Left Anterior Descending Region Research Articles

Evaluation of high‐pressure retrograde coronary venous delivery of FGF‐2 protein

Delivery of angiogenic factors to ischemic myocardium remains a practical challenge. We evaluated the efficiency and efficacy of delivery of fibroblast growth factor-2 (FGF-2) protein via high-pressure retrograde injection into the anterior interventricular vein (AIV) in a porcine model of chronic myocardial ischemia. Labeled FGF-2 protein was delivered to the myocardium of three pigs via the AIV and the left anterior descending (LAD) coronary artery in three others. At 1 hr, the amount of protein in the left ventricle and the LAD region was quantified. Copper stents were implanted in the LAD of 25 pigs, resulting in chronic myocardial ischemia. At 4 weeks, microsphere-derived myocardial blood flow was assessed at rest and during pacing. In eight pigs (AIV FGF), FGF-2 protein (6 microg/kg) was delivered via high-pressure retrograde injection into the AIV. Six pigs (intracoronary FGF) received the same amount of FGF-2 by intracoronary delivery. Five pigs (AIV saline) received a placebo injection into the AIV and six pigs (control) served as controls. Four weeks later, myocardial blood flow was reassessed. At 1 hr, significantly more FGF remained in the left ventricle (1.3 vs. 0.82 microg; P < 0.04) and in the LAD region (1.2 vs. 0.64 microg; P = 0.03) after AIV compared to intracoronary delivery. Four weeks after treatment, resting LAD blood flow (normalized to right ventricular flow) improved slightly in the AIV FGF and intracoronary FGF arms (1.32-1.37 for both; P = 0.11), while it decreased significantly in the AIV saline (1.32-1.23; P = 0.02) and the control arms (1.32-1.19; P = 0.0004). Pacing LAD blood flow decreased significantly in the control arm (1.30-1.23; P < 0.05), but did not change significantly in the other three arms. High-pressure retrograde injection into the AIV may represent an efficient and effective means for delivering angiogenic factors to ischemic myocardium.

Comparison of adenosine, isoflurane, and desflurane on myocardial tissue oxygen pressure during coronary artery constriction in dogs

Objective: To compare adenosine-, isoflurane-, or desflurane-induced hypotension with and without left anterior descending (LAD) coronary artery constriction for the effects on myocardial tissue oxygen pressure (PmO 2) in dogs. Design: Prospective, randomized, nonblinded. Setting: University teaching hospital. Participants: Male nonpurpose-bred dogs (n = 18). Interventions: Dogs were anesthetized with 1.5% isoflurane (n = 12) or 8% desflurane (n = 6). A flow probe and balloon occluder were placed on the LAD artery. A probe that measured myocardial oxygen pressure was inserted into the middle myocardium in the LAD region. Myocardial oxygen consumption (MVO 2) was calculated as LAD flow x arterial minus coronary sinus oxygen content. Measures and Main Results: Measures were made during hypotension produced by adenosine infusion, 2.8% isoflurane, or 14% desflurane with and without LAD constriction to decrease blood flow 30%. Without LAD artery constriction, adenosine infusion increased LAD flow 90% and MVO 2 70%, 2.8% isoflurane produced no change in MVO 2, and 14% desflurane decreased MVO 2 25%, but no treatment changed PmO 2. LAD artery constriction decreased PmO 2 50% by itself. Adenosine infusion during LAD constriction decreased tissue oxygen pressure an additional 60%, 2.8% isoflurane produced no change, and 14% desflurane increased PmO 2 100%. Conclusion: There was an inverse relationship between the effect of adenosine, 2.8% isoflurane, and 14% desflurane on MVO 2 and PmO 2 during ischemia. This is consistent with reports that increasing oxygen demand worsens myocardial ischemia.

Myocardial glucose uptake after dobutamine stress in chronic hibernating swine myocardium

Background In patients with hibernating myocardium, regional uptake of the glucose analog 2–fluorine 18–fluoro-2-deoxy- d-glucose (FDG) is increased under resting conditions. It is unclear whether the degree of increased FDG uptake correlates with the degree of impaired blood flow response and whether chronic changes in the glucose transporters may play a role in the enhanced FDG uptake under fasted conditions. Methods and results Twelve swine were instrumented with a constrictor on the left anterior descending (LAD) artery. Serial echocardiography and positron emission tomography studies were done to assess temporal changes in myocardial function, blood flow, and FDG uptake. One week after surgery (early study), wall thickening, blood flow, and postdobutamine FDG uptake in LAD and remote territories were similar. By approximately 6 weeks (late study), baseline wall thickening in the LAD region was lower than in remote regions (20% ± 7% and 36% ± 6%, P < .05), as was dobutamine-stimulated blood flow (0.92 ± 0.16 mL · min −1 · g −1 and 1.17 ± 0.20 mL · min −1 · g −1 in LAD and remote regions, respectively; P < .05). After the dobutamine infusion, FDG uptake in the LAD region during fasted conditions was higher than in remote regions (0.128 ± 0.053 μmol · min −1 · g −1 and 0.098 ± 0.044 μmol · min −1 · g −1, respectively; P < .05), and the increase was proportional to the impairment in dobutamine blood flow ( r 2 = 0.62, P < .001). After the animals were killed, the LAD region showed a higher content of GLUT4 by immunoblots and a greater degree of translocation as estimated by immunohistochemistry. In 5 additional hibernating pigs studied under resting fasted conditions, FDG uptake and GLUT4 translocation were also higher in the LAD region, in the absence of dobutamine stimulation. Conclusions In hibernating myocardium, regional FDG uptake under fasting conditions is higher than in remote regions, both at rest and after an infusion of dobutamine. The degree of poststress FDG uptake is proportional to the impaired stress-induced blood flow. Total GLUT4 content as well as membrane-bound protein is higher in the hibernating tissue, and these changes may facilitate the observed increase in FDG uptake.

Glyburide decreases myocardial oxygen pressure in dogs.

Reports show that glyburide, an adenosine triphosphate sensitive potassium (K+ATP) channel blocker, will reverse the myocardial protective effect of inhalational anesthesia. We evaluated the effect of glyburide on myocardial tissue oxygen pressure (PmO2) in dogs anesthetized with desflurane. Twelve dogs were anesthetized with 8% end-tidal desflurane for baseline anesthesia. A flow probe was placed on the left anterior descending (LAD) artery. A probe that measured PmO2 was inserted into the middle myocardium in the LAD region. After baseline measures, six dogs received i.v. 1 mg kg(-1) of glyburide and six dogs received sham vehicle treatment. After the glyburide or sham treatment, each dog received an i.v. infusion of adenosine 0.1 microg kg(-1) x min(-1), sodium nitroprusside (SNP) 2-4 microg kg(-1) x min(-1) and 14% end-tidal desflurane in random order. Glyburide decreased LAD artery flow from 59 +/- 9 ml min(-1) to 30 +/- 6 ml min(-1) (P < 0.05) and PmO2 from 44 +/- 16 mmHg to 30 +/- 9 mmHg (P < 0.05). Adenosine infusion increased LAD artery blood flow 180% in the sham-treated dogs but produced no change in the glyburide-treated dogs. Sodium nitroprusside infusion increased LAD artery flow and decreased PmO2 in both the glyburide- and sham-treated dogs. Desflurane (14%) did not reverse the glyburide-induced vasoconstriction but increased PmO2 to 38 +/- 20 mmHg (P < 0.05). Glyburide produced myocardial tissue hypoxia, which was not changed by adenosine, worsened by SNP and improved by 14% desflurane. The improvement in PmO2 with desflurane occurred without a change in myocardial blood flow.

Myocardial tissue oxygen during coronary artery constriction and hypotension in dogs.

Sodium nitroprusside (SNP) may decrease myocardial tissue oxygenation in dogs with normal coronary arteries. We compared SNP- with desflurane-induced hypotension on myocardial tissue oxygen and pH in dogs with left anterior descending artery constriction. Twenty-four dogs were anesthetized with 8% desflurane for baseline anesthesia. Catheters were inserted into the femoral artery and vein and the coronary sinus. A flow probe and flow restriction device was placed on the left anterior descending (LAD) artery. A probe that measured myocardial oxygen pressure was inserted into the middle myocardium in the LAD region. Baseline measures were made of LAD artery flow, arterial and coronary sinus blood gases, and myocardial tissue gases. A 30% decrease in blood pressure was induced with SNP with unrestricted LAD flow (n=6) or when LAD artery flow was restricted by 30% from baseline (n=6). In separate dogs, a 30% decrease in blood pressure was produced with 14 +/- 1% desflurane with unrestricted LAD flow (n=6) or with baseline LAD artery flow restricted by 30% (n=6). During SNP-induced hypotension with no LAD constriction, LAD artery flow and coronary sinus oxygen tension increased but myocardial tissue oxygen tension (PmO2) decreased by 40%. When baseline artery flow was decreased by 30% by LAD constriction, SNP-induced hypotension decreased tissue oxygen pressure by 80%, and ischemic acidosis was produced. During unrestricted LAD artery flow or with a 30% flow restriction, desflurane-induced hypotension produced no significant change from baseline myocardial tissue oxygen tension or pH. During coronary artery constriction, desflurane-induced hypotension maintained myocardial tissue oxygenation and pH better than did SNP-induced hypotension. The divergence between tissue and coronary sinus oxygen tension during SNP suggests that arteriovenous shunting may occur.

Coronary steal phenomenon after repeated endomyocardial biopsies in cardiac transplant recipients?

Background: Repeated endomyocardial biopsies are routinely performed for diagnosis of cellular rejection after heart transplantation. Whilst during the first 3 months weekly biopsies are usually taken, the number of biopsies decreases thereafter. As a complication coronary fistulae have been described.Methods:Thirty-one patients were studied prospectively 3 months and 1 year after orthotopic heart transplantation, 10 of whom were also studied after 2 years. Coronary angiography was performed with triggered injections of a non-ionic contrast material (8ml, with a flow of 4ml/s) at rest, after 10mg i.c. papaverine, during supine bicycle exercise and after 1.6mg sublingual nitroglycerin. Coronary flow reserve of the left anterior descending (LAD) and the left circumflex coronary artery (LCX) was determined by parametric imaging.Results: Coronary flow reserve was significantly higher in the LAD than in the LCX perfusion zone early after heart transplantation. This difference disappeared after 1 and 2 years.Conclusions: Preferential perfusion of the LAD region can be observed after maximal vasodilation with papaverine (=coronary steal phenomenon) which was no longer present 1 and 2 years later. This observation suggests that microvascular shunts are responsible for this steal phenomenon early after transplantation, when endomyocardial biopsies are performed frequently. Later on this flow phenomenon disappears progressively probably due to shunt occlusion by thrombosis.

Utility of Positron Emission Tomography in Predicting Improved Left Ventricular Ejection Fraction after Coronary Artery Bypass Grafting among Patients with Ischemic Cardiomyopathy

The objective of this study was to determine whether preoperative estimates of regional myocardial uptake of ¹⁸-F-fluorodeoxyglucose (FDG) could predict postoperative improvement in ejection fraction in patients undergoing coronary artery bypass grafting (CABG) for ischemic cardiomyopathy. 20 consecutive patients [left ventricular ejection fraction (LVEF) ≤27%] were referred for preoperative positron emission tomography (PET) to measure regional myocardial FDG uptake and were deemed candidates for CABG. All individuals had technically adequate vessels and significant viability. The left anterior descending (LAD) coronary artery was severely diseased in all patients. Because of the importance of the anterior wall to overall ventricular performance, FDG uptake was semiquantitated in those regions and related to postoperative LVEF. 17 patients underwent CABG with an uneventful recovery. LVEF increased from 22 ± 4 to 26 ± 7% 2 weeks postsurgery (p < 0.05), with ≥5% change noted in 7 patients (group 1) and <5% noted in 10 patients (group 2). No preoperative or perioperative clinical variable could predict those with improved ventricular function. The relative amount of FDG uptake in the anterior wall was higher in group 1 compared with group 2 (93 ± 9 vs. 81 ± 13%; p < 0.05) and correlated with the change in LVEF post-CABG (r = 0.50; p < 0.05). >88% of FDG uptake in the LAD region had a positive predictive accuracy of 67% and negative predictive accuracy of 88% for improved LVEF postbypass. Late follow-up estimates of LVEF (median of 10 months) showed that early changes in function were sustained. In summary, among patients with severe coronary artery disease and depressed LVEF, ventricular function may improve early postrevascularization. PET estimates of relative FDG uptake in the anterior wall help predict those individuals who are likely to have the greatest increment in LVEF.

Acute ischemic dysfunction alters coronary flow reserve in remote nonischemic regions: Potential mechanical etiology identified in an acute canine model

Background. Impaired coronary flow reserve (CFR) has been observed in remote nonischemic regions in patients after myocardial infarction. The mechanism for this impairment in remote nonischemic CFR remains undefined. This study evaluates the effect of progressive regional ischemic dysfunction on function in remote nonischemic regions, and the effect of the extent of dysfunction on remote nonischemic coronary flow and CFR. Methods. In an anesthetized open-chest canine model (n = 7) of acute progressive distal and proximal left anterior descending (LAD) coronary artery occlusion, regional myocardial thickening fraction and coronary flow and CFR were measured with Doppler probes. CFR was assessed by an intracoronary injection of 36 μg of adenosine. Changes in thickening fraction and CFR were evaluated for isovolumic, ejection, and diastolic phases. Changes in resting regional flow were also assessed using radiolabeled microspheres. The extent of the ischemic area was defined as regions of myocardium with endocardial microsphere blood flow less than 0.3 mL/min/g. Results. The ischemic area increased from 12% ± 1% of left ventricle with distal occlusion to 30% ± 2% of left ventricle with proximal occlusion ( P < .001). The LAD thickening fraction decreased significantly from baseline (18% ± 1%) to distal (−8% ±1%) and proximal (−4% ± 1%) occlusion ( P <.001 for distal and proximal vs baseline). Isovolumic bulging in the LAD region was associated with a progressive increase in thickening fraction in the remote nonischemic left circumflex (LCX) artery region (baseline 12% ± 1%; distal occlusion 15% ± 2%, P = .014 vs baseline; proximal occlusion 17% ± 2%, P =.02 vs baseline). Most of the increase in remote thickening fraction occurred during the isovolumic phase. There was no significant change in resting flow in remote nonischemic LCX regions or global hemodynamic parameters. However, there was a progressive decrease in remote nonischemic CFR (baseline 2.44 ± 0.3), distal occlusion (2.19 ± 0.31; P = .055 vs baseline), and proximal occlusion (1.79 ± 0.22; P = 0.004 vs baseline, and P = .012 vs distal occlusion). A progressive decrease in CFR was noted in each phase of the cardiac cycle. Conclusion. In a canine model of acute progressive distal and proximal coronary occlusion, we observed a progressive decrease in CFR in remote nonischemic regions concurrent with an increase in the extent of ischemia. The decrease in remote nonischemic CFR was associated with ischemia-induced isovolumic bulging, which placed the remote regions at a mechanical disadvantage. These observations suggest a potential mechanical etiology for the observed impairment in remote CFR. Alterations in remote nonischemic CFR during acute ischemia may have important clinical implications for perfusion scintigraphy.

Effects of Intracoronary Calcium Chloride and Epinephrine on Coronary Blood Flow, Oxidative Metabolism, and Mechanical Function in Canine Normal and Stunned Myocardium

Background : The effects of calcium chloride (CaCI2) on regional mechanical function, coronary blood flow (CBF) and myocardial oxygen consumption (MVO2) were examined in normal and stunned myocardium in an open-chest canine model. The effects were compared with those of epinephrine. Methods : Thirty-one dogs were acutely instrumented under enflurane anesthesia to measure aortic and left ventricular pressure, pulmonary and left anterior descending (LAD) coronary flow, and subendocardial segment length the in LAD region. CaCl2 (0.1, 0.25, 0.5, 0.75 mg/ml of LAD flow, n=16) or epinephrine (4, 10, 20, 30 ng/ml of LAD flow, n=15) was directly infused into the LAD before (normal) and after 15 min of its occlusion and reperfusion (shunned). Simultaneous measurements of arterial and coronary venous contents of oxygen and lactate were made to calculate oxygen (EO2) and lactate (E1ac ) extraction ratio during CaCl2 or epinephrine infusion. Results : Both CaCl2 and epinephrine infusions in normal myocardium resulted in dose-dependent increases in mechanical functions and MVO2. These changes were accompanied by parallel increases in CBF, resulting in no changes of EO2 with CaCl2, while CBF increased more than MVO2 with epinephrine, resulting in a decrease in EOz. After ischemia and reperfusion, mechanical functions and E were significantly depressed, but similar mechanical responses to both agents with resultant unaltered EO2 were observed. E1ac was decreased further during epinephrine, while it remained unaltered during CaCl infusion in stunned myocardium. Conclusions : CaCl2, similar to epinephrine, exerts positive inotropic and lusittopic effects in normal and stunned myocardium in dogs. In addition, CaCl2 has no duect effect on coronary vascular tone in either normal or stunned myocardium, while epinephrine causes direct vasodilation in normal but not in stunned myocardium. (Korean J Anesthesiol 2000; 39: S23-S34)

NITRIC OXIDE DOES NOT MEDIATE CORONARY VASODILATION DURING ACUTE NORMOVOLEMIC HEMODILUTION IN DOGS

S72 INTRODUCTION: Acute normovolemic hemodilution (ANH) is accompanied by increases in coronary blood flow (CBF) that are attributable to the combined effects of reduced blood viscosity and vasodilation [1]. The mechanism for this vasodilation is unknown. While previous findings have implied that endothelium-derived nitric oxide (EDNO) is involved in the systemic vasodilation accompanying ANH [2], the role of this mechanism in the coronary circulation remains to be evaluated. Accordingly, the present study was performed to test the hypothesis that inhibition of EDNO by the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) would compromise myocardial perfusion during ANH. METHODS: After approval from the University Animal Care Committee, studies were conducted in ten open-chest dogs anesthetized with isoflurane and fentanyl. Measurements of myocardial blood flow (MBF) were obtained in the perfusion territories of the left anterior descending (LAD) and circumflex (CX) coronary arteries using radioactive microspheres. Mean aortic pressure (MAP), mean left atrial pressure (MLAP), and heart rate (HR) were measured using standard methods. A Doppler flow transducer was used to measure CBF in the LAD. Two groups were studied. In Group 1 (NOS Inhibition; n=5), the LAD region received an intracoronary (i.c.) infusion of L-NAME (4.5 mg), and the CX region served as a control. Effectiveness of L-NAME was demonstrated by the its ability to inhibit the increases in CBF by the endothelium-dependent coronary vasodilator acetylcholine (20 [micro sign]g/min, i.c.), while having no effect on those by the endothelium-independent coronary vasodilator sodium nitroprusside (80 [micro sign]g/min, i.c.). In Group 2 (Endothelium Intact; n=5), neither the LAD nor the CX region was treated with L-NAME. This was done to validate the use of the CX bed as a control for the LAD bed in Group 1. Data were obtained under baseline conditions (hematocrit; 40 +/- 2 %) and following ANH with 5% dextran-40 to an hematocrit of 20 +/- 1 %. RESULTS: ANH caused similar increases in MBF in LAD and CX regions, whether or not the LAD region was treated with L-NAME (Figure 1). ANH had no effect on MAP, MLAP, or HR.Figure 1DISCUSSION: Pretreatment with L-NAME did not compromise myocardial perfusion during ANH. This finding implies that EDNO does not mediate coronary vasodilation under this condition.

Lymph isolated from a regional scald injury produces a negative inotropic effect in dogs.

Large surface-area burns in patients have been associated with a severe impairment in cardiac performance, as evidenced by a decline in cardiac output. The mechanisms responsible for this profound myocardial dysfunction are largely unknown. We investigated the effects of lymph isolated from the scalded hind limb of dogs on regional myocardial blood flow, coronary vascular reactivity, and contractile performance. Dogs were instrumented with ultrasonic dimension crystals in the myocardium supplied by the left anterior descending (LAD) and by the left circumflex (LCx) coronary arteries. After cannulating a hind limb lymphatic, lymph was infused directly into the LAD before and after a 10-second 100 degrees C hind limb scald. Scalding alone did not alter myocardial contractile performance in the LAD or LCx regions, coronary artery blood flow, or systemic hemodynamics. Interestingly, postburn lymph infused into the LAD resulted in a 38% decline in LAD zone segment shortening (p < 0.01 vs baseline) that lasted throughout the 5-hour observation period. In contrast, segment shortening in the (control) LCx region was unaffected by postburn lymph injections into the LAD. Regional myocardial blood flow (radiolabeled microspheres) in the LAD and LCx regions was unchanged after scald injury or intracoronary injection of postburn lymph. In addition, LAD coronary artery vascular reactivity to acetylcholine and nitroglycerin was also unaffected by the regional thermal injury or by injection of lymph into the LAD. These data suggest that a regional scald injury results in the production and release of a potent myocardial depressant factor(s) that produces a direct negative inotropic effect on the canine myocardium.

Enhanced microvascular relaxations to VEGF and bFGF in chronically ischemic porcine myocardium.

Changes in the vascular responses to vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in chronically ischemic myocardium have not been investigated. Ameroid constrictors were placed on the proximal left circumflex (LCX) artery of seven Yorkshire pigs. Seven to nine weeks later, myocardial blood flow in the collateral-dependent LCX region was reduced, compared with that in the normally perfused left anterior descending (LAD) region. Both growth factors elicited significant relaxations of coronary microvessels. Relaxations to both VEGF and bFGF were inhibited in the presence of either NG-nitro-L-arginine or genistein, suggesting that the relaxations are through the tyrosine kinase-mediated release of endothelium-derived nitric oxide. Microvascular relaxations to both VEGF or bFGF were significantly greater in vessels harvested from the collateral-perfused LCX region, compared with those taken from the normally perfused LAD region. However, relaxation to the endothelium-dependent vasodilator ADP, which does not operate through a tyrosine kinase receptor, was reduced in the collateral-perfused region, compared with the normally perfused territory, suggesting a possible link of tyrosine kinase to the enhanced relaxations to VEGF and bFGF in collateral-perfused coronary microvessels. Northern analysis showed increased expression for both VEGF receptors (flk-1, flt-1) as well as the bFGF receptor 1 (FGFR-1) in the collateral-perfused region compared with that in the normally perfused region. This suggests that the increased relaxation responses to VEGF and bFGF in the ischemic myocardium may be related to increased gene expression of the respective tyrosine kinase receptors.

Angiogenesis induced by acidic fibroblast growth factor as an alternative method of revascularization for chronic myocardial ischemia

The effect of periadventitial administration of acidic fibroblast growth factor (FGF) on coronary microvascular reactivity and blood flow was examined in the collateral-dependent and normally perfused myocardium. Ameroid constrictors were placed on the proximal left circumflex (LCx) coronary artery in 14 pigs. In seven pigs acidic FGF (10 micrograms) was administered into the perivascular space of the proximal LCx artery by using an ethylene vinyl acetate copolymer slow release device. After 7 to 9 weeks coronary arterial microvessels (70 to 150 microns) were studied in a pressurized (40 mm Hg) no-flow state with video microscopy. Relaxation mediated by beta-adrenoceptors and induced by isoproterenol (p < 0.05), and endothelium-dependent relaxation induced by adenosine 5' diphosphate (ADP) (p < 0.05) of isolated microvessels from the collateral-dependent LCx region were markedly reduced compared with the respective responses of vessels from the normally perfused left anterior descending (LAD) artery region. Relaxation induced by the adenylate cyclase activator forskolin and the guanylate cyclase activator sodium nitroprusside were unaltered. Chronic treatment with acidic FGF normalized responses to isoproterenol (p < 0.001 versus nontreated LCx) and ADP (p < 0.001 versus nontreated LCx) in the collateral-dependent LCx region, whereas responses to forskolin and sodium nitroprusside were not changed. Blood flow in the collateral-dependent LCx region (0.49 +/- 0.24 ml/min/gm) was less than that in the normally perfused LAD region (0.80 +/- 0.24 ml/min/gm, p < 0.05). Treatment with acidic FGF improved perfusion in the LCx region (0.80 +/- 0.06 ml/min/gm, p < 0.05) but did not significantly affect blood flow in the LAD territory (0.89 +/- 0.09 ml/min/gm). The periadventitial delivery of acidic FGF normalizes vasomotor regulation by beta-adrenergic and endothelium-dependent mechanisms and improves myocardial perfusion to the collateral-dependent myocardium. This may have implications regarding the treatment of patients with severe coronary artery disease who are not ameneable to conventional methods of revascularization.

Myocardial Kinetics of a Putative Hypoxic Tissue Marker, 99m Tc-Labeled Nitroimidazole (BMS-181321), After Regional Ischemia and Reperfusion

A new nitroimidazole complex, 99mTc-propylene amine oxime-1,2-nitroimidazole (BMS-181321), has been developed to allow the positive imaging of hypoxic myocardium by standard gamma camera techniques. To determine the myocardial kinetics of BMS-181321 during myocardial ischemia and reperfusion, seven open-chest swine were prepared according to a model of extracorporeal coronary perfusion in which left ventricular wall thickening (percent end-diastolic thickness) and substrate use in the left anterior descending (LAD) region ([14C]palmitate and [3H]glucose infusions) were determined. Measurements were obtained at baseline, during 40 minutes of ischemia produced by reducing flow in the LAD distribution by 60%, and during 70 minutes of reperfusion. Three aerobic control hearts were also studied in which LAD blood flow was not reduced. Regional coronary circulation was further assessed in all hearts by use of radiolabeled microspheres injected during ischemia. BMS-181321 (20 to 30 mCi) was injected after 30 minutes of ischemia, and its myocardial uptake was assessed by dynamic planar gamma imaging. Ischemia was associated with declines in fatty acid metabolism (15 +/- 11 mumol.h-1.g dry wt-1, mean +/- SEM), systolic wall thickening (20 +/- 6%), and myocardial oxygen consumption (3 +/- 1 mL.min-1.100 g-1) and an increase in exogenous glucose utilization (75 +/- 13 mumol.h-1.g dry wt-1). Systolic wall thickening recovered by only 8 +/- 3% with reperfusion. Initial distribution of BMS-181321 in the aerobic hearts appeared homogeneous. Washout from the ischemic and reperfused LAD bed was slower than the aerobically perfused LAD bed in the control group (t1/2 = 136 +/- 1 versus 80 +/- 1 minutes, P < .05), allowing visualization of the LAD region during reperfusion. Tissue activity of BMS-181321 was inversely related to LAD blood flow during ischemia (r = -.68 +/- .05), and the ratio of BMS-181321 in the LAD region versus normal myocardium was 1.7 +/- 0.2. Control swine lacked regional deposition of the tracer in the normally perfused LAD distribution. Thus, acute regional ischemia in these studies was visualized as an increase in retention of BMS-181321, suggesting its applicability in the imaging of clinical conditions of myocardial hypoperfusion.

Modulation of the arterial coronary blood flow by asynchronous activation with ventricular pacing.

This study aims to test the assumptions that: (1) coronary arterial flow is attenuated in an early activated region by ventricular pacing; (2) asynchronous mechanical activation caused by ventricular pacing under controlled perfusion pressure and intact coronary tone is associated with reduced coronary flow compared to atrial pacing; and (3) abolishment of vascular tone under controlled perfusion pressure diminishes the expected difference in blood flow between atrial and ventricular pacing. Blood flow velocity (BFV) in the left anterior descending (LAD) and the left circumflex arteries (CFX) and a wall thickening index were measured in 14 open-chest dogs under normal conditions, and constant perfusion pressure. Four pacing sites were used: right atrium (RAp), mid-right ventricle (RVp), mid-left ventricle (LVp), and left ventricular apex (Apexp). Pacing modes were either sequential ventriculoatrial (VA) (protocol A, n = 7), or sequential atrioventricular (AV) (protocol B, n = 7), with a shorter AV difference (30 msec) than normal. BFV was decreased in the LAD during RVp and Apexp pacing by 9.7%-12.9% versus RAp and by 11.6%-14.6% versus LVp (P < 0.05). No BFV variations were observed in the CFX. Flow velocity conductance (FVC = mean blood flow velocity divided by the mean aortic pressure) was higher by 16%-28% in the CFX for the three ventricular pacing sites versus the atrial pacing, and higher by 14.1% +/- 6.1% only in LVp versus RAp pacing in the LAD (P < 0.05). Wall thickening index reduced during ventricular pacing in all three ventricular sites by 50%-64% (P < 0.05) compared to atrial pacing. Under constant perfusion pressure, LAD blood flow decreased with ventricular pacing as compared to right atrial pacing; this was particularly pronounced during the diastolic phase (16.6%-45.5%, P < 0.02). Normalized oscillatory flow amplitude (OFAn) was reduced in RVp pacing compared to RAp and LVp pacing (16.2 +/- 3.5 and 21.7% +/- 4.1%, respectively, P < 0.03). The variations in blood flow and OFAn disappeared with adenosine-mediated maximum vasodilatation. (1) Mean and phasic flows are reduced in the early activated LAD region by ventricular pacing (RVp, Apexp). (2) Under controlled perfusion pressure and intact vascular tone, ventricular pacing compromises blood flow compared with atrial pacing. (3) This effect disappears when vascular tone is eliminated by intracoronary injection of adenosine, suggesting that the coronary autoregulation is responsible for some of the effects.

Myocardial neutrophil infiltration, lipid peroxidation, and antioxidant activity after coronary artery thrombosis and thrombolysis

Neutrophil accumulation and free radical release are implicated in the genesis of reperfusion injury. However, little is known about the changes in myocardial lipid peroxidation and antioxidant activity in relation to coronary artery thrombosis and thrombolysis. To investigate this issue, 18 dogs with electrically induced occlusive thrombus in the left anterior descending (LAD) coronary artery were given tissue-type plasminogen activator (TPA). Sustained reflow (lasting >120 min) occurred in 4 dogs, reocclusion after initial thrombolysis (transient reflow, duration of reflow 5 to 25 min) occurred in 7 dogs, and no reperfusion was evident in 7 dogs. Myocardial neutrophil infiltration was determined by measuring myeloperoxidase (MPO) activity, lipid peroxidation by malondialdehyde (MDA) levels and antioxidant activity by superoxide dismutase (SOD) activity in the myocardial regions supplied by the nonischemic left circumflex (Cx) and the ischemic LAD coronary arteries. In dogs with ischemia alone (no reperfusion), MPO activity and MDA levels in the LAD-supplied myocardium were modestly higher and SOD activity modestly lower than in the corresponding Cx-supplied myocardium. In dogs with sustained reperfusion there was a marked increase in MPO and MDA and a marked reduction in SOD activity in the reperfused myocardium. The MPO and MDA values in the myocardium of dogs with transient reperfusion, although much higher than the corresponding normal myocardial values, were less marked than in the myocardium of dogs with sustained reperfusion, and the SOD activity was preserved in the transiently reperfused regions. Myocardial shortening fraction in the LAD region was worse in dogs with sustained reperfusion than in those with sustained ischemia or transient reperfusion. Thus neutrophil accumulation occurs in the ischemic and reperfused myocardium, mostly in the early phase of reperfusion. Lipid peroxidation occurring during reperfusion correlates with the duration of reperfusion, extent of neutrophil accumulation, and myocardial contractile dysfunction. Lastly, myocardial SOD activity declines markedly during prolonged reperfusion and recovers rapidly when reperfusion is short-lived.

Basic fibroblast growth factor improves myocardial function in chronically ischemic porcine hearts.

The effect of basic fibroblast growth factor (bFGF) administration on regional myocardial function and blood flow in chronically ischemic hearts was studied in 26 pigs instrumented with proximal circumflex coronary artery (LCX) ameroid constrictors. In 13 animals bFGF was administered extraluminally to the proximal left anterior descending (LAD) and LCX arteries with heparin-alginate beads and 13 other animal served as controls. bFGF-treated pigs showed a fourfold reduction in left ventricular infarct size compared to untreated controls (infarct size: 1.2 +/- 0.4% vs. 5.1 +/- 1.3% of LV mass, mean +/- SEM, P < 0.05). Percent fractional shortening (% FS) in the LCX area at rest was reduced compared with the LAD region in both bFGF and control pigs. However, there was better recovery in the LCX area after rapid pacing in bFGF-treated pigs (% FSLCX/% FSLAD, 22.9 +/- 7.3%-->30.5 +/- 8.5%, P < 0.05 vs. prepacing) than in controls (16.0 +/- 7.8%-->14.3 +/- 7.0%, P = NS). Furthermore, LV end-diastolic pressure rise with rapid pacing was less in bFGF-treated than control pigs (pre-pacing; pacing; post-pacing, 10 +/- 1; 17 +/- 3; 11 +/- 1* mmHg vs 10 +/- 1; 24 +/- 4; 15 +/- 1 mmHg, *P < 0.05 vs. control). Coronary blood flow in the LCX territory (normalized for LAD flow) was also better during pacing in bFGF-treated pigs than in controls. Thus, periadventitial administration of bFGF in a gradual coronary occlusion model in pigs results in improvement of coronary flow and reduction in infarct size in the compromised territory as well as in prevention of pacing-induced hemodynamic deterioration.

Effect of dopamine on local segment work and O2 consumption in collateral-dependent myocardium.

To test the hypothesis that dopamine-stimulated work and myocardial O2 consumption (MVO2) in collateral-dependent myocardium would be reduced, Ameroid constrictors were implanted around the circumflex coronary artery (CFX) in nine dogs. Four weeks later, in an anesthetized open-chest preparation, segment length (ultrasonic dimension gauge) and force (miniature force transducer) were measured in myocardium supplied by the CFX and left anterior descending (LAD) coronary arteries. Work in each region was calculated as the systolic area under the force-length curve. Corresponding regional MVO2 was calculated from local O2 extraction (microspectrophotometry) and flow (radiolabeled microspheres). Dopamine infusion (15 micrograms.kg-1.min-1) increased regional work from 262 +/- 56 to 733 +/- 171 mm.g.min-1 in the control (LAD) region, but to a much smaller extent in the collateral-dependent (CFX) region (from 249 +/- 82 to 414 +/- 81 mm.g.min-1). However, regional MVO2 increased to about the same extent in the CFX (from 6.0 +/- 0.7 to 12.4 +/- 0.9 ml O2.min-1 times 100 g-1) and the LAD region (from 7.0 +/- 0.6 to 14.5 +/- 1.3 ml O2.min-1 times 100 g-1). O2 extraction was not elevated in the CFX region. Therefore, the functional impairment was not secondary to O2 supply or consumption limitations.

Adenosine protects against attenuation of flow reserve and myocardial function after coronary occlusion and reperfusion

Total coronary artery occlusion and reperfusion result in attenuation of coronary blood flow reserve, regional myocardial dysfunction, and myocardial leukocyte infiltration. To examine the effects of intracoronary adenosine on these occlusion and reperfusion-induced perturbations, we subjected 14 dogs to total left anterior descending (LAD) coronary artery occlusion (1 hour) and reperfusion (1 hour). Seven dogs received adenosine (3.75 mg/min into the LAD distal to the occlusion) over a 1-hour period starting 5 minutes before reperfusion, and the remaining seven dogs received saline solution. One dog in each group died of ventricular fibrillation during coronary artery occlusion. Coronary flow reserve, measured as peak reactive hyperemia (10 and 20 seconds of total coronary artery occlusion) and peak coronary blood flow response to acetylcholine (0.01 to 1.0 μg) and nitroglycerin (5 to 25 μg), was impaired in the LAD region after LAD occlusion and reperfusion in the saline-treated dogs (all p < 0.01 vs before occlusion and reperfusion); LAD regional myocardial shortening fraction measured by ultrasonic crystals was also diminished after occlusion and reperfusion in saline-treated dogs (−5% ± 1% vs 12% ± 2%; p < 0.02). The adenosine-treated dogs showed total protection against loss of coronary flow reserve (peak reactive hyperemia and blood flow increase in response to acetylcholine and nitroglycerin; all p values not significant vs before LAD occlusion and reperfusion). LAD regional myocardial shortening fraction was also preserved in adenosine-treated dogs (9% ± 2% vs 14% ± 2%; p not significant). Myocardial myeloperoxidase activity, measured as an index of myocardial leukocyte infiltration, was greater ( p < 0.02) in the LAD ischemic-reperfused regions than in nonischemic circumflex regions in the saline-treated dogs. A similar difference in myeloperoxidase activities in the reperfused and control regions was not observed in the adenosine-treated dogs. Thus adenosine protects against loss of coronary flow reserve and regional myocardial function in dogs subjected to coronary artery occlusion and reperfusion.

Regional asynchrony of segmental contraction may explain the "oxygen consumption paradox" in stunned myocardium.

Despite apparently depressed function, stunned myocardium maintains oxygen consumption and has the capacity to increase contractility with inotropic stimulation. We hypothesized that during stunning, O2 demand is maintained because regional segment work is performed, but is asynchronous with global left ventricular contraction, and that inotropic stimulation would restore regional work and synchrony. Thirteen open-chest anesthetized dogs were subjected to three left anterior descending (LAD) coronary artery occlusions (10 min) and reperfusions (15 min) to produce regional myocardial stunning. Segment shortening and force development were measured independently and simultaneously in the LAD (experimental) region and circumflex (control) regions. Regional myocardial work was calculated as the integrated product of instantaneous force and shortening, during two periods: 1) over the entire cardiac cycle (Positive Work), and 2) limited to the systolic portion of the cardiac cycle (Systolic Work). Regional myocardial O2 consumption (MVO2) was calculated from regional blood flow (radiolabeled microspheres) and O2 saturation data (microspectrophotometry). Occlusion of the LAD produced a delay in onset of segment shortening in the ischemic region, but not in regional force development. A time delay of 67-81 ms persisted through the three stages of occlusions and reperfusions. Systolic regional work was depressed to a greater extent (924 +/- 182 to 149 +/- 118 g*mm*min-1) than total positive regional work (1437 +/- 337 to 857 +/- 174 g*mm*min-1). Regional subepicardial MVO2 in the stunned region was not different than in the control region (7.3 +/- 1.5 vs. 6.9 +/- 1.4 ml O2*min-1*100 g-1). Local infusion of isoproterenol reversed the delay in regional shortening from 73 +/- 7 to 21 +/- 8 ms, thereby augmenting systolic work (298%) more than positive work (60%), without a significant increase in MVO2 (7.3 +/- 1.5 to 10.5 +/- 3.2 ml O2*min-1*100 g-1). It is concluded that myocardial stunning decreases regional systolic work due to regional mechanical asynchrony, while MVO2 is used supported total positive work which was not significantly reduced. Isoproterenol restores regional work by restoring synchrony, without greatly affecting regional MVO2.