary artery (LAD) to produce hibernating myocardium. At least 3 months later, flow at rest and during adenosine vasodilation (microspheres), ventricular function and contractile reserve (contrast ventriculography), and (18)F-2-deoxyglucose (FDG) deposition (ex vivo tissue counting) were quantified. Hibernating myocardium (regional dysfunction with reduced resting perfusion) was present in animals with an occluded (n=40) or patent (n=19) LAD. Viability was confirmed by histology and FDG deposition. In collateral-dependent hibernating myocardium, subendocardial flow did not increase above baseline levels during epinephrine or adenosine stimulation, consistent with exhausted subendocardial flow reserve at rest. This was associated with limited contractile reserve and regionally increased FDG deposition. In contrast, subendocardial flow reserve was present in hibernating myocardium distal to a patent artery. Contractile reserve during epinephrine infusion in this group was significantly greater than in animals with an occluded artery. The physiology and metabolism of hibernating myocardium was dependent upon stenosis severity and its effects on subendocardial flow reserve. In collateral-dependent hibernating myocardium, contractile reserve was limited in the setting of exhausted subendocardial flow reserve, thus supporting the hypothesis that metabolic imaging may be preferable for determining viability distal to a complete occlusion.

Myocyte Apoptosis and Reduced SR Gene Expression Precede the Transition from Chronically Stunned to Hibernating Myocardium

A systematic transition from chronic stunning to hibernation occurs as coronary flow reserve decreases to a critical level. Hibernating myocardium exhibits apoptosis-induced myocyte loss and a reduction in the expression of the sarcoplasmic reticulum (SR) Ca2+ATPase but whether similar cellular changes occur in chronic stunning is unknown. Pigs with a chronic left anterior descending coronary artery (LAD) stenosis were studied one (n=9) or two (n=10) months after instrumentation. Anterior hypokinesis with normal levels of resting perfusion developed at each time-point, consistent with chronic stunning. After 1 month, sub-endocardial flow reserve was moderately reduced (adenosine/rest, LAD: 3.60±0.91 v Remote: 6.00±0.54, P<0.01) with no regional differences in SR protein expression, no increase in apoptosis (32±6 v 21±5 nuclei/106myocyte nuclei, p-ns) and no regional myocyte loss (1976±44 v 1955±30 nuclei/mm2, p-ns). After 2 months, sub-endocardial flow reserve in chronically stunned myocardium was severely impaired (LAD: 1.41±0.21 v Remote: 5.59±0.96, P<0.01). There were small but significant reductions in LAD mRNA and protein levels for the SRCa2+ATPase and phospholamban whereas calsequestrin was unchanged. In addition, regional myocyte apoptosis increased (127±24 v 55±9 nuclei/106myocyte nuclei, P<0.01), resulting in the onset of myocyte loss (1293±50 v 1394±32 nuclei/mm2, P<0.01). Apoptosis-induced myocyte loss and reductions in SR protein expression are not invariably present in viable chronically dysfunctional myocardium. They are induced as the propensity of a region to develop reversible ischemia increases (as reflected by coronary flow reserve). The temporal progression indicates that alterations in SR protein expression and myocyte apoptosis precede the transition from chronically stunned to hibernating myocardium.

Increase in the left ventricular stiffness relates to decrease in the subendocardial flow in the isolated underperfused rat hearts

Increase in the left ventricular stiffness relates to decrease in the subendocardial flow in the isolated underperfused rat hearts

Stability of hibernating myocardium in pigs with a chronic left anterior descending coronary artery stenosis: absence of progressive fibrosis in the setting of stable reductions in flow, function and coronary flow reserve

OBJECTIVESThis study was performed to determine whether hibernating myocardium is adaptive or is destined to undergo progressive irreversible injury.BACKGROUNDPrevious studies have suggested that hibernating myocardium eventually results in progressive dysfunction. Since serial studies cannot be performed in humans, the temporal progression of physiologic and structural adaptations was evaluated in pigs with hibernating myocardium.METHODSPigs were instrumented with a left anterior descending coronary artery (LAD) stenosis (1.5 mm) and underwent physiologic studies three to five months later to quantify regional function, perfusion and 18F-2-deoxyglucose (FDG) uptake. Viability was confirmed by histology and contractile reserve.RESULTSHibernating myocardium was characterized by severe regional dysfunction (centerline score, −1.9 ± 0.1), reduced resting subendocardial flow (LAD: 0.85 ± 0.03 vs. normal: 1.02 ± 0.03 ml/min/g, p < 0.01), critically reduced subendocardial flow reserve (adenosine flow: 1.04 ± 0.09 ml/min/g, p = NS vs. rest; epinephrine flow: 0.88 ± 0.07 ml/min/g, p = NS vs. rest) and increased FDG uptake (0.022 ± 0.002 vs. 0.014 ± 0.001 ml/g/min, p < 0.01). Physiologic parameters were not different among animals studied at three (93 ± 1 days, n = 27), four (118 ± 2 days, n = 26) or five months (150 ± 6 days, n = 9). Pathology revealed a small increase in LAD connective tissue (6.4 ± 0.4% vs. 4.0 ± 0.2%, p < 0.001), with no change over this time frame.CONCLUSIONSThus, physiologic and structural features of hibernating myocardium remain constant for at least two months. The absence of functional deterioration or progressive fibrosis suggests that hibernation is adaptive rather than an unstable physiology destined to progress to irreversible injury. The stability of this model appears ideally suited for interventions targeted to improve flow and function in chronically dysfunctional myocardium.

Heart and Kidney, Abstract 130–137, Symposium

A systematic transition from chronic stunning to hibernation occurs as coronary flow reserve decreases to a critical level. Hibernating myocardium exhibits apoptosis-induced myocyte loss and a reduction in the expression of the sarcoplasmic reticulum (SR) Ca2+ATPase but whether similar cellular changes occur in chronic stunning is unknown. Pigs with a chronic left anterior descending coronary artery (LAD) stenosis were studied one (n=9) or two (n=10) months after instrumentation. Anterior hypokinesis with normal levels of resting perfusion developed at each time-point, consistent with chronic stunning. After 1 month, sub-endocardial flow reserve was moderately reduced (adenosine/rest, LAD: 3.60±0.91 v Remote: 6.00±0.54, P<0.01) with no regional differences in SR protein expression, no increase in apoptosis (32±6 v 21±5 nuclei/106myocyte nuclei, p-ns) and no regional myocyte loss (1976±44 v 1955±30 nuclei/mm2, p-ns). After 2 months, sub-endocardial flow reserve in chronically stunned myocardium was severely impaired (LAD: 1.41±0.21 v Remote: 5.59±0.96, P<0.01). There were small but significant reductions in LAD mRNA and protein levels for the SRCa2+ATPase and phospholamban whereas calsequestrin was unchanged. In addition, regional myocyte apoptosis increased (127±24 v 55±9 nuclei/106myocyte nuclei, P<0.01), resulting in the onset of myocyte loss (1293±50 v 1394±32 nuclei/mm2, P<0.01). Apoptosis-induced myocyte loss and reductions in SR protein expression are not invariably present in viable chronically dysfunctional myocardium. They are induced as the propensity of a region to develop reversible ischemia increases (as reflected by coronary flow reserve). The temporal progression indicates that alterations in SR protein expression and myocyte apoptosis precede the transition from chronically stunned to hibernating myocardium.

Simulation studies of the ischemic vulnerability of the subendocardium.

Changes in the subendo-subepi flow ratio were studied by using a simple electronic circuit model of the coronary vessel consisting of a resistor, capacitor and field effect transistor in order to provide a better understanding of the ischemic vulnerability of the subendocardium. The simulated subendo-subepi flow ratio was found to be approximately 1.2 under normal condition. Changes in the flow ratio were observed while varying the main arterial resistance, mean arterial pressure and intramyocardial pressure individually. The mean flow in the subendocardium was found to decrease at a rate faster than that in the subepicardium with the increase in the septal arterial resistance and the intramyocardial pressure. The same tendency was also observed while the arterial pressure was lowered. This decrease in the mean subendocardial flow is considered to be the effect of higher end-systolic resistance in the subendocardial venule compared to that in the subepicardial venule. These results would be helpful in understanding the vulnerability of the subendocardium to ischemia and in providing clinical treatment to patients with that disease.

Problems of coronary flow reserve.

Coronary flow reserve is used to aid understanding why myocardial oxygen consumption may fail to meet demand. Its general aspects are well known, but the problems of using it are not. This manuscript describes three important factors that need to be considered when assessing coronary flow reserve. (1) Maximal flow is usually achieved by giving either increasing doses or else what is thought to be a maximal dose of a vasodilator, or by examining peak reactive hyperemia. Evidence that both these approaches are flawed is provided. (2) Existing methods in humans allow only total reserve to be determined, but this might be inadequate because changes in total reserve might not reflect changes in subendocardial flow reserve. (3) Because there is marked heterogeneity of flow reserve in the left ventricle, measuring total flow reserve does not indicate when small regions are becoming ischemic. More basic research is needed to overcome these difficulties.

Transmural distribution of FDG uptake in stunned myocardium.

Fasting [(18)F]fluoro-2-deoxyglucose (FDG) uptake is increased in viable, chronically dysfunctional myocardium, but the relationship to acute episodes of ischemia remains undefined. To investigate FDG uptake in acute stunning, chronically instrumented pigs (n = 9) and sham controls (n = 8) were studied while in a fasted, closed-chest, anesthetized state. One-hour partial occlusion reduced subendocardial flow from 1.24 +/- 0.14 to 0.35 +/- 0.06 ml. min(-1). g(-1) and wall thickening from 16.8 +/- 2.1 to 3.7 +/- 0.7%. Regional function remained depressed during reperfusion (8.3 +/- 1. 4%) despite the return of flow to resting levels. Triphenyl tetrazolium chloride staining showed no irreversible injury. FDG uptake in stunned myocardium was variably increased and averaged 1. 5-fold higher than that of normal regions, with no consistent transmural variation. Subgroup analysis showed that variability in FDG uptake was related to alterations in insulin levels that varied directly with ischemic risk region.

Response to incremental doses of dobutamine early after reperfusion is predictive of the degree of myocardial salvage in dogs with experimental acute myocardial infarction

OBJECTIVESWe sought to determine whether the inotropic response to dobutamine might be useful for estimating the extent of viable myocardium soon after reperfusion.BACKGROUNDEarly identification of viable myocardium in the presence of severe left ventricular dysfunction after reperfusion is important for clinical decision making.METHODSNine open-chest dogs had left anterior descending coronary artery occlusion for 40 to 180 min, followed by gradual reperfusion. The systolic thickening response to incremental dobutamine doses was measured with ultrasonic crystals and regional flow by microspheres.RESULTSDogs were divided into two groups based on triphenyl tetralozium chloride infarct size (group 1: 9.3 ± 3.0% risk area; group 2: 51.1 ± 4.8%). In group 2 dogs with larger infarcts, regional flow during peak dobutamine was lower than it was in group 1 in endocardial (1.15 ± 0.22 vs. 2.64 ± 0.33 mL·min−1·g−1) and midwall (1.47 ± 0.32 vs. 2.92 ± 0.36 mL·min−1·g−1) layers, and endocardial flow in group 2 failed to increase from baseline (0.96 ± 0.07 vs. 1.15 ± 0.22 mL·min−1·g−1). Group 1 dogs demonstrated a dose dependent increase in systolic thickening with dobutamine versus a blunted response in group 2. The inotropic response to only 10 μg·kg−1·min−1 of dobutamine was predictive of the degree of myocardial salvage.CONCLUSIONSIn the early postischemic stunning phase of reperfusion, the inotropic response to dobutamine is predictive of the degree of myocardial salvage and ultimate infarct size. The ability to distinguish between stunned versus necrotic myocardium early after reperfusion was most likely due to the presence of subendocardial flow reserve during dobutamine in dogs with predominantly salvaged myocardium.

Profound apoptosis-mediated regional myocyte loss and compensatory hypertrophy in pigs with hibernating myocardium.

Myocyte apoptosis is seen in ischemic heart disease, but whether it can occur after reversible ischemia or independent of necrosis and replacement fibrosis is unknown. Pigs were instrumented with a stenosis of the left anterior descending coronary artery to chronically reduce coronary flow reserve over a period of 3 months. At this time, there was viable dysfunctional myocardium having the physiological features of hibernating myocardium. Resting subendocardial perfusion was reduced to 0.65+/-0.08 (mean+/-SEM) mL. min(-1). g(-1) in hibernating myocardium of instrumented pigs compared with 0.98+/-0.14 mL. min(-1). g(-1) in myocardium of sham-operated pigs (P<0.05). There was a critical limitation in subendocardial flow during vasodilation to 0.78+/-0.20 mL. min(-1). g(-1) in instrumented pigs versus 3. 24+/-0.50 mL. min(-1). g(-1) in sham-operated pigs (P<0.001). Histology revealed a regional reduction in myocyte nuclear density to 995+/-100 nuclei/mm(2) in hibernating myocardium from the instrumented group versus 1534+/-65 nuclei/mm(2) in myocardium from the sham-operated group (P<0.05), regional myocyte hypertrophy (myocyte volume per nucleus, 14 183+/-2594 in the instrumented group versus 9130+/-1301 microm(3) in the sham group; P<0.05), and minimal increases in connective tissue (5.8+/-0.9% in the instrumented group versus 3.0+/-0.2% in the sham group, P<0.05). Necrosis was not identified, but apoptosis was increased from 30+/-9 myocytes per 10(6) myocyte nuclei in myocardium from the sham group to 220+/-77 myocytes per 10(6) myocyte nuclei in hibernating myocardium (P<0.05). These findings indicate that reversible ischemia in an area of chronically reduced coronary flow reserve induces regional myocyte loss via an apoptotic mechanism. This may contribute to the progression of chronic coronary disease to heart failure and explain the lack of complete functional recovery after revascularization in hibernating myocardium.

Myocardial blood flow regulation relative to left ventricle pressure and volume in anesthetized dogs

The influence of left ventricle pressure and volume changes on coronary blood flow was investigated in eight anesthetized dogs. Coronary artery pressure-flow relationships were determined at two levels of left ventricular pressure and volume. The distribution of blood flow within the myocardium was also determined when these relationships varied. Reducing left ventricle pressures and volumes increased heart rate. Rate-pressure product, diastolic coronary pressure, myocardial O2 consumption, total, subendocardial and subepicardial flow decreased. Hematocrit and blood gas data were unchanged. The pressure-flow relationships were shifted leftward (p = 0.001) but the range of autoregulation was not altered. At low left ventricle pressures and volumes, the lower coronary artery pressure limit was shifted leftward (from 75 to 45 mm Hg (1 mm Hg = 133.3 Pa)), while total, subendocardial, and subepicardial blood flow did not change compared with the control. Below the lower coronary artery pressure limit, subendocardial but not subepicardial flow decreased, resulting in maldistribution of flow across the left ventricular wall. When coronary pressure was reset between control and the lower coronary artery pressure limit, subendocardial flow was restored. These results show that the lower coronary artery pressure limit can be shifted leftward while the distribution of blood flow across the left ventricular wall is preserved.

Differential 18F-2-deoxyglucose uptake in viable dysfunctional myocardium with normal resting perfusion: evidence for chronic stunning in pigs.

Viable, chronically dysfunctional myocardium can have normal or reduced resting flow. We previously produced hibernating myocardium with reduced resting flow in pigs with a chronic stenosis and hypothesized that hibernation is preceded by chronic stunning with normal resting perfusion. Pigs instrumented with a proximal left anterior descending coronary artery (LAD) stenosis were studied 1 or 2 months later in the closed-chest anesthetized state. Stenosis severity increased from 74+/-5% at 1 month to 83+/-6% at 2 months and was accompanied by anteroapical hypokinesis (wall motion score, 2.1+/-0.1 at 1 month and 1.5+/-0.3 at 2 months; normal=3). Resting perfusion was similar in normal and dysfunctional regions, but the deposition of 18F-2-deoxyglucose (FDG) varied. At 1 month, subendocardial FDG deposition by excised tissue counting was similar in each region (0. 034+/-0.006 mL. g-1. min-1 LAD region versus 0.032+/-0.004 mL. g-1. min-1 in normal regions, P=NS). At 2 months, subendocardial FDG deposition was increased (0.084+/-0.025 mL. g-1. min-1 LAD region versus 0.042+/-0.017 mL. g-1. min-1 in normal regions, P<0.05). Increases in FDG uptake were inversely related to LAD subendocardial flow reserve during adenosine (3.5+/-0.6 at 1 month versus 1.4+/-0.2 at 2 months, P<0.01). These data indicate a progression of physiological adaptations in pigs with viable, chronically dysfunctional myocardium. As coronary flow reserve decreases, fasting FDG uptake increases. Flow at rest remains normal, consistent with "chronic stunning," and contrasts with reduced flow and increased FDG characteristic of hibernating myocardium in similarly instrumented pigs after 3 months. This temporal progression of adaptations supports the hypothesis of a transition from a physiological phenotype of stunning to hibernation.

Tachycardia-induced subendocardial necrosis in acutely instrumented dogs with fixed coronary stenosis.

It has been speculated but never proven that tachycardia-induced ischemia per se may lead to myocardial infarction. In 17 anesthetized dogs, the proximal left anterior descending (LAD) artery was cannulated and perfused via bypass from the left subclavian artery. Distal LAD pressure was reduced by a screw clamp to cause > or =20% decrease in wall thickening during pacing tachycardia but no decrease in resting heart rate (approximately 90 bpm). Dogs were randomly assigned to three groups: 1) control (n = 6) maintained at resting heart rate (approximately 90 bpm) and mean coronary pressure of 49+/-5 mm Hg for 4 h; 2) 4-h ischemia (n = 6), paced at 150 bpm and mean coronary pressure maintained at 59+/-6 mm Hg for 4 h; and 3) 1-h ischemia (n = 5), paced at 150 bpm and mean coronary pressure of 54+/-8 mm Hg for 1 h. Myocardial blood flow and infarct area were measured by radiolabeled microspheres and triphenyl-tetrazolium chloride staining, respectively. Despite the higher coronary pressure in the 4-h ischemia group (P = 0.02), patchy subendocardial necrosis occurred in all these dogs and in two of the 1-h ischemia dogs, and one control dog had minimal papillary muscle necrosis. Infarct area was largest in the 4-h ischemic group (15.5%+/-9.1%) compared with control and 1-h ischemia groups (0.09%+/-0.2% and 1.6%+/-2.1%, respectively) (P < 0.002). Relative (risk/ nonrisk areas) subendocardial flow was lower at the end of ischemia in the 4- and 1-h ischemia groups compared with the control group (0.3+/-0.1 and 0.4+/-0.1 vs 0.9+/-0.2; P = 0.008 and 0.01, respectively). Prolonged tachycardia-induced ischemia, in the face of fixed coronary stenosis causing no ischemia at the resting heart rate, leads to patchy subendocardial necrosis, despite anticoagulation and antiplatelet treatment. Prolonged tachycardia-induced ischemia, in the face of fixed coronary stenosis causing no ischemia at the resting heart rate, leads to subendocardial infarction in dogs. These findings suggest a possible mechanism for postoperative myocardial infarction.

Myocardial blood flow regulation relative to left ventricle pressure and volume in anesthetized dogs

The influence of left ventricle pressure and volume changes on coronary blood flow was investigated in eight anesthetized dogs. Coronary artery pressure-flow relationships were determined at two levels of left ventricular pressure and volume. The distribution of blood flow within the myocardium was also determined when these relationships varied. Reducing left ventricle pressures and volumes increased heart rate. Rate-pressure product, diastolic coronary pressure, myocardial O2 consumption, total, subendocardial and subepicardial flow decreased. Hematocrit and blood gas data were unchanged. The pressure-flow relationships were shifted leftward (p = 0.001) but the range of autoregulation was not altered. At low left ventricle pressures and volumes, the lower coronary artery pressure limit was shifted leftward (from 75 to 45 mmHg (1 mmHg = 133.3 Pa)), while total, subendocardial, and subepicardial blood flow did not change compared with the control. Below the lower coronary artery pressure limit, subendocardial but not subepicardial flow decreased, resulting in maldistribution of flow across the left ventricular wall. When coronary pressure was reset between control and the lower coronary artery pressure limit, subendocardial flow was restored. These results show that the lower coronary artery pressure limit can be shifted leftward while the distribution of blood flow across the left ventricular wall is preserved.Key words: autoregulation, coronary artery pressure-flow relations, myocardial blood flow distribution, left ventricular pressure, left ventricular volume.

Myocardial Distribution of Antegrade Cold Crystalloid and Tepid Blood Cardioplegia

Background. Tepid blood (TB) cardioplegia combines the improved rheologic characteristics and the augmented oxygen and substrate delivery of blood cardioplegia with the advantages of moderate hypothermia. In addition, the intramyocardial distribution of continuous TB cardioplegia may also be better than intermittent cold crystalloid (CC) cardioplegia. We sought to compare the distribution of TB and CC cardioplegia at varying infusion pressures. Methods. In situ, isolated canine hearts were randomized to antegrade, continuous TB (28°C, n = 8) or intermittent CC (n = 8) cardioplegia infused at 50, 75, and 100 mm Hg. The regional distribution of cardioplegia at each pressure was measured by 15-μm colored microspheres. Cardioplegia distribution was measured from three areas each of the right ventricle (inflow, outflow, and apex) and the left ventricle (anterior, lateral, and posterior). Left ventricular samples were subdivided into subepicardial, midmyocardial, and subendocardial. Results. Delivery of cardioplegia to all areas of the right and left ventricles showed a linear pressure–flow relationship over the range of pressures tested. Right ventricular distribution was two-thirds of that to the left ventricle, and left ventricular subepicardial distribution was approximately one half of subendocardial flow in both groups at all delivery pressures. However, the subendocardial to subepicardial ratio was significantly greater with TB cardioplegia than with CC cardioplegia. Transmural right ventricular cardioplegia flow was comparable in both groups. In contrast, left ventricular distribution of CC cardioplegia was greater than TB cardioplegia at all three pressures tested. Conclusions. The pressure–flow relationship in both CC and TB cardioplegia is linear in both the right and left ventricular myocardium over clinically applicable delivery pressures. The distribution of cardioplegia to the right ventricle is not altered by increased pressure.

Pharmacologic heart rate reduction: effect of a novel, specific bradycardic agent on the heart.

Because heart rate (HR) is a major determinant of myocardial oxygen consumption (MVO2) a decrease in HR could prevent ischemia or reduce its consequences. We examined the effects of a novel bradycardic agent of the benzazepinone type, DK-AH 269 (DK), on ventricular function and perfusion in 12 isolated, blood-perfused rabbit hearts. HR was significantly reduced by 1mumol/L DK (160 +/- 28 vs. 124 +/- 23 min-1); diastole lengthened from 235 +/- 69 to 334 +/- 85 ms. Aortic flow tended to fall after DK (50.0 +/- 29.6 vs. 35.6 +/- 21.5 ml/min), but stroke volume remained unchanged (0.29 +/- 0.16 vs. 0.28 +/- 0.17 ml) following DK. Peak left-ventricular pressure (LVPmax) (106 +/- 29 vs. 92 +/- 35 mmHg) and dp/dtmax (1482 +/- 582 vs. 1247 +/- 644 mmHg/s) were decreased. dp/dtmin, as a measure of early relaxation, was also decreased (-1361 +/- 362 vs, -1125 +/- 488 mmHg/s), whereas the end-diastolic pressure (LVPed) was increased (20 +/- 12 vs. 25 +/- 17 mmHg). Coronary blood flow (CBF) per beat was not affected by DK: 0.07 +/- 0.02 vs. 0.07 +/- 0.02 ml. However, the coronary resistance increased with DK from 0.76 +/- 0.29 to 1.13 +/- 0.66 mmHg/(ml/min/100 g). The MVO2 was decreased (6.8 +/- 3.4 vs. 5.9 +/- 2.8 ml/min/100 g). The relation between subendocardial and subepicardial flow (colored microspheres) was unchanged after DK (1.12 +/- 0.22 vs. 1.13 +/- 0.16). Using electrical pacing to restore the control HR, dp/dtmax, LVPed, and MVO2 were nearly restored to predrug levels. In contrast, stroke volume, LVPmax, dp/dtmin and CBF per beat were less than control. In summary: DK effectively reduces heart rate and increases diastole. In parallel with the moderately reduced contractile function, MVO2 is reduced whereas CBF per beat is preserved. These results suggest that this novel bradycardic agent could be useful in treating unwanted tachycardia in the experimental setting, postoperative tachycardia in patients with heart disease or be useful even in treating coronary heart disease.

Elevated right atrial pressure does not reduce collateral blood flow to ischemic myocardium.

Right atrial pressure (RAP) may become substantially elevated during heart failure and has been reported to reduce collateral flow to the ischemic myocardium of isolated hearts. The effect of elevated RAP on blood flow to collateral-dependent and normal myocardium of in situ hearts was studied in 20 open-chest anesthetized dogs with acute occlusion of the left anterior descending coronary artery. Regional myocardial blood flow was measured with radioactive microspheres while RAP was elevated by restricting right ventricular (RV) outflow with constant aortic pressure. Increasing RAP from 3.8 +/- 0.5 to 21.5 +/- 0.8 and then to 34.3 +/- 0.9 mmHg did not reduce blood flow to any transmural region of LV normal or collateral-dependent myocardium. Further elevation of RAP to 49.3 +/- 1.1 mmHg reduced subepicardial but not subendocardial collateral flow. Blood flow to normal RV increased. Retrograde flow and peripheral coronary pressure increased as RAP was elevated. Previously injected 11-micron microspheres were present in the retrograde flow when RAP was elevated; thus retrograde capillary flow contributed to the retrograde flow. The results explain discrepancies among previous reports, and they are consistent with a waterfall phenomenon in the coronary collateral circulation.

Cyclooxygenase blockade limits blood flow to collateral-dependent myocardium during exercise

Cyclooxygenase blockade has been found to cause vasoconstriction of coronary collateral vessels in open-chest animals. This study was carried out to determine whether cyclooxygenase blockade can limit blood flow to collateral-dependent myocardium during exercise. Studies were performed in 8 adult mongrel dogs in which intermittent followed by permanent occlusion of the left anterior descending coronary artery produced an area of collateral-dependent myocardium. Myocardial blood flow was measured with radioactive microspheres at rest and during treadmill exercise to produce heart rates of 215 +/-0 7 beats/min. At rest collateral zone blood flow (1.00 +/- 0.10 ml/min per g) was significantly less than normal zone flow (1.23 +/- 0.14) (P < 0.05). During control exercise blood flow increased 91 +/- 22% in the collateral zone and 102 +/- 28% in the normal zone (each P < 0.05). Thirty minutes after cyclooxygenase blockade with indomethacin (5 mg/kg i.v.) blood flow in the normal zone and the collateral zone was not different from control during resting conditions. Indomethacin did not change heart rate or arterial pressure during exercise, but significantly increased the aortic-to-distal coronary pressure gradient from 33 +/- 3 to 40 +/- 5 mmHg (P < 0.05). Indomethacin increased transcollateral resistance during exercise by 42 +/- 10% (P < 0.05); this was associated with a 27 +/- 11% decrease in subendocardial flow in the collateral zone (P < 0.05) with no significant change in subepicardial flow, and no change in normal zone blood flow. These findings demonstrate that in the intact awake animal cyclooxygenase blockade causes coronary collateral vasoconstriction which can impair blood flow to the dependent myocardium during exercise.

Onset of segmental relaxation dysfunction with decreased myocardial tissue perfusion: Modulation by propofol

To estimate myocardial oxygen needs by studying the effects of reduced coronary blood flow on segmental myocardial function. To study the tolerance of limited oxygen supply to a myocardial segment during propofol administration. A prospective experimental study. An experimental animal laboratory in a university. Eighteen adult dogs, weighing 20 to 35 kg. Open thorax open pericardium experiments were performed under standard anesthetic conditions. Segment length gauges were placed subendocardially in an anteroapical and in a basal segment. Flow to the anteroapical segment was reduced by tightening a micrometer-controlled snare placed around the second diagonal coronary artery. Left ventricular pressure-length signals allowed for identification of onset of relaxation dysfunction. Myocardial tissue flow at onset of relaxation dysfunction was defined as critical flow. Tracer microspheres were used to measure subepicardial, midwall, and subendocardial flow at critical flow. Stability of the model and reproducibility of critical flow were studied in a first series of six dogs with the hearts paced at 110 beats/min. Hemodynamics, left ventricular, and segmental myocardial function during critical flow were stable. Subendocardial critical flow was identical with each flow reduction (45% +/- 5, 44% +/- 8, and 43% +/- 5 of baseline myocardial tissue flow). In a second series of six dogs, critical flow was measured at pacing rates 100 beats/min, 150 beats/min, and 100 beats/min with propranolol, 0.1 mg/kg, pretreatment. Critical flows were 38% +/- 5, 55% +/- 6, and 17% +/- 2 of baseline, respectively (p < 0.05). In a third series of six dogs, critical flow was measured during sufentanil, 0.6 microgram/kg/min, and increasing doses of propofol (P0: 0.0 mg/kg/h, P4: 4.0 mg/kg/h and P8: 8.0 mg/kg/h). Heart rate was kept constant at 110 beats/min. When compared with P0, hemodynamic and left ventricular contraction parameters were stable at P4 but were decreased at P8. At P0, critical flow was: 0.63 +/- 0.14, at P4: 0.34 +/- 0.09, and at P8: 0.25 +/- 0.07 mL/min/g (p < 0.05). Critical myocardial tissue flow was reproducible and sensitive for altered myocardial oxygen needs. The negative inotropic properties of P decreased myocardial oxygen needs during unchanged hemodynamic and left ventricular contraction parameters. A higher P dose depressed left ventricular function.

The effects of cyanosis on myocardial blood flow, oxygen utilization, and lactate production in dogs

To elucidate differences in myocardial blood flow and metabolism between cyanotic and normal hearts, a model of chronic cyanosis was created in five adult mongrel dogs by anastomosing the inferior vena cava to the left atrium. After 6 to 9 months, myocardial blood flow, the ratio of subendocardial to subepicardial flow, oxygen consumption, oxygen extraction ratio, and lactate consumption in these cyanotic dogs and five control dogs were determined under baseline conditions and during pharmacologic stress with isoproterenol (0.2 μg/kg/min). Radioactive microspheres were used to determine left and right ventricular blood flow rates, and arterial and coronary sinus differences in oxygen and lactate levels were measured. At baseline and during stress, oxygen consumption and oxygen extraction ratios were identical in control and cyanotic hearts. Total myocardial blood flow was increased with stress and did not differ between cyanotic and control hearts. Left ventricular muscle from cyanotic hearts did exhibit lower endocardial/epicardial blood flow ratios than those of control hearts at rest, and the relative subendocardial flow decreased further with stress. During isoproterenol infusion, myocardial lactate production, indicative of anaerobic metabolism, was evident in two of five cyanotic animals and none of the control dogs. The relative subendocardial ischemia and its further aggravation by stress in cyanotic hearts may contribute to the pathophysiologic basis of myocardial dysfunction in cyanotic heart disease. (J T HORAC C ARDIOVASC S URG 1995;109:849-53)