Pharmacokinetic analysis of coronary venous retroinfusion: a comparison with anterograde coronary artery drug administration using metoprolol as a tracer.

Plasma and myocardial tissue concentrations of metoprolol were studied in ischemic and nonischemic areas of 22 pigs after 90 (n = 19) and 16 (n = 3) min of left anterior descending coronary artery occlusion. Group A (n = 6) received simultaneous intravenous metoprolol (0.2 mg/kg body weight) and tritium-labeled (3H)-metoprolol (0.2 mg/kg) retrogradely into the coronary vein. In group B (n = 5), metoprolol and 3H-metoprolol were administered in the same way, but at half the volume to study the influence of derived coronary venous pressure on the myocardial concentration of drug. In group C (n = 3), metoprolol was given retrogradely and saline solution was infused into the left anterior descending artery before induced death to wash out metoprolol from the coronary veins. To rule out a possible influence of the development of myocardial necrosis on drug distribution, metoprolol was retroinfused after 1 min of arterial occlusion in three pigs (group D). In group E (n = 5), metoprolol (0.2 mg/kg) was infused anterogradely into the left anterior descending artery. Peak plasma concentration was significantly higher after intravenous infusion of metoprolol (1,188 +/- 503 nmol/liter) than after coronary venous infusion (417 +/- 155 nmol/liter; p less than 0.001). In groups A and B, the nonischemic myocardial concentration of metoprolol was 250 to 300 pmol/g, whether the drug was infused intravenously or into the coronary vein. Coronary venous retroinfusion, however, resulted in a substantial accumulation of metoprolol in the ischemic myocardium. In group A pigs, subendocardial myocardial concentration was 16,800 +/- 7,774, mid-myocardial 39,590 +/- 18,043 and subepicardial 57,143 +/- 29,030 pmol/g (mean +/- SE). The ischemic myocardial concentration in pigs from group B was somewhat less pronounced, probably secondary to a lower coronary venous pressure (15 +/- 3 mm Hg) with the lower volume of infusion (6.1 +/- 0.3 ml) in group B compared with 32 +/- 5 mm Hg with a 14 +/- 1 ml infusion in group A. Coronary artery anterograde administration resulted in myocardial ischemic and nonischemic zone drug concentrations similar to those observed after retroinfusion into the coronary vein. With both modes of administration, there was a transmyocardial gradient from a somewhat lower drug concentration in the subendocardium, toward an increasing level in the mid-myocardium, to the highest concentration in the subepicardial zone of the ischemic myocardium. Coronary venous retroinfusion resulted in pronounced drug accumulation in the ischemic myocardium. The derived coronary venous pressure during infusion influenced the concentration of drug.(ABSTRACT TRUNCATED AT 400 WORDS)     

Local beta-adrenergic blockade does not reduce infarct size after coronary occlusion and reperfusion: A study of coronary venous retroinfusion of metoprolol

Summary Previous studies have demonstrated pronounced ischemic zone myocardial concentrations of metoprolol following coronary venous retroinfusion in pigs with coronary artery ligation. The effect of coronary venous retroinfusion of metoprolol on myocardial infarct size was studied in 16 pentobarbital-anesthetized open-chest pigs undergoing 60-minute occlusion of the left anterior descending coronary artery followed by 3 hours of reperfusion. Pigs in the experimental group (n=8) were given 0.4 mg/kg (1.0 mg/ml) of metoprolol via the anterior interventricular vein over a period of 5 minutes, beginning immediately after coronary occlusion followed by 0.2 mg/kg/hr intravenously. Control pigs (n=8) received the same volume of saline as the treated group. The risk area and the necrotic area were assessed by monastral blue dye and triphenyl tetrazolium chloride staining, respectively. Metoprolol did not influence hemodynamics. Plasma concentrations of metoprolol were within therapeutic levels. The administration of the beta-blocker resulted in a trend toward reduced norepinephrine concentrations, both in the aorta and coronary vein after coronary occlusion, but it did not prevent norepinephrine overflow following reperfusion. Infarct size expressed as a percentage of the risk area was 77±11% in the control group and 75±12% (mean ± SD; NS) in the treated group. Thus, metoprolol retroinfusion did not reduce infarct size and did not prevent catecholamine overflow after reperfusion. It is concluded that the beneficial effects of metoprolol in acute infarction are probably unrelated to local beta-adrenergic blockade, at least in the pig, an animal with a paucity of coronary collateral blood flow.     

Pressure-length loop in the ischemic segment during left circumflex coronary artery stenosis and its modification by afterload reducing in excised perfused canine hearts

Summary By using excised perfused heart preparations, we investigated the regional myocardial functions in the presence of a flow-limiting coronary stenosis of the left circumflex coronary artery (LCX) (approximately a 50% flow reduction of pre-ischemic control), as well as global cardiac functions during afterload reducing, while keeping left ventricular end-diastolic pressure (LVEDP) and heart rate constant. After inducing the LCX stenosis, cardiac output (CO), peak left ventricular pressure (peak LVP) and stroke work (SW) decreased from pre-ischemic control values, i.e., 81.1±3.2%, p<0.005, 88.1±3.8%, p<0.02 and 72.2±5.7%, p<0.005, respectively (n=7), whereas pressure-length (P-L) loop areas changed as follows; ischemic control values of the left anterior descending coronary artery (LAD) and LCX regions were 96.6±6.0%, n.s. and 72.6±9.0% of pre-ischemic control, p<0.02, respectively.Following afterload reducing with LCX stenosis, CO increased gradually, while the ischemic regional function started to further aggravate, and the initial point of further ischemic aggravation obtained in this experiment occurred at 63.5±6.9 mm Hg of mean aortic pressure (AoP). These results suggested that the increase of total cardiac function such as CO following afterload reducing was probably induced at the expense of aggravated regional ischemia. Therefore it was concluded that the treatment of ischemic myocardium by reducing afterload pressure should be done very carefully.     

Lack of thromboxane A2 involvement in the arrhythmias occurring during acute myocardial ischemia in dogs

Summary Coronary artery occlusion (CAO) followed by reperfusion of the ischemic myocardium has been associated with the onset of ventricular arrhythmias. It has been suggested that platelet aggregates in the ischemic area may release thromboxane A₂ (TxA₂) which may then be responsible for the arrhythmias that occur during reperfusion. To study this possibility, the effect of TxA₂ synthetase inhibition on arrhythmias was examined in anesthetized dogs during occlusion and for 60 minutes following release. Imidazole (30 mg/kg) was infused intravenously for 10 minutes, followed by continuous infusion of 100 mg/kg/hr for 125 minutes. The left anterior descending coronary artery was occluded, 5 minutes after the initial dose, for 60 minutes. Three minutes after release of CAO, TxB₂ concentrations were significantly higher in the arterial blood of vehicle-treated animals (2.06±0.53 pmoles/ml) than in either CAO + imidazole (0.66±0.16 pmoles/ml) or sham-CAO animals receiving imidazole (0.66±0.09 pmoles/ml). However, CAO dogs whether receiving imidazole or 0.9% NaCl generated a significantly greater number of ectopic beats during and after occlusion than sham-CAO animals. Therefore, release of TxA₂ does not appear to be a major causative factor in the generation of reperfusion arrhythmias in dogs following coronary artery occlusion.Predoctoral Fellow of the Ischemia-Shock Research Center of Jefferson Medical College.     

The relevance of coronary sinus interventions in cardiac surgery.

The concept of arterialization of the coronary venous system was first discussed almost 100 years ago. Subsequently, those attracted by this approach have chosen the coronary veins as an alternative route for interventional and surgical therapy. Modern techniques of coronary sinus interventions (CSI) have been suggested mainly for temporary support and protection of ischemic myocardium. Based on the dense meshwork structure of the venous vasculature, CSI may be effective even in the presence of serious coronary artery disease. Three major techniques have been suggested for different indications in cardiology and cardiac surgery: 1) ECG-synchronized retroperfusion of arterial blood, which is supposed to positively affect ischemic myocardium by phasic supply of oxygen to deprived areas mainly in cardiac emergencies, 2) retroinfusion of cardioplegia in the arrested heart, which is now a well-established clinical technique, and 3) intermittent coronary sinus occlusion during antegrade cardioplegic delivery in the arrested heart and in the early reperfusion period after surgical revascularization, or in cardiac emergencies. The beneficial effect of pressure-controlled intermittent coronary sinus occlusion is assumed to result from cyclic occlusion and release of the coronary sinus shifting venous blood to underperfused regions, thereby facilitating substrate delivery and subsequent washout of metabolites. Experimental studies and first clinical trials suggest that all methods of CSI are safe and feasible, and the ultimate goals of reduction of infarct size and preservation of jeopardized ischemic myocardium will be achieved.     

Influence of dipyridamole on infarct size and on cardiac nucleoside content following coronary occlusion in the dog

Summary The effects of 3 different doses (0.02, 0.1, 0.5 mg/kg/h) of dipyridamole on myocardial infarct size were evaluated in pentobarbital anesthetized open-chest dogs following sequential coronary occlusion of two medium sized coronary arteries in the same heart. The first coronary occlusion produced a control infarct, the other a test infarct under the influence of the drug. Dipyridamole infusion was started 10 min before the second occlusion at a rate of 0.02 (group A, n=9), 0.1 (group B, n=10) or 0.5 (group C, n=9) mg/kg/h respectively and continued to the end of reperfusion (90 min). Biopsy samples were obtained at the end of each occlusion period and at the end of the second reflow period. Infarct size was determined using post mortem angiography and pNBT staining. Control and treated infarct sizes, expressed as a percentage of the perfusion area, were 21.9±5.4% vs. 25.2±7.7% in group A (n=9), 21.8±7.3% vs. 18.3±5.2% in group B (n=9), and 22.3±7.7% vs. 16.2±4.8% in group C (n=8). There were no significant differences between control and treated infarct sizes in the 3 groups. After 90 min coronary occlusion tissue adenosine contents in the ischemic myocardium were significantly higher (42±7 nmol/gww in group C and 40±5 nmol/gww in group B) than those in the nonischemic myocardium, and dipyridamole enhanced these levels (395±6 nmol/gww in group C: p<0.01, 55±10 nmol/gww in group B). Dipyridamole did not affect the tissue inosine levels in the ischemic myocardium after 90 min coronary occlusion. ATP and creatine phosphate levels were not affected by dipyridamole during ischemia or during reflow. The accumulated adenosine was not phosphorylated to AMP and on to ATP upon reperfusion.     

Effects of endothelin-1 on epicardial coronary tone,coronary blood flow,ECG-ST change and regional wall motion in anesthetized dogs

Summary The effects of intracoronaryadministrated endothelin-1 on coronary hemodynamics and regional myocardial function were studied in anesthetized open-chest dogs. Epicardial coronary diameter (CoD) and coronary blood flow (CBF) were measured by a sonomicrometer of 10 MHz piezoelectric crystals and an electromagnetic flow probe on the left circumflex coronary artery (LCX). Regional wall motion was sonomicrometrically measured at regions supplied by the LCX and left anterior descending artery (LAD) and electrocardiograms were recorded. Endothelin-1, administered as a bolus injections into the LCX via an intracoronary cannula, in a dose-dependent manner reduced COD and CBF. The extent of the reduction of COD and CBF at a dose of 300 pmol was 12.3±1.5% (P<0.01) and 86±5% (p<0.01), respectively, of the control. The extent of CBF reduction and deterioration of systolic wall motion were linearly related with the dosage of endothelin-1. ST-elevation (lead II) and fatal ECG abnormalities, including complete atrioventricular block or ventricular fibrillation, were observed with doses above 60 and 100 pmol, respectively. Coronary angiography revealed that filling defects of dye were propagated from the third or distal branches to those of more proximal arteries when the doses of endothelin-1 were cumulatively infused into the LCX. Accordingly, lethal myocardial ischemia induced by endothelin-1 is produced by critical obstruction of rather small coronary vessels.Part of the study was supported by Grants-in-Aid for Scientific Research (Nos. 02454259, 02404045) from the Ministry of Education, Science, and Culture, Japan, and a Research Grant for Cardiovascular Disease (1S-1) from the Ministry of Health and Welfare, Japan.     

Factors affecting penetration of retrograde coronary venous injections into normal and ischemic canine myocardium: assessment by contrast echocardiography and digital angiography

Summary This experimental study described myocardial echo contrast enhancement through coronary venous injections. Retrograde administration of renografin was performed in 15 closed-chest dogs. Two-dimensional echocardiography was used to study myocardial echo contrast enhancement before and after coronary artery occlusion. Digital subtraction venography was used to assess delivery, drainage and shunting of the retrograde injectate. Systolic/diastolic blood pressure in the great cardiac vein measured 7±3/1±0.6 mm Hg and increased to 29±11/5±3 after coronary sinus occlusion and to 55±2.3/15±12 mm Hg during coronary sinus contrast injection. Myocardial contrast echo appearance in a midpapillary left ventricular short axis cross-section was limited to the anteroseptal region, extending to 28.4±11.3% of the section circumference after great cardiac vein injections and 35.3±17% after coronary sinus injections (difference NS). After occlusion of the left anterior descending coronary artery, great cardiac vein contrast injections resulted in opacification of 36.6±9.7% of the section circumference (N.S. vs preocclusion control) and opacified most, but not all asynergic segments. After occlusion of the circumflex coronary artery, myocardial echo contrast uptake was restricted to the septum and the anterior wall. The ischemic and asynergic posterolateral myocardial segments were not opacified. Digital subtraction coronary venography revealed rapid drainage of retrogradely injected contrast to the right atrium, in spite of coronary sinus balloon occlusion via venovenous anastomoses.Retrograde coronary venous contrast injections may help define myocardial regions which are accessible with retrograde coronary venous interventions.Dr. Punzengruber was supported by a Grant from the Max Kade Foundation, New York     

Potential risk of provisional stenting in left main coronary artery bifurcation in multivessel‐related acute coronary syndrome

We present a case of an elderly man suffering from an acute coronary syndrome (ACS) with preshock vital signs and remarkable ST–T wave depression in leads V4–V6, and ST elevation in lead aVR. Coronary angiography showed total occlusion of the right coronary artery (RCA) and impending occlusion in the distal left main coronary artery (LMCA) with a tandem lesion in the proximal left anterior descending artery (LAD). After insertion of an intra‐aortic balloon pump both the LAD and left circumflex artery (LCX) were dilated alternatively; and cross‐over stenting in the LMCA bifurcation was subsequently performed. However, total occlusion of the LCX occurred and it caused acute hemodynamic collapse and ventricular fibrillation storm. Immediate installation of percutaneous cardio‐pulmonary support system allowed stent deployment to be performed in the RCA and subsequent reopening of the LCX that led to a return to sinus rhythm. The patient recovered almost normal left ventricular wall motion and previous activity without any neurological deficit within 2 weeks. Provisional stenting in ACS in the LMCA bifurcation with multivessel disease has a potential risk of acute hemodynamic collapse; a planned two‐stent deployment strategy may assure a higher rate of safety in such cases. © 2011 Wiley‐Liss, Inc.     

Platelet depletion in experimental myocardial infarction

Summary Accumulation of platelets in the microvasculature after acute myocardial ischemia may exacerbate tissue injury through the formation of microthrombi and by the release of vasoactive substances. To assess the role of platelets in myocardial ischemic injury and infarction, circulating platelets were reduced by 94±2% (mean±S.E.M.) with sheep antiserum to canine platelets. Regional myocardial ischemia was produced by occlusion of the left circumflex coronary artery (LCCA) for 90 min followed by reperfusion for 5 hours. Infarct size did not differ significantly between antiplatelet serum and nonimmune serum groups: 36±8vs. 43±4% of the area at risk, determined by a post-mortem dual staining technique (p>0.05). A second occlusion-reperfusion control group, sacrificed at 24 hours, did not differ from 5 hr reperfused groups with regard to infarct size. Coronary sinus thromboxane B₂ (TXB₂) concentrations were not altered significantly by platelet depletion. Histopathologic examination confirmed the presence of necrosis in the infarcted myocardium and revealed substantial leukocytic infiltration in both groups. The results suggest that circulating platelets are not required for the full expression of myocardial ischemic injury resulting from temporary coronary artery occlusion followed by reperfusion.     

Thrombolytic effects of intracoronary streptokinase on canine coronary artery thrombosis

Summary The thrombolytic and hemodynamic properties of intracoronary streptokinase (SK) application were studied in anin-vivo canine model with left circumflex coronary artery thrombosis, initiated by electrical stimulation (150 A, DC for 6 h) of the artery's intima via an implanted silver wire. In pentobarbitalanesthetized, open-chest dogs acute myocardial ischemia was determined by a dehydrogenase-dependent staining of the coronary artery perfusion area. Thrombus weight was determinedpost-mortem.Saline-treated control animals developed coronary thrombosis after 3.1±0.4 h of stimulation. Thrombus weight was 64±3.1 mg. Acute infarct volume was 32±3.1% of total left ventricle, and 53±6.2% of the coronary artery risk region for infarction. At occlusive thrombosis, blood pressure, ventricular pressure and the LV dP/dt_max fell significantly, whereas heart rate and the end-diastolic filling pressure increased. Severe ST-segment elevation and loss of R wave voltage indicated myocardial ischemia. At 20 min into thrombotic vessel occlusion, 2,000 IU/min SK were infused by way of a Sonescatheter advanced to the thrombus. Coronary thrombosis consistently lysed after 12±0.7 min of SK infusion, and coronary blood flow as well as hemodynamics were restored. Only minor acute infarction was found indicating viability of ischemic jcopardized myocardium. In another group, the continuous SK-infusion (20 IU/kg/min) concomitant with electrical vessel stimulation prevented coronary thrombosis and acute ischemia, and no significant hemodynamic alterations were noted.These results indicate that intracoronary SK-infusion can lyse acute thrombosis as sequel of electrical stimulation. This prevents development of acute myocardial infarction. Continuous SK-infusion can completely prevent coronary thrombosis in response to intimal injury.Professor Dr. Otto Bayer in memoriam     

Intermittent coronary sinus occlusion after coronary arterial ligation results in venous retroperfusion

Coronary sinus occlusion retards necrosis of ischemic myocardium. To test the hypothesis that coronary sinus occlusion induces retrograde venoarterial flow, the coronary arteriovenous pressure gradient and the coronary arterial oxygen saturation were measured distal to a left anterior descending coronary artery ligature in dogs. In parallel, we constructed a mathematical model of known coronary physiology to characterize pressure and flow patterns during coronary sinus occlusion. In dogs, coronary sinus occlusion produced a systolic pressure gradient between the coronary artery and the coronary sinus of -20 +/- 9 mm Hg (higher venous pressure, p less than 0.0001) and a positive diastolic gradient of 3 +/- 5 mm Hg (lower venous pressure p less than 0.01). An average reduction in the oxygen saturation in the ligated coronary artery of 20 +/- 13% was also observed (p less than 0.005) consequent to admixture of venous (desaturated) blood. By graded inflation of the coronary sinus balloon, it was demonstrated that desaturation of arterial blood typically occurs above a coronary sinus systolic pressure of 40-50 mm Hg. The mathematical model indicates the possibility of venoarterial pressure gradients and reversal of flow at the microcirculatory level during coronary sinus occlusion. These studies provide evidence that retrograde flow into the ischemic zone occurs in association with intermittent coronary sinus occlusion. Thus, alternating flow over the ischemic territory may be the mechanism of myocardial salvage during intermittent coronary sinus occlusion.     

Nisoldipine Selectively Induces Coronary Vasodilation and Improves Mild Myocardial Ischemia in Dogs: A Potential Role of Cellular Acidosis

We examined whether nisoldipine, a calcium (Ca) channel blocker, increases coronary blood flow (CBF) without decreasing aortic blood pressure (AoP) with ischemic and nonischemic hearts, and whether the presence of cellular acidosis in ischemic myocardium contributes to the augmentation of coronary vasodilation due to nisoldipine. In 42 dogs, coronary perfusion pressure (CPP) was reduced so that CBF decreased to 60% of the baseline, and CPP was maintained constant thereafter. First, we administered nisoldipine into a systemic vein in the ischemic and nonischemic hearts. Second, nisoldipine was administered into the canine coronary artery of the ischemic myocardium with and without administration of either sodium bicarbonate (NaHCO3), sodium hydroxide (NaOH), or amiloride. Nisoldipine (0.25–4.0 mg/kg, IV) increased CBF by 59% in the ischemic myocardium more than the nonischemic myocardium (by 34%) without reducing AoP. The infusion of nisoldipine (40 ng/kg/min, IC) increased CBF markedly by about 55% in the ischemic myocardium with increases in fractional shortening (FS; 11 ± 2% to 21 ± 2%) and lactate extraction ratio (LER; –19 ± 4% to 15 ± 2%). Increases in CBF, FS, and LER were markedly attenuated during administration of nisoldipine with concomitant administration of either NaHCO3 or NaOH. Furthermore, the extent of increases in CBF (54 ± 2 mL/100 g/min), FS (13 ± 2%), and LER (–17 ± 4%) were also markedly attenuated due to the concomitant treatment with amiloride. We conclude that myocardial cellular acidosis plays an important role in mediating coronary vasodilation affected by nisoldipine in the ischemic myocardium. H+ may modulate the property of voltage-dependent Ca channels via Na+–H+ exchange.     

Effect of Presence of Ramus Intermedius Artery on Location of Culprit Lesions in Acute Left Circumflex Coronary Artery Occlusion

Background and aimCoronary artery anatomy frequently affects location of atherosclerotic plaques and subsequent culprit lesions. We sought to clarify whether presence or absence of Ramus Intermedius coronary artery (RI) would affect location of culprit lesions in acute left circumflex (LCX) coronary artery occlusion.MethodsThe study included 180 patients, 100 with a diagnosis of non-ST elevation myocardial infarction (NSTEMI) and 80 with ST elevation myocardial infarction (STEMI). All culprit lesions were located in the LCX coronary artery. RI group included 45 patients and the No RI group included 135 patients.ResultsCulprit LCX lesions were similarly located at a comparable distance from LCX ostium in both groups and the presence of RI was not associated with significantly more proximally located culprit LCX lesions (34.7 ± 15.2 mm compared to 30.8 ± 17.9 mm respectively, p > 0.05). The frequency distribution of culprit lesions’ distance from LCX ostium showed no significant difference between both groups in any of the segments studied (10 mm each). There was no significant difference between both groups regarding markers of myocardial necrosis size as cardiac biomarkers (peak cardiac troponin-T 1077.4 ± 361.2 pg/dl vs 926 ± 462.2 pg/dl respectively, p = 0.13), (peak creatine kinase-MB 232.2 ± 81 ng/dl vs 194.7 ± 99.2 ng/dl respectively, p = 0.07) or left ventricular ejection fraction (EF 46.3 ± 6.3% vs 48.3 ± 8.3% respectively, p = 0.76).ConclusionPresence of RI coronary artery, as an additional flow divider, may not be associated with more proximal culprit lesions, compared to its absence, in cases of acute LCX coronary artery occlusion. Possible underlying pathophysiologic mechanisms remain to be clarified.     

A case of myocardial infarction due to the left main trunk lesion, in which percutaneous coronary recanalization and emergency coronary-aorto bypass graft, and subsequent percutaneous coronary angioplasty were effective not only from a viewpoint of survival but from comeback to social life

A case of acute myocardial infarction due to the lesion in the left main coronary artery was reported. A 50-year male was referred to our department for suspected acute myocardial infarction. Physical examination on admission revealed slight cyanosis with cold sweating due to severe chest pain. Pulse was irregular and heart rate was 78 beats/min. Blood pressure was 100/80 mmHg. A series of electrocardiograms (ECG) and laboratory data provided the diagnosis of wide-ranged anterolateral infarction in the left ventricle. Emergency coronary angiograms taken without delay showed a subtotal occlusion (99% stenosis) of the left main coronary trunk (LMT) before the initiation of intracoronary thrombolysis (PTCR). Following the intracoronary infusion of urokinase of 1,200,000 units, symptoms and ECG changes transiently improved but worsened later, and LMT stenotic lesion and delayed filling of myocardium were similar with before PTCR. Emergency coronary-aorto bypass graft (CABG) was undertaken without a significant delay to both the left anterior descending artery (LAD) and left circumflex coronary artery (LCX). With these treatments, the patient could survive despite the wide area of infarction due to LMT lesion. Coronary angiograms performed 37 days after the CABG showed that the graft to LAD was completely occluded and the LCX graft was patent with partial stenosis. Treadmill test at this time induced an anginal episode with ischemic ECG changes on moderate exercise, indicating the presence of significant area of ischemic myocardium. For salvage of the ischemic myocardium, percutaneous transluminal coronary angioplasty (PTCA) was successfully performed for the LMT stenosis, resulting in no episode of angina nor ischemic ECG changes during exercise loading.(ABSTRACT TRUNCATED AT 250 WORDS)     

Grading the angiographic extent of collateral filling

Angiography frequently demonstrates a collateral circulation in severe coronary artery disease. An easily applicable method to quantify collateral flow might be a useful adjunct for the assessment of the hemodynamic effects of coronary artery disease. The purpose of this study was to validate a visual scaling of the extent of angiographic collateral filling by comparison with flowmeter- and microsphere-derived measurements of collateral flow. In 12 open-chest dogs, collaterals from the circumflex artery were angiographically visualized (n = 80) by creating acute critical left anterior descending artery occlusion. The extent of collateral filling was graded in four levels from 0 = no visible filling to 3 = complete epicardial filling. Collateral filling correlated with the change in flow of the collateral supplying circumflex artery (Q; r = 0.84) which was + 5.3 ±4.6% with grade 1, + 9.1 ±3.5% with grade 2 and + 14.6 ±4.7% with grade 3 (p < 0.01). In parallel, coronary flow reserve decreased from 4.1 ±0.8 with grade 0 to 2.9 ±0.2 with grade 3 (p < 0.01). Colored microspheres were injected subselectively into the circumflex artery of 9 dogs (45 injections). The ratio of microspheres counted in the collateralized myocardium of the left anterior descending artery to the total number injected increased from 0.6 ±0.9% for grade 0 to 17.1 ±2.8% with grade 3 (p < 0.01). Absolute collateral flow derived from microsphere counts averaged 5.5 ±0.9 ml/min with grade 3 and closely correlated with collateral filling grade (r = 0.88). Semiquantitative grading of angiographic collateral filling in response to acute coronary occlusion in a canine model correlates with an increase in collateral source artery flow, absolute collateral flow and a decrease in source artery flow reserve. These data suggest that this scale might be a simple but useful adjunct tool to assess the hemodynamic significance of a collateral circulation.This work was supported by a grant from the NLHBI 1 R01 HL40865. Dr. Schuhlen is the recipient of a grant from the Deutsche Forschungsgemeinschaft (#Schu657/1-1 and 1–2).     

Effect of nifedipine on the myocardial and vascular response to myocardial ischemia

Summary Nifedipine reduces reactive hyperemia following brief coronary artery occlusions. To determine whether this is related to improvement in collateral blood flow to ischemic myocardium or alterations in myocardial oxygen consumption, ten chloralose anesthetized dogs were instrumented with coronary sinus catheters, circumflex artery flowmeters, and ultrasonic microcrystals for measurement of myocardial segment shortening. Myocardial oxygen consumption and circumflex coronary artery flow were determined at rest and during incremental infusions of isoproterenol. Myocardial blood flow measured with microspheres and segmental function were assessed during and following 30- and 60-second coronary artery occlusions. Thirty minutes after the intravenous administration of nifedipine, 10 g/kg iv, all measurements were repeated. Nifedipine did not alter myocardial oxygen consumption or the relationship between oxygen consumption and circumflex coronary artery flow either at rest or during isoproterenol infusion. Following 60-second coronary occlusions, nifedipine reduced peak circumflex coronary artery flow (176±99 vs. 128±68 cc/min) and reactive hyperemia debt repayment (221±84 vs. 158±66%; p<0.01). Nifedipine did not alter flow to ischemic segments during coronary artery occlusions (0.16±0.10 vs. 0.19±0.13 ml/min/g mean transmural flow). Furthermore, nifedipine did not affect the severity of ischemic segment dysfunction, nor the rate of recovery of ischemic segment function following release of coronary artery occlusion. We conclude that the reduction in reactive hyperemia induced by nifedipine was not related to alterations in the severity of hypoperfusion in ischemic areas, or alterations in myocardial oxygen consumption. Reductions in reactive hyperemia produced by nifedipine did not impair recovery of mechanical function in postischemic myocardium.This study was supported in part by grants HL01162 and HL20598 from the National Heart, Lung and Blood Institute of the National Institutes of Health, Bethesda, Maryland; and by a grant-in-aid from the American Heart Association, Minnesota Affiliate, Inc. Dr. Homans was a fellow of the American Heart Association, Minnesota Affiliate, and recipient of National Research Service Award (HL06575) from the National Heart, Lung and Blood Institute of the National Institute of Health at the time that this work was performed.     

Acute myocardial ischaemia in the anaesthetised pig: local catecholamine release and its relation to ventricular fibrillation

Summary In anaesthetised open-chest pigs, sequential myocardial samples were obtained before and after occlusion of the distal half of the LAD. These samples were analysed histofluorimetrically to determine the density of catecholamine containing neurones in each sample (quantified morphometrically), and radioenzymatically for total tissue noradrenaline content. Following coronary artery occlusion, 75% of the animals (24 out of 32) died in ventricular fibrillation in the first 30 min, the other 25% (8/32) survived the first 60 min of myocardial ischaemia. Coronary artery occlusion led to a significant reduction in the density of fluorescing fibres in the ischaemic myocardium of animals which fibrillated (from 1.25±0.2% to 0.67±0.10% at 15 min) whereas in the survivors there was no significant change in fluorescing area during the course of the experiment. Animals which fibrillated had a significant reduction in tissue noradrenaline concentration of the ischaemic myocardium (from an initial concentration of 612±72 to 402±64 ng/g ww) within the first 5 min of ischaemia. It is concluded that in this model of myocardial ischaemia, the development of ventricular fibrillation in the early phase seems to be related to the release of noradrenaline from the sympathetic neurones after the onset of myocardial ischaemia.Supported by Deutsche Forschungsgemeinschaft Hi 137/8-1     

Systemic and cardiac catecholamines during elective PTCA and during immediate PTCA for acute myocardial infarction

This study investigated arterial and coronary venous catecholamine concentrations in patients undergoing either elective coronary angioplasty (PTCA) or direct PTCA for acute myocardial infarction. We included 17 patients with stenoses of the left anterior descending coronary artery (LAD) and 10 patients with acute anterior myocardial infarction (AMI) undergoing PTCA. During the initial balloon dilatation arterial and coronary venous plasma concentrations of norepinephrine and epinephrine were determined. In elective PTCA, coronary occlusion (2 min) resulted in a transient increase of arterial concentrations of norepinephrine (2.04±0.30 vs. 1.26±0.13 nmol/L before dilatation) and epinephrine (0.52±0.08 vs. 0.34±0.04 nmol/L) in the first minute of reperfusion, whereas coronary venous concentrations of catecholamines were not changed after dilation. Among the 10 patients with AMI, immediate reperfusion of the LAD (TIMI grade 3) was achieved in 6 patients. In these patients, baseline arterial concentrations for norepinephrine (3.91±1.16 nmol/L) and epinephrine (4.68±2.07 nmol/L) were elevated and no transcardiac gradient for catecholamines was found. In the first minute after successful reopening of the LAD we detected a distinct rise of the transcardiac norepinephrine gradient from –0.10±0.53 to 85.02±24.64 nmol/L, which declined in the fifth minute of reperfusion to 4.36±2.30 nmol/L. Conversely, venous epinephrine and arterial concentrations for both catecholamines remained unchanged within the observation period. In the four patients with incomplete (TIMI 0–2) reopening of the LAD, we found no cardiac washout of norepine phrine. In summary, a transient rise of systemic catecholamines, but no cardiac release of norepinephrine was observed in patients after brief coronary occlusion. Conversely, a massive washout of norepinephrine from the infarcted myocardium occurred during AMI.Presented in part at the 67th Annual Scientific Sessions of the American Heart Association, Dallas, Texas, November 1994     

重组腺相关病毒2型载体-血管内皮生长因子165改善小型猪慢性心肌缺血的研究

目的应用重组腺相关病毒2型载体(recombinant adenovirus-associated virus2,rAAV2)介导血管内皮生长因子165(vascular endothelial growth factor,VEGF165)基因转染,观察其促进小型猪慢性缺血心肌血管生成并改善心肌血流灌注和心功能的有效性。方法小型猪左冠状动脉回旋支(LCX)放置血管缩窄环,建立慢性心肌缺血模型。5周后行心电图、冠状动脉造影和心脏核磁共振成像检查确认LCX闭塞或相应心肌的缺血。动物随机分为实验组和对照组,每组8只,分别在心肌内直接注射rAAV2-VEGF165(1×1012virus genome)或磷酸盐缓冲液。治疗后3个月和6个月,观察心肌VEGF mRNA和蛋白的表达;6个月后,观察心肌毛细血管和小动脉密度,行冠状动脉造影进行LCX血流分级,应用心脏核磁共振成像观察心肌灌注及左心室功能。结果放置血管缩窄环后5周,所有动物均出现LCX完全/次全闭塞或LCX支配区域的心肌缺血。基因治疗后3个月,实验组心肌VEGF mRNA和蛋白表达显著高于对照组;6个月时,实验组VEGF表达水平较3个月时下降。基因治疗后6个月,VEGF组心肌毛细血管密度和小动脉密度[分别为(1404.06±250.48)/mm2和(167.81±36.29)/mm2]均高于对照组[分别为(976.88±344.79)/mm2和(116.56±34.48)/mm2](P<0.05);潘生丁负荷后心肌灌注成像显示VEGF组心肌灌注明显优于对照组(P<0.05),且较治疗前有改善(P<0.05);两组左心室功能在治疗前后均无明显变化。结论在小型猪慢性心肌缺血模型中,心肌内注射rAAV2-VEGF165后外源VEGF基因的表达至少可持续3个月;rAAV2-VEGF165能够促进缺血心肌毛细血管和小动脉生成并改善心肌灌注。