Terrence M. Yau

Cardiopulmonary bypass induced inflammation: pathophysiology and treatment. An update

Cardiac surgery with cardiopulmonary bypass (CPB) induces an acute phase reaction that has been implicated in the pathogenesis of several postoperative complications. Recent data indicate that a complex sequence of events leads to the final activation of leukocytes and endothelial cells (EC), which is responsible for cell dysfunction in different organs. Activation of the contact system, endotoxemia, ischemia and reperfusion injury and surgical trauma are all potential triggers of inflammation following CPB. Different pro- and anti-inflammatory mediators (cytokines, adhesion molecules) are involved and their release is mediated by intracellular transcription factors (nuclear factor-kappa B, NF-kappa B). In this review, we examine recent advances in the understanding of the pathophysiology of the CPB-induced acute phase reaction and evaluate the different pharmacological, technical and surgical strategies used to reduce its effects. Emphasis is given to the central role of transcription factor NF-kappa B in the complex mechanism of the inflammatory reaction and to the effects of compounds such as heparin and glycosaminoglycans, phosphodiesterase inhibitors and protease inhibitors whose role as anti-inflammatory agent has only recently been recognized.

Acute Kidney Injury After Cardiac Surgery Focus on Modifiable Risk Factors

Background— Acute kidney injury (AKI) after cardiac surgery is a major health issue. Lacking effective therapies, risk factor modification may offer a means of preventing this complication. The objective of the present study was to identify and determine the prognostic importance of such risk factors. Methods and Results— Data from a multicenter cohort of 3500 adult patients who underwent cardiac surgery at 7 hospitals during 2004 were analyzed (using multivariable logistic regression modeling) to determine the independent relationships between 3 thresholds of AKI (>25%, >50%, and >75% decrease in estimated glomerular filtration rate within 1 week of surgery or need for postoperative dialysis) with death rates, as well as to identify modifiable risk factors for AKI. The 3 thresholds of AKI occurred in 24% (n=829), 7% (n=228), and 3% (n=119) of the cohort, respectively. All 3 thresholds were independently associated with a >4-fold increase in the odds of death and could be predicted with several perioperative variables, including preoperative intra-aortic balloon pump use, urgent surgery, and prolonged cardiopulmonary bypass. In particular, 3 potentially modifiable variables were also independently and strongly associated with AKI. These were preoperative anemia, perioperative red blood cell transfusions, and surgical reexploration. Conclusions— AKI after cardiac surgery is highly prevalent and prognostically important. Therapies aimed at mitigating preoperative anemia, perioperative red blood cell transfusions, and surgical reexploration may offer protection against this complication.

Fundamentals of Reperfusion Injury for the Clinical Cardiologist

Case presentation: S.B. is a 48-year-old man who suffered an acute anterior myocardial infarction and received fibrinolytic therapy. The patient died ≈12 hours after reperfusion. K.R. is a 68-year-old diabetic woman who underwent conventional coronary artery bypass graft surgery and developed low output syndrome after reperfusion postoperatively. V.A. is a 55-year-old man who developed a stunned myocardium after percutaneous coronary reperfusion. What is reperfusion injury, and why is it important? Reperfusion of coronary flow is necessary to resuscitate the ischemic or hypoxic myocardium. Timely reperfusion facilitates cardiomyocyte salvage and decreases cardiac morbidity and mortality. Reperfusion of an ischemic area may result, however, in paradoxical cardiomyocyte dysfunction, a phenomenon termed “reperfusion injury.” Modalities for reperfusion include not only thrombolysis, but also percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), and cardiac transplantation. Reperfusion injury has been observed in each of these situations. We discuss here the fundamental principles of reperfusion injury from a mechanistic and pharmacological standpoint. ### What is reperfusion injury, and why is it important? The myocardium can tolerate brief periods (up to 15 minutes) of severe and even total myocardial ischemia without resultant cardiomyocyte death. Although the cardiomyocytes suffer ischemic injury, the damage is reversible with prompt arterial reperfusion. Indeed, such transient periods of ischemia are encountered in the clinical situations of angina, coronary vasospasm, and balloon angioplasty, and are not associated with concomitant myocyte cell death.1,2⇓ With increasing duration and severity of ischemia, however, greater cardiomyocyte damage can develop, with a predisposition to a spectrum of reperfusion-associated pathologies, collectively called reperfusion injury.3 Reperfusion injury results in myocyte damage through myocardial stunning, microvascular and endothelial injury, and irreversible cell damage or necrosis (termed lethal reperfusion injury; Figure 1).3,4⇓ Figure 1. Mechanisms and mediators of reperfusion injury. Reperfusion strategies are required to resuscitate the ischemic myocardium. In the clinical realm, these include …

A propensity score case‐control comparison of aprotinin and tranexamic acid in high‐transfusion‐risk cardiac surgery

BACKGROUND:  Cardiac surgery with cardiopulmonary bypass may result in excessive fibrinolysis and platelet (PLT) dysfunction, resulting in impaired hemostasis and excessive blood loss. Prophylactic use of the antifibrinolytic drugs aprotinin and tranexamic acid is thought to prevent these hemostatic defects. Their relative clinical utility and safety in high‐transfusion‐risk cardiac surgery, however, is not known.

The independent association of massive blood loss with mortality in cardiac surgery

BACKGROUND:  Although the association between massive perioperative blood loss (MBL) and adverse outcomes is well recognized, it is unclear whether MBL is an independent risk factor or, instead, simply a marker for other adverse events or severity of illness. The objective of this cohort study was to quantify the independent association of MBL in cardiac surgery with all‐cause in‐hospital mortality.

Construction of a bioengineered cardiac graft

OBJECTIVES Currently available graft materials for repair of congenital heart defects cause significant morbidity and mortality because of their lack of growth potential. An autologous cell-seeded graft may improve patient outcomes. We report our initial experience with the construction of a biodegradable graft seeded with cultured rat or human cells and identify their 3-dimensional growth characteristics. METHODS Fetal rat ventricular cardiomyocytes, stomach smooth muscle cells, skin fibroblasts, and adult human atrial and ventricular cardiomyocytes were isolated and cultured in vitro. These cells were injected into or laid onto biodegradable gelatin meshes, and their rate of proliferation and spatial location within the mesh was evaluated by using a cell counter and histologic analysis. RESULTS Rat cardiomyocytes, smooth muscle cells, and fibroblasts demonstrated steady proliferation over 3 to 4 weeks. The gelatin mesh was slowly degraded, but this process was most rapid after seeding with fibroblasts. Human atrial cardiomyocytes proliferated within the gelatin meshes but at a slower rate than that of fetal rat cardiomyocytes. Human ventricular cardiomyocytes survived within the gelatin mesh matrix but did not increase in number during the 2-week duration of evaluation. Grafts seeded with rat ventricular cells exhibited spontaneous rhythmic contractility. All cell types preferentially migrated to the uppermost surface of each graft and formed a 300- to 500-microm thick layer. CONCLUSIONS Fetal rat ventricular cardiomyocytes, gastric smooth muscle cells, skin fibroblasts, and adult human atrial cardiomyocytes can grow in a 3-dimensional pattern within a biodegradable gelatin mesh. Similar autologous cell-seeded constructs may eventually be applied to repair congenital heart defects.

Recombinant factor VIIa for intractable blood loss after cardiac surgery: a propensity score-matched case-control analysis.

BACKGROUND:  Cardiac surgery is occasionally complicated by massive blood loss that is refractory to standard hemostatic interventions. Recombinant factor VIIa (rF‐VIIa) is being increasingly used as rescue therapy in such cases, but little information is available on its safety and efficacy for this indication.

Autologous porcine heart cell transplantation improved heart function after a myocardial infarction.

OBJECTIVE Fetal cardiomyocyte transplantation improved heart function after cardiac injury. However, cellular allografts were rejected despite cyclosporine (INN: ciclosporin) therapy. We therefore evaluated autologous heart cell transplantation in an adult swine model of a myocardial infarction. METHODS In 16 adult swine a myocardial infarction was created by occlusion of the distal left anterior descending coronary artery by an intraluminal coil. Four weeks after infarction, technetium 99m-sestamibi single photon emission tomography showed minimal perfusion and viability in the infarcted region. Porcine heart cells were isolated and cultured from the interventricular septum at the time of infarction and grown in vitro for 4 weeks. Through a left thoracotomy, either cells (N = 8) or culture medium (N = 8) was injected into the infarct zone. RESULTS Four weeks after cell transplantation, technetium 99m-sestamibi single photon emission tomography demonstrated greater wall motion scores in the pigs receiving transplantation than in control animals (P =.01). Pigs receiving transplantation were more likely to have an improvement in perfusion scores (P =.03). Preload recruitable stroke work (P =.009) and end-systolic elastance (P =. 02) were greater in the pigs receiving transplantation than in control animals. Scar areas were not different, but scar thickness was greater (P =.02) in pigs receiving transplantation. Cells labeled with bromodeoxyuridine in vitro could be identified in the infarct zone 4 weeks after transplantation. Swine receiving transplantation gained more weight than control animals (P =.02). CONCLUSION Autologous porcine heart cell transplantation improved regional perfusion and global ventricular function after a myocardial infarction.

The efficacy of the Cox/maze procedure combined with mitral valve surgery: a matched control study

OBJECTIVE To evaluate the results of the maze procedure combined with mitral valve (MV) surgery in patients with chronic atrial fibrillation (AF). METHODS From 1994--1999, 47 patients with chronic AF underwent the maze procedure combined with MV surgery (maze group). They were compared to 47 patients matched for age, sex, left ventricular function and type of MV surgery (non-maze group). The maze group had less severe symptoms but larger left atrium, and AF of longer duration than the non-maze group. One surgeon performed all operations in both groups of patients. RESULTS There were two early deaths in the maze group (4.5%) and one (2.2%) in the non-maze group. The duration of cardiopulmonary bypass (P=0.0001) and aortic crossclamping (P=0.0001) were greater in the maze group. Mean follow-up was 26+/-3 months in the maze group and 32+/-4 months in the non-maze group, and was 100% complete. Three-year survival was 96+/-3% for the maze group compared to 85+/-7% for the non-maze group (P=0.16). At the latest follow-up, 75% of the maze patients were in sinus rhythm compared to 36% of the non-maze patients (P=0.0004); 38% of the maze group were on coumadin postoperatively, compared to 69% in the non-maze group (P=0.003); and patients in the maze group were on fewer antiarrhythmic medications (P=0.0002). Three-year freedom from thromboembolic complications was 100% for the maze group compared to 83+/-7% for the non-maze group (P=0.03). CONCLUSIONS In this retrospective study the maze procedure did not seem to increase operative mortality of MV surgery, was effective in eliminating atrial fibrillation, and reduced the risk of thromboembolic complications and the need for long-term anticoagulation after mitral valve repair or replacement with a bioprosthesis.

Fetal cell transplantation: A comparison of three cell types☆☆☆★★★

OBJECTIVE We have previously reported that fetal cardiomyocyte transplantation into myocardial scar improves heart function. The mechanism by which this occurs, however, has not been elucidated. To investigate possible mechanisms by which cell transplantation may improve heart function, we compared cardiac function after transplantation of 3 different fetal cell types: cardiomyocytes, smooth muscle cells (nonstriated muscle cells), and fibroblasts (noncontractile cells). METHODS A left ventricular scar was created by cryoinjury in adult rats. Four weeks after injury, cultured fetal ventricular cardiomyocytes (n = 13), enteric smooth muscle cells (n = 10), skin fibroblasts (n = 10), or culture medium (control, n = 15 total) were injected into the myocardial scar. All rats received cyclosporine A (INN: ciclosporin). Four weeks after transplantation, left ventricular function was evaluated in a Langendorff preparation. RESULTS The implanted cells were identified histologically. All transplanted cell types formed tissue within the myocardial scar. At an end-diastolic volume of 0.2 mL, developed pressures in cardiomyocytes group were significantly greater than smooth muscle cells and skin fibroblasts groups (cardiomyocytes, 134% +/- 22% of control; smooth muscle cells, 108% +/- 14% of control; skin fibroblasts, 106% +/- 17% of control; P =.0001), as were +dP/dt(max) (cardiomyocytes, 119% +/- 37% of control; smooth muscle cells, 98% +/- 18% of control; skin fibroblasts, 92% +/- 11% of control; P =. 0001) and -dP/dt(max) (cardiomyocytes, 126% +/- 29% of control; smooth muscle cells, 108% +/- 19% of control; skin fibroblasts, 99% +/- 16% control; P =.0001). CONCLUSIONS Fetal cardiomyocytes transplanted into myocardial scar provided greater contractility and relaxation than fetal smooth muscle cells or fetal fibroblasts. The contractile and elastic properties of transplanted cells determine the degree of improvement in ventricular function achievable with cell transplantation.