Varying Characteristics of Atherogenesis and Cardiopulmonary Bypass Inflammatory Response

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BACKGROUND: Over the last decade there has been a tremendous growth in our understanding of genetic influences upon atherogenesis, coagulation, and fibrinolysis. Atherosclerosis plays a major role in the pathophysiology of coronary, cerebral, and peripheral vascular disease. Interventions directed towards the prevention of ASCVD have focused on the use of pharmacological agents (such as anticoagulants and anti-hypertensives) and recommendations for certain lifestyle changes (such as dietary restrictions, cessation of cigarette smoking, and exercise). However, despite these preventive measures, ASCVD remains a major cause of perioperative morbidity and mortality as well as a challenge to our health care and welfare systems. In the United States, coronary artery disease (CAD) alone results in 1.1 million myocardial infarctions each year, and is the most common cause of death. Conventional and modifiable risk factors such as smoking, and the presence of hypertension, diabetes mellitus, hypercholesterolemia, and hyperlipidemia, fail to predict a large proportion of events related to ASCVD. For example, over one-third of coronary thromboses occur in individuals without identifiable conventional risk factors. During the past decade there has been extensive research into the mechanisms of ASCVD, and there has been an accumulation of evidence for the role of infection, chronic inflammation, hypercoagulability, impaired fibrinolysis, and genetic-environmental interactions in its pathogenesis. This has led to the identification of several new and novel plasma markers for ASCVD, including C-reactive protein (CRP), homocysteine, fibrinogen, and intercellular adhesion molecules. Elevated levels of all four of these markers have been found to be independently associated with an increased risk of ASCVD. The strength of the association between these plasma markers and the location and extent of ASCVD as well as the frequency of cardiovascular events such as myocardial infarction and stroke has been examined in several observational and interventional studies. Correlation between findings has not always been consistent. In addition, very little is known about how levels of these plasma markers vary in patients with ASCVD in response to an acute inflammatory stimulus such as cardiopulmonary bypass, or their potential value as predictors of perioperative morbidity. Numerous studies have examined the cellular, subcellular, and humoral inflammatory responses to cardiac surgery and cardiopulmonary bypass (CPB). Cardiac surgery and CPB induce a coagulation and inflammatory response associated with significant patient morbidity and mortality primarily by activation of the cellular elements of blood by CPB circuit materials. Similarly, tissue (especially myocardial) ischemia, reperfusion injury, hypothermia, organ hypoperfusion, and drugs used to modify coagulation (e.g., heparin and protamine) may also induce a coagulation and inflammatory response. There is wide interpersonal variation in the frequency and severity of adverse outcome after CPB and cardiac surgery which can probably be divided into environmental and genetic causes. Environmental sources of variability include anesthetic and surgical techniques, duration and severity of insults, infection, and other therapies that we can manipulate. Genetic variability is also an important variable in a wide variety of cardiovascular inflammatory and coagulation outcomes. To date there has been little systematic work relating genetic phenotype to outcomes after CPB. It seems logical and important to establish phenotypes that are associated with those adverse outcomes and subsequently target susceptible individuals. Possible targets are fibrinogen, prothrombin, factor V, factor VII, factor XIII, protein C, protein S, plasminogen activator inhibitor-I and tissue plasminogen activator. DESIGN NARRATIVE: Enrolled patients will undergo the following procedures while in the hospital. (i) Blood sampling: All patients will have blood samples drawn at 7 time points beginning prior to induction of anesthesia through to the fifth postoperative day. A total of 140 mls of blood will be drawn: 50 mls at the initial blood draw, and 15 mls at each subsequent sample time (see Protocol Schema). The first 4 blood samples will be taken from a routinely placed arterial or central venous line. The last 3 blood samples will also be taken from the arterial or central venous line if they have not yet been removed; otherwise these 3 samples may require phlebotomy from an upper extremity peripheral vein. These will be drawn at the same time as other routine postoperative blood samples if they are required. Blood samples will be used to measure various genetic and plasma markers of chronic inflammation and hypercoagulability and fibrinolysis. (ii) Epiaortic echocardiography: All patients will have their ascending aorta scanned using a sterile ultrasound probe held by the surgeon. This procedure is routinely performed on a majority of patients undergoing cardiac surgery at the Brigham and Women's Hospital to identify areas of atherosclerotic plaque and to determine the most suitable sites for aortic cannulation. There are no known risks or complications of epiaortic scanning, and the procedure takes approximately one minute. The epiaortic scan is routinely recorded on videotape and will be analyzed for the presence and extent of atherosclerosis. (iii) Transesophageal echocardiography: Intraoperative transesophageal echocardiography (TEE) is used in approximately 70% of patients undergoing coronary artery bypass surgery at Brigham and Women's Hospital. The adverse events after TEE are sore throat, dental injury, and esophageal injury. The frequency of mild sore throat after TEE probe insertion is unknown, but it is usually mild and persists for only a day or two. Other, much less frequent, problems include injury to the teeth (one person in 3000), and injury to the esophagus or stomach (one person in 3000). Some more recent data indicate that the rate of esophageal injury is approximately 1:7000. If the risk appears to be higher in a patient, TEE will not be performed. Examples of increased risk are chronic steroid use, prior esophageal or gastric surgery, and esophageal stricture of difficulty with probe insertion. These contraindications for TEE will not be exclusions for enrollment or the remainder of the study. Accordingly there is no expectation of increased risk to the patient, as the probe will have already been placed. There is minimal perceived risk from the required additional probe manipulation or non-ionizing (ultrasound) radiation required for data collection. (iv) Medical record review: In addition to the blood collections and epiaortic screening outlined above, we will also review the patient's medical records for demographic and hemodynamic information, as well as for results of routine preoperative coronary angiography and intraoperative echocardiography. Evidence of any adverse outcomes will be recorded. No other procedures will differ from the standard of care for these patients. There are no alternatives to participation in this study other than not to participate. After discharge from the hospital the patients will receive via mail a questionnaire containing the following: (i) SF-36 (ii) Duke Activity Status Index (iii) Seattle Angina Questionnaire (iv) Dyspnea Index (v) Recurrent hospitalization and procedures questionnaire The questionnaire will be mailed at 6 weeks; 6 months; and 1, 2, 3, 4, and 5 years.

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