Acute myocardial infarction and blood transfusion: lessons learned from animal models and clinical studies

In this issue of Blood Transfusion, Bulle et al. analyze the incidence of adverse cardiopulmonary events in an animal model of acute myocardial infarction (MI) and transfusion¹. Blood transfusion in patients with acute MI may be indicated to improve oxygen delivery or reduce the risk of bleeding in the setting of anti-platelet agents or therapeutic anticoagulation^2,3. Specifically, the management of acute MI may include concurrent administration of thrombolytic, antithrombotic, or antiplatelet therapies around the time of percutaneous coronary revascularization procedures, increasing the risk of bleeding and acute anemia. In addition, chronic anemia is often present in older patients with acute MI, especially in those with chronic kidney disease, congestive heart failure, or a history of coronary artery disease⁴. Several observational studies have associated acute and chronic anemia with adverse outcomes in patients with acute MI^5,6. While most individuals are able to increase oxygen delivery and extraction of oxygen from RBCs over a range of hemoglobin concentrations, some patients with acute MI have reduced end-organ oxygen utilization and do not tolerate reductions in oxygen delivery with anemia⁷. In the setting of acute or chronic anemia, red blood cell (RBC) transfusion may be beneficial by sustaining oxygen delivery to myocardial cells and decreasing myocardial oxygen demand in patients with acute coronary occlusions or mitigate oxygen supply/demand mismatches in patients with non-occlusive MI. Concurrently, plasma components are at times transfused to patients with acute MI to reverse anticoagulation prior to coronary revascularization procedures or to treat coagulopathy in the setting of bleeding.

Despite their potential benefits, blood transfusions include biologically active products that may induce immune responses and expand vascular volume. With advances in transfusion medicine, complications related to transfusion-transmitted infections, transfusion-related acute lung injury (TRALI), and severe hemolytic reactions have become rare^8,9. However, transfusion may induce circulatory overload resulting in pulmonary edema (transfusion associated circulatory overload, TACO) and associated adverse patient outcomes. TACO remains the leading cause of transfusion-associated morbidity and mortality, and many of the risk factors for TACO, such as ischemic cardiomyopathy or chronic kidney disease, parallel those for acute MI^10,11. Pulmonary edema is a recognized adverse outcome in clinical trials of acute MI and RBC transfusion. In the CRIT and REALITY trials, there was an increased number of cases of pulmonary edema in the liberally compared to restrictively transfused group^12,13. Given the hemodynamic and physiologic complexity of patients with myocardial infarction and acute or chronic anemia as well as the unclear risk/benefit of transfusion, it is not surprising that there is significant variation in transfusion practice in this setting¹⁴. Furthermore, the identification and distinction of TACO from other pulmonary transfusion reactions and acute respiratory distress syndrome (ARDS) remains challenging clinically¹⁵.

While animal models have been used to study the pathogenesis of TRALI for many years, the investigation of TACO in an experimental model is a recent advance^16,17. Leading this effort, the authors of this manuscript have conducted a series of rat model experiments investigating the pathogenesis of TACO. In the animal model utilized by Bulle et al. in the current and prior studies, the left anterior descending coronary artery is ligated, causing a myocardial infarct, and isovolemic anemia is induced through the exchange of arterial blood for a colloid solution. The investigators then monitored changes in respiratory and hemodynamic parameters (heart rate, mean arterial pressure, central venous pressure, and left ventricular end diastolic pressure) prior to and following transfusion of blood products. Their initial publication provided animal model data supporting the hypothesis that the combination of either cardiac or renal impairment and transfusion is needed for the development of TACO¹⁸. Subsequent investigations provided empirical data affirming clinical observations that the risk for TACO increases with transfused volume and that prophylactic diuretics mitigate the rise in cardiac filling pressures associated with transfusion^19–22.

The current study by Bulle et al. examined the impact of plasma component transfusion in comparison with albumin and crystalloid infusions on pulmonary and hemodynamic measures in their rat model of TACO¹. The impact of component processing and modifications on recipient outcomes is an area of high interest in transfusion medicine research; in the current study, the investigators compared transfusion of solvent/detergent-treated pooled plasma (SDP) and fresh frozen plasma (FFP) on their primary outcome, post-transfusion changes in cardiac filling pressures, finding no differences between these blood products²³. Nor were there clear numerical differences in cardiac filling pressures in rats transfused red cell units rather than plasma components^18,19. Lastly, the authors found that albumin infusions increased heart rate, blood pressure, and end-diastolic filling pressure in parallel with if not greater than that seen with plasma components.

It is important to attempt to translate the results of these animal model experiments into clinical practice. The standard of care for patients with ST-elevation myocardial infarction (STEMI) is timely percutaneous coronary intervention with the goal of restoring coronary artery blood flow to limit infarct size and downstream cardiovascular complications, such as congestive heart failure and arrhythmia. In STEMI patients with acute anemia due to blood loss, there is decreased venous return to the heart which may increase oxygen demands. In this scenario of hypovolemia related to bleeding, the risk for TACO is significantly reduced. The results of these animal model studies support clinical intuition that STEMI patients without significantly elevated cardiac filling pressures, due to heart failure or kidney disease, are typically able to tolerate transfusion without developing TACO. While periprocedural bleeding has been associated with worsened short- and long-term outcomes, the incidence of these bleeding events is thankfully low^24,25. This low incidence is in part due to advances in percutaneous coronary interventions including increased use of radial artery access, which when compared with femoral artery access, is associated with fewer bleeding complications^26,27. In addition, rapid on-site monitoring of activated clotting time (ACT) has been shown to be important in reducing the risk of bleeding in patients receiving unfractionated heparin²⁸.

In contrast to patients with acute hospital-acquired anemia, patients with congestive heart failure and acute MI are more likely to have chronic anemia and a differential response to transfusion, including the likelihood of TACO²⁹. Chronic inflammation is a key factor in the development of anemia in patients with congestive heart failure and chronic kidney disease³⁰. The impact of transfusion on both hemodynamic parameters such as central venous pressure and systemic vascular resistance often differ in this chronic state. In chronically anemic patients with acute MI, the assessment of oxygen delivery is recognized to be challenging, and thresholds for RBC transfusion remain an area of ongoing investigation. Pre-procedure plasma transfusion to reverse anticoagulation may precipitate TACO, and one study showed that factor concentrates are associated with less pulmonary edema compared to plasma transfusion for this indication³¹. Indeed, the investigators acknowledge that the physiology of chronic heart and kidney failure need to be incorporated into future animal models of TACO, and the results of these experiments will hopefully provide additional evidence to guide transfusion practice.

In clinical practice, randomized controlled trials of RBC transfusion and acute MI have to date had conflicting outcomes. Two small trials of RBC transfusion found lower mortality with restrictive transfusion practice in patients with acute MI as compared to the more recent REALITY trial, which favored long-term outcomes with a restrictive transfusion practice^13,32. When these trials were combined in meta-analysis, there were no differences in mortality between RBC treatment strategies, though with wide confidence intervals³. However, these trials were not adequately powered to resolve questions regarding the benefits and risks of RBC transfusion, including TACO, in the setting of acute MI and chronic heart failure. The Myocardial Ischemia and Transfusion (MINT) trial is powered to fill some of these knowledge gaps by enrolling 3500 patients with acute and chronic anemia experiencing acute MI (Type 1, 2, or 4)³³. In addition, this trial of RBC transfusion strategies incorporates preventative measures for TACO acknowledged by this series of animal model experiments, including the consideration of transfusion volumes and prophylactic diuretics in trial subjects with a history of congestive heart failure or reduced ejection fraction.

In patients with acute MI, the risks and benefits of transfusion are complex and may be dynamic compared to other patient populations. The response to transfusion may be a function of the acuity and degree of anemia as well as a patient's ability to compensate for it, which can be further impacted by ongoing myocardial ischemia and bleeding related to anticoagulant and antithrombotic therapies. Transfusion may mitigate the risk of bleeding or myocardial ischemia but may result in adverse events such as TACO. Incorporating both pre-clinical and clinical studies of transfusion in the setting of acute MI allow for integration of knowledge to guide best transfusion practice and prevent adverse events such as TACO.