Major Determinants Of Infarct Size Research Articles

Larger infarct size but equal protection by ischemic conditioning in septum and anterior free wall of pigs with LAD occlusion.

The ischemic area at risk (AAR) is one major determinant of infarct size (IS). In patients, the largest AAR is seen with a proximal occlusion of the left anterior descending (LAD) coronary artery, which serves parts of the septum and of the anterior free wall. It is not clear, whether regional differences in the perfusion territories also impact on IS and the magnitude of cardioprotection by ischemic conditioning. We have retrospectively analyzed 132 experiments in pigs, which have a similar LAD perfusion territory as humans. The LAD was occluded for 60 min with subsequent 180 min reperfusion. Cardioprotection by either local ischemic pre‐ or postconditioning or remote ischemic pre‐ or perconditioning was induced in 93 pigs. The AAR was demarcated by blue dye staining, and IS was assessed by triphenyltetrazolium chloride (TTC) staining. Using digital planimetry, the AAR was separated into sections unequivocally located in the septum (AARS) or the anterior free wall (AARAFW). Relative IS was calculated for AARS or AARAFW. AARAFW was larger than AARS (51 ± 9% vs. 34 ± 8% of total AAR; mean ± SD, P < 0.001). Regional myocardial blood flow (microspheres) was not different between septum and anterior free wall. IS without ischemic conditioning tended to be larger in AARS than in AARAFW (50 ± 17% vs. 44 ± 19%; % of AARAWF or AARS, respectively; P = 0.075). Also, with robust IS reduction by ischemic conditioning, the difference in relative IS remained (AARS: 27 ± 16%; AARAFW: 21 ± 16%; P = 0.01). There is a somewhat greater susceptibility for infarction in septal than anterior free wall myocardium. However, ischemic conditioning still reduces IS in both septal and anterior free wall myocardium.

Infarct Size Reduction in Patients With STEMI: Why We Can Do It!

Major progress has been made over the last three decades for the treatment of patients with ST elevation myocardial infarction (STEMI). The major objective of this treatment is to reduce infarct size, which is the major prognostic factor in this population. Most of the efforts have been focused on improving reperfusion therapy in order to open as quickly as possible, and to prevent reocclusion, of the culprit coronary artery. During the past years, preclinical research has allowed researchers to well-characterize animal models of acute MI and precisely describe the major determinants of infarct size, that is area at risk, collateral flow, duration of ischemia, and timing of the protective intervention with respect to reflow. Recent reports have clearly demonstrated that lethal reperfusion injury exists, that it is of significant importance, and that it can be prevented by protective interventions applied immediately before reflow. Time has come to, on top of reperfusion therapy, better protect the muscle against lethal reperfusion injury. Although many past infarct size reduction studies have been negative, recent proof-of-concept studies have shown that infarct size reduction is possible in patients with STEMI, at least in part because the major determinants of infarct size have been taken into account. Accumulated knowledge from animal models together with encouraging results obtained in phase II infarct size reduction clinical trials should help us improve the design of future studies aimed at reducing infarct size in patients with STEMI.

Determination of the myocardial area at risk after reperfused acute myocardial infarction with different imaging techniques: cardiac magnetic resonance imaging, multidetector computed tomography and histopathological validation

The myocardial area at risk (AAR) is a major determinant of infarct size. Which imaging technique is the most appropriate to accurately measure its size remains debated.

Symptom-to-door time in ST segment elevation myocardial infarction: Overemphasized or overlooked? Results from the AMI-McGill study

Ischemic time is a major determinant of infarct size in ST segment elevation myocardial infarction (STEMI). Emphasis is placed on reducing the door-to-reperfusion therapy time component, whereas the symptom-to-door time is often overlooked. To correlate the symptom-to-door time with left ventricular ejection fraction (LVEF) in patients with STEMI. Acute Myocardial Infarction (AMI)-McGill was a cohort study of consecutive patients with STEMI who presented to three adult university hospitals. Multivariate linear regression was performed to correlate the symptom-to-door time with postinfarction LVEF adjusted for reperfusion method, prior myocardial infarction and components of the Thrombolysis In Myocardial Infarction (TIMI) risk score. There were 188 patients, with a mean age of 66 years. On arrival to hospital, 23% of patients were in Killip class II to IV and 87% received reperfusion therapy (20% fibrinolytic therapy and 67% primary percutaneous coronary intervention). The median symptom-to-door time was 120 min (first quartile: 60 min, third quartile: 290 min) and the median door-to-reperfusion therapy time was 93 min (first quartile: 54 min, third quartile: 155 min). Three variables were independently correlated with LVEF in the study's regression model: symptom-to-door time (beta: -0.66, 95% CI -1.18 to -0.14; P=0.01), Killip class II to IV on arrival (beta: -6.43, 95% CI -11.87 to -0.99; P=0.02) and anterior territory of the infarction (beta: -5.86, 95% CI -10.55 to -1.18; P=0.02). Symptom-to-door time was negatively correlated with postinfarction LVEF in patients with STEMI. Strategies to shorten this delay, such as educating high-risk patients about the symptoms of AMI, should be considered.

Effect of Systemic Blood Pressure on Microcollateral Circulation Evaluated by Real-Time Contrast Echocardiography

In acute myocardial infarction, residual collateral-derived myocardial blood flow (CBF) within the ischemic area is one of the major determinants of infarct size. Management of systemic blood pressure (sBP) related to maintain collateral circulation is still difficult. The aim of this study was to reveal the influence of sBP on the rescue of area at risk by collateral circulation. Real-time myocardial contrast echocardiography just after the onset of complete occlusion of the left circumflex coronary artery was performed in collateral-rich open-chest dogs. The video intensity of the ischemic area was evaluated during the occlusion and the CBF (A x beta) was calculated from a replenishment curve: y = A (1 - e(-beta t)). To analyze the effect of sBP on the collateral circulation, sBP was altered by infusion of nitroglycerin or etilefrine hydrochloride. To evaluate the defect size (%DS), every end-systolic myocardial contrast echocardiography image after left circumflex coronary artery occlusion was converted into binary images using custom offline software. The %DS increased and CBF slightly decreased at low sBP. The %DS decreased and CBF increased at high sBP. At excessively high sBP, %DS increased and CBF decreased again. Real-time myocardial contrast echocardiography, which is a useful noninvasive method to evaluate the collateral perfusion quantitatively, has a crucial role in the decision of patient treatment and management strategy of acute myocardial infarction.

Timing of treatment for myocardial reperfusion injury.

Early reperfusion of acute myocardial infarctions halts cell death due to ischemia but causes further injury, probably by oxidant mechanisms. We identified the window of opportunity during which antioxidants must be present in therapeutic concentrations to prevent reperfusion injury during 90 min of ischemia and 48 h of reperfusion in 57 dogs. We examined the effect on myocardial infarct size of intravenous infusion of N-2-mercaptopropionyl glycine (MPG), a diffusible antioxidant with a plasma half-time of 7 min, by using a series of protocols with a range of timing. Whereas infusions of MPG for > or =3 h reduced infarct size by approximately 50%, infusions for 1 h only (the first, second or third hours of reperfusion) caused only small reductions. A statistical analysis that focused on identifying components of group membership responsible for differences revealed that duration of treatment was a major determinant of infarct size. If begun any time within the first hour of reperfusion, infusions of > or =3 h markedly diminished infarct size. Because reperfusion injury proceeds for the first 3 h of reperfusion, but decreases thereafter, adequate protection is needed for > or =3 of the first 4 h of reperfusion, but more prolonged protection is not necessary.

Left ventricular function after coronary artery reperfusion

Left ventricular dysfunction and dilation after reperfusion relate to the amount of infarcted and dysfunctional myocardium and will continue to be important determinants of morbidity and mortality. There is marked heterogeneity in the anatomic and pathophysiologic presentation of patients with acute myocardial infarction prior to thrombolyste, and many of these individual settings resemble those in animal species with various degrees of collateral formation. Three major determinants of infarct size are responsible for this heterogeneity and include the risk area, the duration of the coronary occlusion, and the level of the residual coronary blood flow via collaterals or a partially patent artery. All 3 of these determinants will influence the initial and late results of reperfusion therapy on infarct size and ventricular function. However, in addition to late or unsuccessful thrombolysis, there are other important factors determining outcome: inadequate reflow, residual coronary stenosis, and coronary reocclusion, factors that can be associated with late progressive left ventricular dilation and dysfunction. The risk factors for left ventricular dysfunction and dilation after reperfusion can now be identified, and such patients should undergo coronary angiography prior to hospital discharge and, if appropriate, revascularization of the infarct-related artery (and perhaps other vessels). In other patients, if serial studies reveal progressive left ventricular failure and dilation late after reperfusion, despite therapy with an angiotensin-converting enzyme (ACE) inhibitor, and if repeat coronary angiography identifies significant coronary stenoses and areas of hibernating or stunned myocardium, revascularization may limit progression of dilation and improve left ventricular function. Thus, many events occur during the evolution of myocardial infarction and after thrombolysis for which treatment is possible, and there is good reason to expect that left ventricular function can be improved well beyond the modest increase now observed with thrombolytic therapy. This, in turn, could have a further significant impact on morbidity and mortality after reperfusion.

Acute myocardial infarction in dogs with experimental diabetes

The aim was to examine whether diabetes interferes with the development of myocardial injury in a canine ischaemia-reperfusion model. Non-insulin-requiring diabetes was induced in dogs by the streptozotocin-alloxan method. After 75 d, the dogs were anaesthetised and myocardial infarction was provoked by occluding the left anterior descending coronary artery for 2 h followed by 6 h reperfusion. Diabetic dogs had higher blood glucose [9.4(SEM 1) mmol.litre-1], fructosamine [417(57) mumol.litre-1], and glycated haemoglobin [3.3(0.7)%], than control dogs [5.5(0.6), p = 0.04, 243(15), p = 0.01, and 0.7(0.2), p = 0.003, respectively], and they also had higher serum lipids (p = 0.001) and platelet aggregation (p = 0.03). Area at risk was similar in diabetic and control dogs but in contrast to controls (r = 0.78, p = 0.007), area at risk and infarct size were not correlated in diabetics (r = 0.08). In both groups, collateral flow was the major determinant of infarct size: r = -0.73 in controls (p = 0.02) and -0.97 in diabetics (p = 0.001). In spite of higher subendocardial collateral flow in diabetics [representing 21.6(6)% of the flow in the corresponding non-ischaemic zone] than in controls [11.2(6)%], infarct size was similar in both groups. However, the mean observed infarct size in the diabetic group [7.5(2.8)% of the left ventricle] was significantly (p < 0.03) larger than the mean predicted infarct size [5.2(2)%]. Multivariate analysis confirmed that diabetes, as well as collateral flow, is an independent (p = 0.03) predictor of infarct size. For a given collateral flow, diabetic dogs develop larger infarcts than controls. Further studies are required to investigate the biochemical mechanism(s) underlying this deleterious effect. However, this may partly explain the poor prognosis of myocardial infarction in diabetic persons.

Controlled reperfusion of the regionally ischemic myocardium with leukocyte-depleted blood reduces stunning, the no-reflow phenomenon, and infarct size

Open-chest sheep underwent 90 minutes' occlusion of the diagonal branch of the left anterior descending coronary artery, followed by vented cardiopulmonary bypass. After 30 minutes of cardioplegic arrest, simulating distal anastomoses, the occlusion on the coronary artery branch was released. Controlled reperfusion (40 to 50 mm Hg, 135 to 150 ml/min) for the first 20 minutes was delivered at the aortic root with either unmodified whole blood (control, n = 7) or blood passed through leukocyte filters (filters, n = 7). Serial measurements were made during 3 additional hours reperfusion off cardiopulmonary bypass. During ischemia, the major determinants of infarct size, which include area at risk, collateral myocardial blood flow, and rate-pressure product were not significantly different between groups. Overall, during reperfusion, mean left ventricular stroke work index in the filter group was greater than in the control group (28.7 +/- 5.8 versus 12.6 +/- 6.4 x 10(3) erg/gm, p less than 0.05), as was mean rate of rise of left ventricular pressure (1900 +/- 260 versus 1348 +/- 279 mm Hg/sec, p less than 0.05). Myocardial blood flow to the area at risk at 3 1/2 hours of reperfusion in the filter group was also significantly better than in the control group (0.57 +/- 0.15 versus 0.27 +/- 0.05 ml/min/gm, p less than 0.05), as was necrotic area as a percentage of area at risk (40% +/- 6% versus 70% +/- 5%, p less than 0.05). These results demonstrate amelioration of myocardial stunning and the no-reflow phenomenon, as well as decreased infarct size. We conclude that controlled reperfusion with leukocyte-depleted blood is superior to whole-blood reperfusion for the surgical treatment of acute regional ischemia.

Reduction in reperfusion injury by blood-free reperfusion after experimental myocardial infarction

Because myocardial reperfusion injury may be caused by various blood constituents, a transient period of blood-free reperfusion was evaluated in closed chest dogs subjected to a 90 min angioplasty balloon occlusion of the left anterior descending coronary artery. In the treated group (n = 13), the balloon remained inflated for an additional 15 min while the infarct vessel was perfused with an acellular oxygenated perfluorochemical emulsion (Fluosol). The balloon was then deflated, permitting blood reperfusion. In the control group (n = 13), the balloon was deflated after 90 min of coronary occlusion. One week after infarction, the area at risk was defined in vivo by monastral blue dye staining, and the area of myocardial necrosis was assessed using triphenyltetrazolium chloride staining with histologic confirmation. Major determinants of infarct size, including rate-pressure product, area at risk and severity of myocardial ischemia (assessed by the extent of ST segment elevation during coronary occlusion), were not significantly different in the two groups. Treated dogs demonstrated a 47% reduction in infarct size expressed as a percent of the area at risk compared with control dogs (27.0 +/- 4.4% versus 50.8 +/- 4.4%, p less than 0.01). Treated dogs also demonstrated a superior global left ventricular ejection fraction (57.5 +/- 2.5% versus 51.0 +/- 2.2%, p less than 0.05) and anterolateral (regional) ejection fraction (32.6 +/- 3.6% versus 19.8 +/- 3.9%, p less than 0.05) compared with values in control dogs assessed by contrast ventriculography after 1 week of reperfusion. It is concluded that a transient period of blood-free reperfusion with an oxygenated perfluorochemical reduces reperfusion injury in a canine model of myocardial infarction.

Evaluation of Free Radical Injury in Myocardium

Abundant evidence now is available that free radicals are produced in excess when myocardium is reperfused following an episode of ischemia and that free radicals can injure myocytes and endothelial cells. Free radicals may contribute to either reversible or irreversible manifestations of cell injury from ischemia and reperfusion. Several investigators have observed that post-ischemic contractile dysfunction (myocardial stunning) can be attenuated by a variety of anti-free radical therapies, and there seems to be general agreement that free radical injury contributes to stunning. Whether free radicals are an important cause of lethal myocyte injury ("lethal reperfusion injury") remains controversial. Using similar interventions and animal models, both positive and negative results have been reported from a growing number of studies done to test the effect of anti-free radical therapies on infarct size. Proposed explanations include differences in: 1) dose of drug and onset or duration of treatment, 2) duration of occlusion or reperfusion, 3) methods of measuring infarct size or area at risk, and 4) failure of some studies to control for baseline variation in the major determinants of infarct size, e.g., collateral blood flow. At present, none of these explanations seems sufficient to resolve the question.

Influence of leukopenia on collateral flow, reperfusion flow, reflow ventricular fibrillation, and infarct size in dogs

Leukocytes contribute to myocardial damage during ischemia and reperfusion. However, the mechanism involved has not been clearly elucidated. The purpose of the present study was to determine whether leukocyte-induced myocardial damage is flow mediated. In open-chest dogs submitted to 2 hours of ischemia, area at risk, infarct size, and regional myocardial blood flow before, during, and after ischemia were measured. Leukopenia was induced by a two-step method (chemotherapy and antineutrophil serum) in a group of 14 dogs as compared to a control group of 18 dogs. The relation of infarct size to the major determinants of infarct size was analyzed by uni- and multilinear regressions. Seven control dogs had ventricular fibrillation at reperfusion compared to one dog with leukopenia. In the group with leukopenia the mean infarct size was smaller (31.1 ± 5.8% of area at risk) than in the control group (47.7 ± 2.9, p = 0.02). In addition, the two multiple linear regression equations were significantly different ( p = 0.01). Myocardial blood flow to the central ischemic zone did not change significantly between 20 and 120 minutes of ischemia in the control dogs (n = 12; subendocardial = 0.08 ± 0.03 vs 0.07 ± 0.03 ml/min/gm; subepicardial = 0.20 ± 0.07 vs 0.20 ± 0.05 ml/min/gm) and in the dogs with leukopenia (n = 12; 0.07 ± 0.02 vs 0.07 ± 0.02 ml/min/gm and 0.15 ± 0.004 vs 0.18 ± 0.04 ml/min/gm). A similar reduction in myocardial blood flow was observed after 6 hours of reperfusion in the control dogs (0.34 ± 0.07 ml/min/gm vs 1.02 ± 0.11 at baseline, p < 0.01) and in the dogs with leukopenia (0.25 ± 0.04 vs 0.81 ± 0.08 ml/min/gm, p < 0.01). It was concluded that the leukocyte-dependent myocardial injury did not appear to be mediated through a flow mechanism during either ischemia or reperfusion.

Regional redistribution of myocardial blood flow after coronary occlusion and reperfusion in the conscious dog

Early and late changes in regional myocardial blood flow distribution within the left circumflex coronary arterial bed after occlusion and after occlusion and reperfusion were compared with the extent of myocardial tissue necrosis. Radiolabeled microspheres, 15 μm, were used to study regional myocardial blood flow in conscious dogs at 5 minutes, 2 and 6 hours and 1 month after coronary occlusion. Blood flow was measured in conscious dogs whose hearts were reperfused for 72 hours after 2, 6 and 24 hours of occlusion. Blood flow was measured in four distinct transmural myocardial zones dellneated by dye injections and gross infarct features of the occluded left circumflex coronary bed. After occlusion, myocardial flow was redistributed from deep layers to outer layers, and within 6 hours after occlusion collateral flow was increased to the outer zones in excess of redlstributed flow. After reperfusion, blood flow greatly increased to regions containing predominantly normal tissue, and flow was redlstrlbuted away from the necrotic zones. The indigenous collateral circulation was a major determinant of infarct size in the occluded and reperfused myocardium. The concept of a migrating and narrowing marginal zone is discussed.