Blood Flow In Ischemic Myocardium Research Articles

The diagnostic role of resting myocardial blood flow in STEMI patients after revascularization.

The value of semiquantitative resting myocardial perfusion imaging (MPI) in coronary artery disease (CAD) is limited. At present, quantitative MPI can be performed by a new cadmium zinc tellurium single-photon emission computed tomography (CZT-SPECT) scan. The quantitative index of resting myocardial blood flow (MBF) has received little attention, and its manifestations and clinical value in the presence of unstable coronary blood flow have not been clarified. In patients with ST-segment elevation myocardial infarction (STEMI), whether resting MBF can provide additional value of blood flow than semi-quantitative resting MPI is not sure. We also explored the influencing factors of resting MBF. This was a retrospective clinical study. We included 75 patients with STEMI in the subacute phase who underwent resting MPI and dynamic scans after reperfusion therapy. General patient information, STEMI-related data, MPI, gated MPI (G-MPI), and resting MBF data were collected and recorded. According to the clinically provided culprit vessels, the resting MBF was divided into ischemic MBF and non-ischemic MBF. The paired Wilcoxon signed-rank test was used for resting MBF. The receiver operating characteristic (ROC) curves were used to determine the optimal threshold for ischemia, and multiple linear regression analysis was used to analyze the influencing factors of resting MBF. There was a statistically significant difference between the ischemic MBF and non-ischemic MBF [0.59 (0.47-0.72) vs. 0.76 (0.64-0.93), p < 0.0001]. The ROC curve analysis revealed that resting MBF could identify ischemia to a certain extent, with a cutoff value of 0.5975, area under the curve (AUC) = 0.666, sensitivity = 55.8%, and specificity = 68.7%. Male sex and summed rest score (SRS) were influencing factors for resting MBF. To a certain extent, resting MBF can suggest residual ischemia after reperfusion therapy in patients with STEMI. There was a negative correlation between male sex, SRS, and ischemic MBF. A lower resting MBF may be associated with more severe myocardial ischemia.

The Interaction of Biology and Emotion: Uncovering a New Phenotype of Nonobstructive Coronary Artery Disease

Posttraumatic stress disorder (PTSD) results from direct or indirect exposure to trauma or highly stressful circumstances. The situations that precipitate PTSD can vary in frequency, extent, intensity, and amount of exposure. The twin study by Vaccarino et al. (1) in the current issue of Biological Psychiatry is an important and appropriately designed longitudinal study of PTSD and ischemic myocardial blood flow in 283 adult male twins from the Vietnam Era Twin Registry. The cardiovascular disease phenotype of ischemia resulting from impaired microvascular function was assessed using positron emission tomography myocardial blood flow (MBF) responses to adenosine stress.

TRAF1 Exacerbates Myocardial Ischemia Reperfusion Injury via ASK1-JNK/p38 Signaling.

BackgroundAfter acute myocardial infarction, the recovery of ischemic myocardial blood flow may cause myocardial reperfusion injury, which reduces the efficacy of myocardial reperfusion. Ways to reduce and prevent myocardial ischemia/reperfusion (I/R) injury are of great clinical significance in the treatment of patients with acute myocardial infarction. TRAF1 (tumor necrosis factor receptor–associated factor 1) is an important adapter protein that is implicated in molecular events regulating immunity, inflammation, and cell death. Little is known about the role and impact of TRAF1 in myocardial I/R injury.Methods and Results TRAF1 expression is markedly induced in wild‐type mice and cardiomyocytes after I/R or hypoxia/reoxygenation stimulation. I/R models were established in TRAF1 knockout mice and wild type mice (n=10 per group). We demonstrated that TRAF1 deficiency protects against myocardial I/R–induced loss of heat function, inflammation, and cardiomyocyte death. In addition, overexpression of TRAF1 in primary cardiomyocytes promotes hypoxia/reoxygenation‐induced inflammation and apoptosis in vitro. Mechanistically, TRAF1 promotes myocardial I/R injury through regulating ASK1 (apoptosis signal‐regulating kinase 1)–mediated JNK/p38 (c‐Jun N‐terminal kinase/p38) MAPK (mitogen‐activated protein kinase) cascades.ConclusionsOur results indicated that TRAF1 aggravates the development of myocardial I/R injury by enhancing the activation of ASK1‐mediated JNK/p38 cascades. Targeting the TRAF1–ASK1–JNK/p38 pathway provide feasible therapies for cardiac I/R injury.

Abstract 15272: Wnt11 Delivered in Mesenchymal Stem Cell-Derived Media Promotes Angiogenesis Through Non-canonical Wnt-PKC-JNK Pathway

Background: Wnt11 is involved in many developmental and cellular processes. We have previously reported that Wnt11 overexpressing (MSC Wnt11 ) significantly improved cardiac function and increased angiogenesis. Here, we aimed to elucidate how Wnt11 delivered by MSC increase blood vessel formation. Methods and Results: An acute myocardial infarction (MI) model in SD rats was developed by ligation of the left anterior descending (LAD) coronary artery. Conditioned medium (CdM) collected from MSC Wnt11 (CdM Wnt11 ) was injected immediately into the ischemic border area. Rats treated with CdM Wnt11 showed a significantly improved cardiac function. Furthermore, CdM Wnt11 increased blood vessel density and regional blood flow in ischemic myocardium. Fluorescent immunostaining showed that both vWF-positive single endothelial cell numbers and microvessel numbers were significantly increased in CdM Wnt11 treated myocardium. In vitro studies showed that CdM Wnt11 significantly increased number and length of capillary-like structure (CLS) formation and promoted human umbilical vein endothelial cells (HUVECs) migration. These results were confirmed by directly treating HUVECs with recombinant Wnt11 proteins (5μg/ml) or over-expressing Wnt11 in HUVECs (H Wnt11 ). However, these effects could be abolished by using a Wnt11 neutralizing antibody. Immunostaining and Western blotting results revealed upregulation of p-pan-PKC and p-JNK in H Wnt11 . Real-time PCR analysis indicated that the expression of novel PKCs including PKCδ, PKCε, PKCη, and PKCθ was significantly upregulated in H Wnt11 . Moreover, the effect of Wnt11 on CLT formation and HUVECs migration were abrogated when the JNK inhibitor SP600125 at 5 μM and the PKC inhibitor Calphostin-C at 0.1 μM were added to the culture system. Conclusion: Our data suggests, for the first time, that Wnt11 in MSC-derived media improved cardiac function and promoted angiogenesis in ischemic myocardium. The effect of Wnt11 in angiogenesis is mediated by novel PKCs, with JNK as its downstream mediator.

Transplantation of bone marrow-derived endothelial progenitor cells overexpressing Delta-like-4 enhances functional neovascularization in ischemic myocardium

Delta‑like‑4 (Dll‑4) prevents excess angiogenic sprouting and promotes the formation of a well‑differentiated vascular network. Therefore, transplantation of Dll‑4‑overexpressing endothelial progenitor cells (EPCs) was hypothesized to be superior to transplantation of EPCs in the treatment of ischemic heart disease. In the current study, EPCs harvested from C57BL/6 mouse bone marrow were infected in vitro with Dll‑4 (EPCDll‑4+) or Dll‑4 knockdown (EPCDll‑4‑) with recombinant lentiviral vectors and the control cells were non‑transfected or transduced with mock vectors (EPCnull). Eight‑week‑old C57BL/6 mice underwent ligation of the left anterior descending artery to establish a myocardial infarction (MI) model. The ligated animals were randomly divided into 5 groups, which, following one week, were intravenously injected with EPCs, EPCnull, EPCDll‑4+, EPCDll‑4‑ or medium. Two weeks later, echocardiographic assessment, western blotting, fluorescent microsphere and histological studies were performed. The results demonstrated that the number of mature vessels and blood flow in ischemic myocardium were increased in the EPCDll‑4+ group, but were markedly decreased in the EPCDll‑4‑ group compared with the control groups. The expression levels of Dll‑4, hairy/enhancer of split (Hes)‑related protein 1 (Hey‑1), phosphorylation of mammalian target of rapamycin (mTOR) and p70S6 kinase (p70S6K) were significantly increased in the EPCDll‑4+ group, while they were markedly decreased in the EPCDll‑4‑ group. Furthermore, for EPCDll‑4+‑treated animals, an enhanced cardiac function was observed as assessed by echocardiography. Thus, the transplantation of Dll‑4‑overexpressing EPCs stimulates neovascularization effectively, increases the blood flow to the ischemic zone and improves cardiac function. These effects may be due to the activation of Notch/Hey‑1/mTOR/p70S6K signaling pathways, which are initiated by Dll‑4.

Myocardial topical negative pressure increases blood flow in hypothermic, ischemic myocardium

Objectives. Hypothermia protects the myocardium from oxidative injury during ischemic stress and reperfusion. We have previously shown that topical negative pressure (TNP) of −50 mmHg significantly increases microvascular blood flow in the underlying myocardium in normal, ischemic, and reperfused porcine myocardium. The present study was designed to elucidate the effect of TNP between −50 mmHg and −150 mmHg on microvascular blood flow in ischemic myocardium during hypothermia. Design. The microvascular blood flow in the myocardium was recorded, in seven pigs, using laser Doppler velocimetry. Analyses were performed in the epicardium and in the myocardium, after 40 minutes of occlusion of the LAD followed by cooling to 31°C. Results. A TNP of −50 mmHg applied to the epicardium, from 23.3±3.8 PU to 104.2±31.3 PU (*p<0.05), and in the myocardium, from 35.0±7.2 PU to 74.2±21.8 PU (*p<0.05). Conclusions. Only a TNP level of −50 mmHg significantly increased the microvascular blood flow in both the epicardium and in the myocardium during hypothermia.

Gated SPECT imaging to detect changes in myocardial blood flow during progressive coronary occlusion

The ability to track dynamic changes in myocardial blood flow (MBF) and wall motion with serial gated perfusion imaging may be a limiting factor in assessing new therapies. The purpose of this study was to determine whether gated Tc-99 m sestamibi (MIBI) SPECT imaging can track small changes in MBF in a model of progressive ischemia. Eight pigs (20 kg) underwent lateral thoracotomy for placement of an ameroid constrictor on the left circumflex coronary artery (LCX) and indwelling femoral and left atrial catheters for serial microsphere determinations of absolute MBF. Animals underwent concurrent left atrial microsphere and Tc-99 m sestamibi (0.3 mCi/Kg IV) injections at weekly intervals over 6 weeks per animal. Gated SPECT imaging was acquired for each injection using high resolution collimation and standard processing. The animals were sacrificed on day 42. Mean signal intensity (SI) from regions of interest (ROI) corresponding to control and ischemic MBF by microspheres was measured for three SPECT short-axis images. Mean contrast ratio (MCR) was calculated from the ratio of ischemic to control SI per slice. Regional wall motion (RWM) from gated images was scored 1-5 using a 16 segment model and a score index (RWMI) was calculated. MBF decreased progressively (27% below resting values [P < 0.0001]) but with a clear and significant partial recovery by day 42 (13% improvement from peak ischemia, [P < 0.01]). SPECT perfusion and gated RWM closely paralleled the dynamic pattern of MBF caused by the ameroid constrictor. SPECT MCR decreased 21% from baseline scans in the LCX territory (P < 0.0001) and improved 11% from peak ischemia (P < 0.01) while the gated RWMI (1.0 at baseline) peaked at 1.36 and improved to 1.13 by day 42. Gated SPECT-a technique readily available-tracks dynamic changes in MBF closely with both perfusion and RWM. For trials of new therapies for the alleviation of chronic ischemia, these findings have direct implications for measuring efficacy.

Impact of Resting and Ischemic Blood Flow on Infarct Probability in Ischemic Preconditioning—a New Approach to Infarct Size-Blood Flow Data by Logistic Regression

The linear regression analysis of infarct size (IS)vischemic myocardial blood flow (MBF) does not account for the heterogeneity of MBF and infarcted tissue; moreover, it cannot assess a blood flow threshold for infarction (MBFT) accurately, as with ischemic preconditioning (IP) the close relationship between ischemic MBF and IS otherwise observed is lost. Finally, the impact of resting blood flow on myocardial infarction cannot be considered in such analysis. Therefore, in a retrospective data analysis of 32 enflurane-anaesthetized swine undergoing 90 min severe ischemia and 120 min reperfusion without (CON,n=12) or with IP induced by either 3 (IP3,n=8) or 10 min ischemia (IP10,n=12) and 15 min reperfusion, a MBFT was assessed by logistic regression (LR) in individual tissue pieces. MBFT was arbitrarily defined as that ischemic MBF (microspheres) at which infarct probability was 0.2, derived from the ratio of infarcted (n=141, TTC) to all tissue samples (n=684). The duration of the preconditioning ischemia and MBF both at rest and during the sustained ischemia were significant predictors of infarct probability. Ischemic MBFT at an infarct probability of 0.2, was 0.089±0.023 ml/min/g in CON. MBFT was decreased to 0.051±0.03 ml/min/g with IP3 (P<0.05vCON) and further to 0.004±0.037 ml/min/g with IP10 (P<0.05vCON, IP3). Corresponding to the leftward shift of MBFT, the relationships between infarct probability and MBF were shifted in parallel by IP with no change in their slopes.

Role of nitric oxide in regulation of coronary blood flow during myocardial ischemia in dogs

Objectives. This study was undertaken to examine whether nitric oxide released in ischemic myocardium decreases the coronary vascular resistance and attenuates the severity of contractile and metabolic dysfunction.Background. Endothelium-derived relaxing factor, recently identified as nitric oxide, is a potent relaxant of coronary smooth muscle.Methods. The left anrterior descending coronary artery was perfused through an extracorporeal bypass tube placed in the carotid artery in 56 open chest dogs. After hemodynamic stabilization, we occluded this bypass tube to decrease coronary blood flow to one third of the control flow. Thereafter, we maintained a constant coronary perfusion pressure(40.9 ± 3.1mm Hg).Results. Under ischemic conditions, the coronary arteriovenous differences in nitrate and nitrite (end products of nitric oxide) increased (from 3.5 ± 0.4 [mean ± SEM] to 12.9 ± 2.1 μmol/liter, p < 0.01). n0-Monomethyl l-arginine (3 μg/kg body weight per min, intracoronary) decreased the coronary arteriovenous differences in nitrate and nitrite (5.0 ± 0.9 μmol/liter, p < 0.05) and coronary blood flow (from 29.8 ± 0.5 to 18.1 ± 1.1 ml/100 g per min, p < 0.001). Fractional shortening (from 3.7 ± 1.0 to −1.3 ± 0.7%, p < 0.001) and lactate extraction ration (from −44.0 ± 4.1 to −59.2 ± 4.9%, p < 0.005) of the perfused area also decreased. These values were restored by the concomitant administration of l-arginine. Blood flow to the endomyocardium was decreased relative to the epimyocardium. A reduction in coronary blood flow and worsening of myocardial contractile and metabolic functions due to the administration of nG-monomethyl l-arginine during ischemia were observed in denervated hearts. A reduction in coronary blood flow in ischemic myocardium was observed with the administration of nW-nitro-l-arginene methyl ester as well, although neither nW-nitro-l-arginine methyl ester nor nG-monomethyl l-arginine changed coronary blood flow and myocardial contractile and metabolic functions in the nonischemic myocardium. The cyclic guanosine monophosphate content of epicardial coronary artery increased due to myocardial ischemia; this increased was attenuated with nG-monomethyl l-arginine treatment.Conclusions. We conclude that endogenous nitric oxide predominantly decreases the coronary vascular resistance of ischemic endomyocardium, thereby improving myocardial contractility and metabolic function.

Effects of Endothelin-1 at Pathophysiologic Concentrations on Coronary Perfusion and Mechanical Function of Normal and Postischemic Myocardium

We assess hemodynamic, vascular, and hormonal effects of endothelin-1 (ET-1) at pathophysiologic levels on normal and ischemic myocardium. Thirty conscious chronically instrumented dogs were studied before, during, and after a 10-min coronary artery occlusion (CAO) performed either during ET-1 infusion (2.5 ng/kg.min, n = 15) or during placebo infusion (n = 15). ET-1 infusion produced an increase in plasma ET-1 (from 1.3 +/- 0.1 to 11.5 +/- 1.1 pM, p < 0.0001) during CAO (pathophysiologic value). Left anterior descending artery (LAD) blood flow (measured by Doppler flow probe) decreased similarly during CAO with ET-1 or placebo (p = 0.0001, NS, ET-1 vs. placebo). Both endocardial and epicardial blood flows in ischemic regions also decreased (p = 0.0001) during CAO but were threefold greater with ET-1 than with placebo (endocardium 42 +/- 7 vs. 14 +/- 2 ml/min/100 g, p = 0.003). No significant difference in myocardial blood flows between groups was observed in control regions. CAO produced increases (p < 0.005) in heart rate (HR), mean aortic pressure (AOP), and ventricular pressures but no change in atrial pressures. The changes in these parameters were comparable in the ET-1 and placebo groups. Despite the greater residual flow during CAO, however, ET-1 decreased the function of the ischemic zone during reperfusion as assessed by systolic shortening (p < 0.05). Atrial natriuretic factor (ANF), unchanged during CAO with placebo, increased from 38.3 +/- 6.1 to 53.3 +/- 10 pM with ET-1 (p = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of short-term, diet-induced hypercholesterolemia on systemic hemodynamics, myocardial blood flow, and infarct size in awake dogs with acute myocardial infarction.

Short-term cholesterol feeding has been shown to affect vasomotor tone and increase infarct size in anesthetized rabbits. The purpose of the study was to determine whether acute hypercholesterolemia reduced collateral flow to ischemic myocardium and increased infarct size in the awake dog. Acute myocardial infarction was produced in awake dogs by a 4-hour left anterior descending coronary artery occlusion followed by 6-hour reperfusion after either a cholesterol-supplemented diet (n = 14) or a control diet of dog chow (n = 15) for 10 days. Infarct size was determined using nitroblue tetrazolium staining. In two subgroups, a 15-minute transient occlusion of the left anterior descending coronary artery was produced before the diet treatments and was compared with occlusion after diet treatments, so that the effects of hypercholesterolemia of collateral flow could be determined by paired comparisons. Cholesterol feeding increased plasma cholesterol to 288 +/- 52 mg/dl, which was twofold to threefold that in the control group (127 +/- 35 mg/dl), but had no effects on baseline systemic hemodynamics and myocardial blood flow. Coronary artery occlusion produced similar increases in heart rate, mean aortic pressure, left atrial pressure, and plasma norepinephrine in both groups of animals. However, cholesterol feeding reduced collateral flow to ischemic myocardium and increased infarct size, compared with the control group. The infarct size correlated with ischemic myocardial blood flow in both groups, but the slopes of regression lines relating the two variables did not differ between the two groups. Short-term, diet-induced hypercholesterolemia increased infarct size in awake dogs. This change results, at least in part, from a decrease in collateral blood flow to ischemic myocardium during coronary artery occlusion.

ACE inhibitors for the treatment of myocardial ischemia?

Apart from their established use in the treatment of hypertension and heart failure, ACE inhibitors have been suggested to exert anti-ischemic effects. This article reviews the mechanisms of systemic and intracardiac angiotensin formation, as well as its interaction with the bradykinin, the prostaglandin, and the sympathetic nervous system. While high doses of angiotensin can precipitate myocardial ischemia. experimental data on a potential beneficial effect of ACE inhibitors on ischemic myocardial blood flow and function are inconsistent and controversial. Pooling the few available clinical data, several ACE inhibitors may attenuate myocardial ischemia at rest and during exercise. However, a significant fraction of patients does not benefit or even deteriorates. Recent experimental studies suggest a beneficial role of ACE inhibitors in attenuating reperfusion arrhythmias and postinfarction left ventricular remodeling. Unless the mechanisms and determinants of potential anti-ischemic actions of ACE inhibitors can be better defined, their use for treatment of myocardial ischemia cannot be recommended at present.

Vasodilator synchronized retroperfusion: Quantitative assessment of flow-function relation in acutely ischemic canine myocardium

To investigate whether addition of vasodilator drugs can increase the beneficial effects on the ischemic myocardium of diastolic synchronized retroperfusion (DSR), low doses of verapamil (2 μg/kg/min) or nitroglycerin (0.7 μg/kg/min) were infused through DSR in open-chest dogs undergoing 180 minutes of proximal left anterior descending coronary artery occlusion. Verapamil-DSR (n = 6), nitroglycerin-DSR (n = 6) or DSR alone (n = 8, controls) were started 10 minutes after the onset of occlusion and maintained for 170 minutes. Regional myocardial blood flow (MBF) (microspheres) and left ventricular function (endocardial ultrasonic crystals) were simultaneously assessed in nonischemic and ischemic zones in the 3 groups, before and after 10 and 180 minutes of coronary occlusion. DSR alone significantly increased ischemic regional MBF, endocardial/epicardial flow ratio and endocardial segmental length shortening. Verapamil DSR increased both nonischemic and ischemic regional MBF but reduced the endocardial/epicardial flow ratio and worsened ischemic contractile function. Nitroglycerin DSR did not modify ischemic transmural flow compared with DSR alone, but abolished the beneficial endocardial/epicardial blood flow redistribution, resulting in no additional improvement of contractile function. Thus, ischemic MBF and function are not improved by addition of small amounts of verapamil or nitroglycerin to the arterial retroperfusate in this model of acute myocardial ischemia.

Myocardial blood flow during cardiac tamponade in dogs with coronary occlusion: Effects of isoproterenol

To determine the effects of cardiac tamponade in dogs with ligation of the left anterior descending coronary artery, fluid was introduced into the pericardial space to raise right and left atrial and pericardial pressures, first to 7 to 9 mm Hg and then to 11 to 12 mm Hg. Normal and ischemic myocardial blood flow fell approximately 20% to 25% during mild tamponade (1.27 ± 0.16 to 1.00 ± 0.06 ml/min/gm and 0.52 ± 0.12 to 0.39 ± 0.08 ml/min/gm, respectively) and by 50% during moderate tamponade (0.66 ± 0.08 and 0.23 ± 0.05 ml/min/gm, respectively). The inner/outer left ventricular wall blood flow ratio decreased modestly from 1.16 to 1.08 ( p < 0.025) in normal areas but increased from 0.53 to 0.61 ( p < 0.05) in the ischemic regions, suggesting possible epicardial vessel compression. Isoproterenol resulted in prompt decreases in pericardial and filling pressures, 16% increase in aortic pressure, and 200% rise in cardiac output. Normal myocardial blood flow more than doubled (1.55 ± 0.12 ml/min/gm, p < 0.001). Although average ischemic blood flow rose slightly to 0.42 ± 0.10 ml/min/gm, the increase was not significant. Furthermore, changes in ischemic blood flow were heterogeneous with frank decrease in one dog. Therefore, although isoproterenol has salutary hemodynamic effects, its unpredictable action on myocardial blood flow should cause one to use it cautiously in those with tamponade who are believed to have coronary occlusive disease.

Measurement of local blood flow in acute myocardial infarction: loss of 15-micron microspheres during the first hour.

Distribution of radiolabelled microspheres is widely utilized for determination of regional blood flow in experimental myocardial infarction studies. The purpose of this investigation was evaluation of the microsphere method during 1 h of regional ischaemia. Special attention was focused upon loss of preocclusion microspheres from ischaemic myocardium; mechanisms for loss and blood flow distribution in non-ischaemic left ventricle. Microspheres (15 micron) were injected into the left atrium in nine pentobarbital anaesthetized cats prior to coronary artery occlusion and again after 1 h of occlusion. Preocclusion blood flow estimates were lower in ischaemic compared with non-ischaemic myocardium (1.36 vs. 1.62 cm3 X min-1 X g-1, P = 0.002), corresponding to 16% apparent loss. In endocardial ischaemic tissue, development of oedema could account for the loss. In epicardial ischaemic tissue, oedema was not present and loss was therefore due to migration of microspheres. Epicardial loss increased in proportion to restoration of left ventricular contractility. There was no evidence for significant microsphere loss through lymphatic pathways. In non-ischaemic left ventricular tissue, myocardial blood flow was evenly distributed from apex to base, and also between endocardial and epicardial layers. This study quantitates an important limitation to measurements of local blood flow in ischaemic myocardium by radiolabelled microspheres.

Regional myocardial tissue blood flow during beta-adrenergic blockade in cat hearts with acute ischaemia.

Selective beta 1- or beta 2-adrenergic blockade was achieved by practolol or IPS 339, respectively, in cats with acute ligation of a coronary artery. During blockade, heart rate was kept constant by atrial pacing and blood pressure reduction was prevented by aortic clamping. Regional myocardial blood flow was measured by the distribution of 15 micron labelled microspheres. Practolol slightly reduced epicardial blood flow in ischaemic myocardium, while blood flow in border and normally perfused myocardium remained unchanged. Following IPS 339, myocardial tissue flow increased in normally perfused myocardium, on average by 37% in the endocardium and 30% in the epicardium. No changes occurred in the other regions. The flow changes brought about by IPS 339 were unrelated to haemodynamic changes, and the coronary vascular resistance was reduced. These results are indicative of coronary vasodilation related to beta 2-adrenergic receptor blockade and was confined to well-oxygenated areas surrounding the acutely ischaemic zone.

Effect of hyaluronidase on substrate exchange and blood flow in the ischaemic myocardium of the dog.

The mechanism for reduced myocardial ischaemic injury by hyaluronidase was studied in open chest anaesthetized dogs. Repeated coronary artery occlusions were performed and the effect of hyaluronidase (225 NF units per kg) was studied during infusion of noradrenaline 0.125 mg/kg . min. Ischaemic injury was measured as the sum of ST-segment elevations (sigma ST) at 10-15 sites. Regional myocardial blood flow was determined by tracer microspheres. Blood for metabolic studies was sampled from a local coronary vein draining ischaemic tissue and from the coronary sinus draining predominantly non-ischaemic tissue. Hyaluronidase reduced sigma ST and increased subepicardial and transmural blood flow in ischaemic myocardium, but flow was not significantly changed in the ischaemic subendocardium or in non-ischaemic myocardium. Hyaluronidase had no significant effect on arterio-local venous differences of oxygen, glucose, lactate or free fatty acids across the ischaemic myocardium. In conclusion, reduction of myocardial ischaemic injury by hyaluronidase can be explained by increased collateral blood flow and not by an effect on fluxes of substrates across the ischaemic myocardium.

Prostacyclin in experimental myocardial ischemia: Effects on hemodynamics, regional myocardial blood flow, infarct size and mortality

To determine the actions of prostacyclin in acute myocardial ischemia, the left anterior descending coronary artery was ligated in 26 anesthetized dogs. At 15 and 45 minutes after coronary ligation, regional myocardial blood flow (ml/min per 100 g) and cardiac output (ml/min) were measured by the radiolabeled microsphere technique (strontium-85 or cerium-141 18 to 10μ]). The dogs were randomly allocated 17 minutes after coronary ligation to a control group (n = 17) or to treatment with prostacyclin infusion at 0.32 μg/kg per min for 6 hours (n = 9). Heart rate and cardiac output were unchanged (p > 0.05) by prostacyclin; mean systemic arterial pressure decreased from 121 ± 8 to 90 ± 3 mm Hg (mean ± standard error of the mean) (p < 0.01) and systemic vascular resistance from 2,690 ± 339 to 2,372 ± 398 dynes · s · cm −5 (p < 0.05). Prostacyclin reduced blood flow in nonischemic myocardium from 116 ± 12 to 80 ± 3 ml/min (p < 0.01); flow in the ischemic zone was unchanged (p > 0.05) from 22 ± 5 to 20 ± 4 ml/min. Thus, the ratio of ischemic to nonischemic flow was increased by prostacyclin from 0.20 ± 0.03 to 0.25 ± 0.05 (p < 0.05); neither the ischemic nor the nonischemic endocardial/epicardial flow ratio was altered (p > 0.05). In the control dogs, all variables remained constant (p > 0.05) from 15 to 45 minutes. Mortality to 6 hours after coronary ligation was 0 of 9 in prostacyclin-treated versus 6 of 17 (35 percent) in control dogs (p < 0.06). Surviving dogs were killed 24 hours after ligation and infarct size, determined by planimetry and weight techniques, was 18 ± 2 percent of left ventricle in prostacyclin-treated dogs versus 22 ± 2 percent in control dogs (p > 0.05). Thus, prostacyclin in acute myocardial ischemia decreases myocardial oxygen demands, maintains ischemic myocardial blood flow while decreasing nonischemic flow, and greatly reduces early mortality.

The influence of combined intra-aortic balloon counterpulsation and hyperosomotic mannitol on regional myocardial blood flow in ischemic myocardium in the dog.

We investigated the combined effectiveness of intra-aortic balloon counterpulsation and hyperosmotic mannitol (25%) on regional myocardial blood flow during acute coronary insufficiency. Cardiac output and paced heart rate were held constant in chloralose-anesthetized dogs during right heart bypass. Acute coronary insufficiency was produced by ligation of the proximal left anterior descending coronary artery (LAD). Regional myocardial blood flow was measured using radioactive microspheres. Left ventricular end-diastolic pressure, mean aortic pressure, maximum left ventricular dp/dt, and hematocrit were unchanged by combined mannitol infusion and balloon pumping. Studies of combined treatment with balloon pumping and mannitol immediately after the second of two 13-minute consecutive reversible ligations of the LAD demonstrated that (1) collateral coronary blood flow increased 46% (P less than 0.02) in ischemic myocardium compared with mannitol infusion along during the first LAD ligation, and (2) collateral coronary blood flow increased 27% (P less than 0.05) in ischemic myocardium compared with balloon pumping along during the first LAD ligation. Studies in which combined treatment was delayed until 20 minutes after LAD ligation demonstrated that collateral coronary blood flow was elevated by 33% (P les than 0.05) in ischemic myocardium compared to control studies in which balloon pumping alone had no effect. The results suggest that the increase in collateral coronary blood flow was in part a result of an increased transmural pressure gradient produced by balloon diastolic augmentation and the ability of mannitol to reduce coronary vascular resistance in ischemic myocardium.

Improvement in Myocardial Function and Coronary Blood Flow in Ischemic Myocardium after Mannitol

The purpose of this study was to evaluate the effect of hyperosmolality on the performance of, and the collateral blood flow to, ischemic myocardium. The myocardial response to mannitol, a hyperosmolar agent which remains extracellular, was evaluated in anesthetized dogs. Mannitol was infused into the aortic roots of 31 isovolumic hearts and of 15 dogs on right heart bypass, before and during ischemia. Myocardial ischemia was produced by temporary ligation of either the proximal or mid-left anterior descending coronary artery. Mannitol significantly improved the depressed ventricular function curves which occurred with left anterior descending coronary artery occlusion. Mannitol also significantly lessened the S-T segment elevation (epicardial electrocardiogram) occurring during myocardial ischemia in the isovolumic hearts and this reduction was associated with significant increases in total coronary blood flow (P < 0.005) and with increased collateral coronary blood flow to the ischemia area (P < 0.005).THUS, INCREASES IN SERUM OSMOLALITY PRODUCED BY MANNITOL RESULT IN THE FOLLOWING BENEFICIAL CHANGES DURING MYOCARDIAL ISCHEMIA: (a) improved myocardial function, (b) reduced S-T segment elevation, (c) increased total coronary blood flow, and (d) increased collateral coronary blood flow.