De novo alloreactive memory CD8+ T cells develop following allogeneic challenge when CNI immunosuppression is delayed.

Allospecific memory T cells are a recognized threat to the maintenance of solid-organ transplants. Limited information exists regarding the development of alloreactive memory T cells when post-transplant immunosuppression is present. The clinical practice of delaying calcineurin inhibitor (CNI) initiation post-transplant may permit the development of a de novo allospecific memory population. We investigated the development of de novo allospecific memory CD8+ T cells following the introduction of CNI immunosuppression in a murine model using allogeneic cell priming. Recipient mice alloprimed with splenocytes from fully mismatched donors received cyclosporine (CyA), initiated at 0, 2, 6, or 10days post-prime. Splenocytes from recipients were analyzed by flow cytometry or enzyme-linked immunosorbent assay for evidence of memory cell formation. Memory and effector CD8+ T cell development was prevented when CyA was initiated at 0day or 2days post-prime (p<0.001), but not 6days post-prime. Following a boost challenge, these memory CD8+ T cells were capable of producing a similarly sized population of secondary effectors as recipients not treated with CyA (p>0.05). Delaying CyA up to 6days or later post-prime permits the development of functional de novo allospecific memory CD8+ T cells. The development of this potentially detrimental T cell population in patients could be prevented by starting CNI immunosuppression early post-transplant.

C. sinensis ablates allograft vasculopathy when used as an adjuvant therapy with cyclosporin A.

Immunosuppressive treatments are available to suppress acute cardiac rejection; however, no viable treatment exists for long-term cardiac graft failure. Moreover, extended use of calcineurin inhibitor immunosuppressants, the mainstay of the current therapeutic for cardiac transplantation, leads to significant associated pathologies such as nephrotoxicity and increased risk of cardiac disease. For the last ten years alternatives to calcineurin inhibitors, or adjuvant therapies designed to complement their activities, have been explored. In tandem with this development, there has been considerable interest in Traditional Chinese Medicines (TCM) as sources for novel therapeutics. Our study examines the ability of the TCM Cordyceps sinensis to reduce acute and chronic rejection associated with cardiac transplantation. The objectives of this study were to first determine if oral delivery of the extract could reduce acute rejection in a rat heterotopic heart model of transplantation. The second objective was to determine, in vitro, if a sterile, aqueous extract of C. sinensis could decrease CD8+ T cell activity. The third objective was to determine if oral delivery of the extract could ablate allograft vasculopathy in a mouse abdominal aortic transplant model. We found that oral delivery of the extract demonstrated a reduction in acute rejection when used in conjunction with a sub-therapeutic dose of Cyclosporine. Further, we found, using a mixed lymphocyte reaction, that the extract was able to significantly reduce CD8+ T cell activity. Finally, we demonstrate that oral delivery of the extract, used with a therapeutic dose of Cyclosporine to suppress acute rejection, ablates allograft vasculopathy.

Composite arterial grafts versus conventional grafting for coronary artery bypass grafting.

OBJECTIVES: Composite arterial grafts for coronary artery bypass grafting surgery allow complete arterial revascularization but are limited by the inflow of a single internal thoracic artery supplying all the grafted vessels. We reviewed the safety of composite arterial grafts using either bilateral internal thoracic arteries or a single internal thoracic artery and radial artery. METHODS: From January 1999 to July 2002, 402 consecutive patients receiving composite grafts only were compared to a control group of patients (n = 542) undergoing coronary artery bypass grafting with internal thoracic artery and saphenous veins operated upon by the same surgeons. Two different statistical approaches were used to compare groups in this retrospective analysis. First, propensity score analysis with greedy matching technique was used to match patients from each group. Second, a multivariate analysis was performed looking at a combined patient outcome of death, intra-aortic balloon counterpulsation utilization, myocardial infarction, stroke, and prolonged ventilation on all patients in both groups. RESULTS: After matching by propensity score, the major clinical outcomes in composite arterial (n = 249) and control (n = 249) groups were found to be similar. The in-hospital mortality in the composite group was 1.2% as compared with 0.4% in matched patients (P =.62). However, patients in the composite group were found to have a significantly longer pump time (P <.0001), longer clamp time (P <.0001), increased incidence of prolonged mechanical ventilation (12.8% vs 4.8%; P =.002), and higher incidence of combined morbidity outcome (13.6% vs 6.4%; P =.007) as compared with matched patients. Multivariable analysis showed that composite arterial grafting was an independent predictor of the combined morbidity outcome with an odds ratio of 2.1 (1.2-3.7). CONCLUSIONS: These findings suggest that composite arterial grafting may be associated with an increase in risk-adjusted patient morbidity when compared with a conventional coronary artery bypass grafting group, although a mortality difference was not demonstrable.

ICU readmission after cardiac surgery.

OBJECTIVES: The increasing cost of intensive care unit (ICU) care and limited resources lead us to evaluate predictors of ICU readmission in a large group of patients undergoing coronary artery bypass surgery (CABG) at one institution. METHODS: Two thousand one hundred and seventeen consecutive patients undergoing CABG surgery between January 1999 and August 2001 were reviewed retrospectively. The reasons for readmission were determined by reviewing the physician's progress notes, the nurse's progress notes and the discharge summary. RESULTS: A total of 75 patients were readmitted to ICU during the study period for a readmission rate of 3.6%. Eight of these were readmitted a second time, and three a third time, for a total of 86 readmissions. Forty-seven patients died, for a mortality of 2% among patients that were not readmitted to the ICU, compared to 17% among those who were readmitted (P<0.0001). Median hospital length of stay was 6 days for patients not readmitted and 23 days for those readmitted (P<0.0001). The most common reason for readmission was respiratory failure, accounting for 47% of readmissions (n=40). Multivariate analysis using a stepwise logistic regression analysis revealed that preoperative renal failure (odds ratio 2.13; CI 1.03-4.41) and prolonged mechanical ventilation of >24 h (odds ratio 10.52; CI 6.18-17.91) were the only independent predictors for readmission to the ICU after CABG. CONCLUSIONS: Identification of patients that have preoperative renal failure or that required initial ventilation for more than 24 h after CABG may help to identify patients at risk of ICU readmission. Preemptive strategies designed to optimize these high-risk patients may improve outcomes.

Use of autologous blood as part of the perfusate for cardiopulmonary bypass: a priming technique.

In an attempt to replace the oncotic and protein coating capabilities of serum albumin in the perfusate, we established a priming protocol that used autologous blood as part of the perfusate solution. Prior to March 1, 1999, our standard priming protocol was 1650 ml of crystalloid with 250 ml of 5% serum albumin and 5,000 units of heparin. After removing albumin from our prime, our standard protocol was altered to include 40 ml of the patient's autologous blood in 1,800 ml of crystalloid and 10,000 units of heparin. To determine the intraoperative effects of using albumin/crystalloid primes (Group A), autologous blood/crystalloid primes (Group B) and crystalloid primes (Group C), a total of 178 patients were sequentially evaluated. Intraoperative parameters evaluated were total protein (TP), colloid osmotic pressure (COP), platelets (Plts) and fluid requirements during cardiopulmonary bypass (CPB). During an overlapping 12-month period of time, 1,092 consecutive cardiac surgical cases using CPB (584 albumin prime; 508 autologous blood prime) were evaluated for clinical outcomes in terms of mortality and length of hospitalization. In addition, over a period of 15 months, 1,458 patients in both the autologous blood/crystalloid group and the crystalloid only group were evaluated for the incidence of high-pressure excursions (HPE) after going on bypass. Comparative reviews of TP, COP and Plts demonstrated no significant difference 10 min after the start of bypass between Groups A and B. However, in Group C, there was a statistically significant increase in the intraoperative fluid requirements during CPB, compared to both of the other groups. There was no significant difference in the incidence of HPE, with an occurrence of 1.04% in the crystalloid only group and 1.11% in the autologous blood/crystalloid group. Autologous blood perfusates were identical to albumin perfusates in their platelet protection and reduction of fluid shifts during the intraoperative period.

Assessment of new onset postcoronary artery bypass surgery atrial fibrillation: current practice pattern review and the development of treatment guidelines.

BACKGROUND: The incidence of postcoronary artery bypass graft (CABG) atrial fibrillation (AF) is 22.5% at the QEII Health Sciences Centre and the mean length of stay is 5.5 days greater than for those patients who do not experience this complication. Appropriate pharmacological management is important to prevent the potential morbidity from AF, such as thromboembolism, congestive heart failure, cardiogenic shock and coronary ischemia. This project compared current practice patterns in the management of post-CABG AF with local practice pattern beliefs and evidence from the primary literature. Subsequently, treatment guidelines were designed to help guide a rationale treatment approach. OBJECTIVE: To promote appropriate treatment strategies for post-CABG AF and increase local practitioner awareness of drug-use outcomes by developing consensus treatment guidelines. DESIGN: There were three phases. In phase 1, a retrospective chart analysis of 35 post-CABG AF patients over three consecutive months was conducted to assess current practice patterns. All published studies on this subject were also collected and analysed. A survey of pharmacological treatment preferences was distributed to local stakeholders during phase 2. The third phase involved the development and implementation of treatment guidelines. RESULTS: This study identified a highly variable approach to the treatment of post-CABG AF. The mean number of agents used to treat AF post-CABG was two (range 1-4); all patients (100%) were prescribed rate-controlling agents and 37% were prescribed an antiarrhythmic drug. There was also a mismatch between practice pattern beliefs and actual practice. CONCLUSIONS: This reinforced the need for a consistent treatment approach that was facilitated with the development and implementation of local guidelines.

Preoperative prediction of prolonged mechanical ventilation following coronary artery bypass grafting.

OBJECTIVE: Few studies have attempted to evaluate who would require prolonged mechanical ventilation following heart surgery. The objectives of this study were to identify predictors of prolonged ventilation in a large group of coronary artery bypass grafting (CABG) patients from a single institution. METHODS: One thousand, eight hundred and twenty-nine consecutive patients undergoing CABG were reviewed retrospectively and evaluated for preoperative predictors of prolonged ventilation which included: age, gender, ejection fraction (EF), renal function, diabetes, angina status, New York Heart Association Class, number of diseased vessels, urgency of the procedure, re-operation, chronic lung disease (COPD) and intraoperative variables such as IABP, inotropes, stroke and myocardial infarction. Prolonged ventilation was defined as > or = 24 h. Stepwise logistic regression analysis was performed. RESULTS: Patients were on average 65.4+/-10.6 years of age, 30% were diabetic, 80% had triple vessel disease and 93% were of functional class III/IV. The mean ejection fraction was 60+/-16 percent. Overall peri-operative mortality was 2.7%. There were 157 patients that required prolonged ventilation with a peri-operative mortality of 18.5% (P < 0.001). Preoperative independent predictors of prolonged ventilation were found to be: unstable angina (OR 5.6), EF < 50 (OR 2.3), COPD (OR 2.0), preop. renal failure (OR 1.9), female gender (OR 1.8) and age > 70 (OR 1.7). Based on these predictors, a model was created to estimate of the risk of prolonged ventilation in individual patients following CABG with results ranging from < or = 3% in patients without any risk factors to > or = 32% in patients with five or more independent risk factors. Certain intraoperative variables were strong predictors of prolonged ventilation and included: stroke (OR 12.3), re-operation for bleeding (OR 6.9) and perioperative MI (OR 5.8). CONCLUSION: We were able to create a stable model where several preoperative and intra-operative variables were shown to be predictive of prolonged ventilation after CABG surgery. The ability to identify patients at increased risk for prolonged ventilation may allow the development of pre-emptive strategies and more effective resource allocation.

Waiting for cardiac surgery: results of a risk-stratified queuing process.

BACKGROUND: The Queen Elizabeth II Health Sciences Centre uses a weekly peer-review conference of cardiovascular experts to prioritize each surgical case to 1 of 4 queues with the use of standardized criteria of coronary anatomy, stress test result, and symptoms. We examined the hazard of waiting as well as the impact of waiting on surgical outcomes. METHODS AND RESULTS: Analysis was performed for 2102 consecutive patients queued for CABG, aortic valve replacement, or CABG+aortic valve replacement between January 1, 1998, and December 31, 1999. Among 1854 patients undergoing surgery, median waiting times on the respective queues were as follows: in-house urgent group, 8 days; semiurgent A group, 37 days; semiurgent B group, 64 days; and elective group, 113 days. There were 13 deaths (12 cardiac) that occurred during the waiting period (0.7% of the patients). Of the 8.7% patients upgraded to a more urgent queue, 86.1% required hospitalization before surgery. Although female sex was not associated with prolonged waiting time, it was predictive of urgent status (P=0.001). The incidence of postoperative complications was 25.0%, and operative mortality was 2.86%. Both were more frequent among patients undergoing surgery early (P=0.01); however, this difference was attributable to the in-house urgent queue. The median length of stay was 7 days for all patients and was not affected by waiting time. CONCLUSIONS: Death and upgrades while the patients were waiting tended to occur early in the queuing process, and prolonged waiting was not associated with worse surgical outcomes. The cost of reducing waiting times could in part be offset by prevention of hospital admissions among upgraded patients.

Transmyocardial laser revascularization remodels the intrinsic cardiac nervous system in a chronic setting.

BACKGROUND: Prospective trials have demonstrated that transmyocardial laser revascularization (TMLR) imparts symptomatic relief to patients with refractory angina. Because peak clinical effectiveness of TMLR is usually delayed by several months, it has been proposed that ventricular denervation is one mechanism whereby TMLR imparts symptomatic relief. We have demonstrated that TMLR does not denervate the heart in the acute setting, nor does it modify the intrinsic cardiac nervous system (ICNS) in the acute setting. However, the long-term effects of TMLR on the ICNS remain unknown. METHODS AND RESULTS: A holmium:yttrium-aluminum-garnet laser created 20 channels through the anterolateral left ventricular free wall of 10 dogs. Four weeks later, the function of cardiac sensory inputs to the ICNS was studied by applying veratridine (7.5 micromol/L) to ventricular sensory fields. Chronotropic and inotropic responses elicited by cardiac sympathetic or parasympathetic efferent neurons stimulated electrically (10 Hz, 4 V, 4 ms) or chemically (nicotine 5 to 20 microgram/kg IV) were also assessed. Chemical activation of epicardial sensory neurites with veratridine elicited expected ICNS excitatory responses. Electrical stimulation of sympathetic and parasympathetic efferent neurons induced expected altered cardiac responses. In contrast, the responsiveness of the ICNS to systemically administered nicotine was obtunded. CONCLUSIONS: Although chronic TMLR does not affect cardiac afferent or extracardiac efferent neuronal function, it does "remodel" the ICNS so that its responsiveness to a known potent chemical agonist (ie, nicotine) becomes obtunded. Remodeling of the ICNS may account in part for the delayed symptomatic relief that TMLR imparts to patients with refractory angina.

Prevention of allograft heart valve failure in a rat model.

OBJECTIVE: Allograft heart valves are commonly used in cardiac surgery. Despite mounting evidence that these valves are immunogenic, leading to premature failure, current clinical practice does not attempt to minimize or control such a response. The objective of this study was to evaluate immune modulatory approaches to ameliorate allograft valve failure in a rat model. METHOD: Aortic valve grafts were implanted infrarenally into Lewis rat recipients (n = 32). There were 4 transplant groups: syngeneic grafts (Lewis to Lewis), untreated allografts (Brown Norway to Lewis), allograft recipients treated with cyclosporine (INN: ciclosporin) (10 mg/kg per day for 7 or 28 days), and allograft recipients treated with anti-alpha4 integrin and anti-beta2 integrin monoclonal antibodies for 7 days. At 7 and 28 days the valves were examined for structural integrity and cellular infiltration. RESULTS: Both cyclosporine and anti-alpha4/beta2 integrin treatment resulted in significant reduction in leaflet infiltration by macrophages (ED1(+)), T cells (CD3(+)), and CD8(+) T cells at 7 days with preservation of structural integrity when compared with control allografts. Twenty-eight days after implantation, daily treatment with cyclosporine preserved leaflet structural integrity and inhibited cellular infiltration. However, a short course of cyclosporine (7 days) failed to prevent destruction of the valves at 28 days. CONCLUSIONS: Immune modulatory approaches aimed at T-cell activation or trafficking decrease leaflet cellular infiltration and prevent allograft valve structural failure. However, short-course therapy does not appear to be sufficient and must be maintained to allow long-term preservation of leaflet structural integrity (28 days).

Function of human intrinsic cardiac neurons in situ.

We sought to determine the behavior of intrinsic cardiac neurons in human subjects undergoing cardiac surgery and to correlate their activity with hemodynamics status. A lead II electrocardiogram, pulmonary artery pressure, and systemic arterial pressure were recorded along with extracellular activity generated by right atrial neurons in 10 patients undergoing coronary artery bypass surgery. Identified neurons generated spontaneously activity that was, for the most part, unrelated to the cardiac cycle. Most neurons were activated by gentle mechanical distortion of ventricular epicardial loci. The activity generated by neurons in each patient increased when arterial pressure increased and decreased when arterial pressure fell. Intrinsic cardiac neurons continued to generate activity during cardioplegia and cardiopulmonary bypass, but at reduced levels. Normal neuronal activity was restored postbypass. It is concluded that human intrinsic cardiac neurons generate spontaneous activity and that many receive inputs from ventricular mechanosensory neurites. The latter may account for the fact that their behavior depends, in part, on cardiac dynamics. They are also sensitive to intravenously administered pharmacological agents. These data also indicate that cardiopulmonary bypass and cardioplegia do not induce residual depression of their function.

Thrombosed giant coronary artery aneurysm presenting as an intracardiac mass.

Giant coronary artery aneurysms are rare in adults and are usually found in association with Kawasaki's disease arising in childhood. We report a case of a thrombosed giant right coronary artery aneurysm presenting as an intracardiac mass detected after inferior wall myocardial infarction. Histologic analysis indicated that fibromuscular dysplasia was the underlying cause of the aneurysm.

Double valve replacement in a patient with anticardiolipin antibody syndrome.

Cardiopulmonary bypass (CPB) was used during the replacement of the aortic and mitral valves in a 43-year-old female patient. The case was complicated by the presence of a rare hypercoagulable condition called anticardiolipin (antiphospholipid) antibody syndrome. The course of bypass was uneventful and the patient was released from the intensive care unit on the first postoperative day. CPB in the presence of anticardiolipin antibodies is an unusual situation that requires diligent hematological monitoring. Since 1989 there have been only 14 reported cases of these antibodies and cardiopulmonary bypass. Eight of these have involved valve replacements.

Transmyocardial laser revascularization does not denervate the canine heart.

BACKGROUND: Transmyocardial laser revascularization has been used as an indirect approach to improve myocardial perfusion in patients with refractory angina not amenable to conventional therapy. Three mechanisms have been proposed for its therapeutic effects: direct perfusion of the ischemic myocardium through patent channels; induction of angiogenesis; and regional denervation. We sought to determine whether transmyocardial laser revascularization modifies afferent and efferent axonal function within the affected myocardium. METHODS: Studies were performed in 9 dogs that were artificially ventilated and underwent thoracotomy. Changes in ventricular dynamics and intrinsic cardiac neuronal activity were monitored before and after creating 20 transmural channels in the left ventricular ventral free wall with a holmium:yttrium-aluminum-garnet laser in response to three stimuli: application of veratridine or bradykinin to the epicardial sensory neurites of intrinsic cardiac afferent neurons; sympathetic or parasympathetic efferent neuronal activation either electrically (4 V, 10 Hz, 5 ms) or chemically (nicotine, 5 microg/kg intravenously), and direct cardiomyocyte beta-adrenergic receptor stimulation (isoproterenol hydrochloride, 5 microg intravenously). RESULTS: Sensory neurites of right atrial afferent neurons in the studied epicardial region responded similarly to chemical stimulation before and after transmyocardial laser revascularization. Transmyocardial laser treatment did not reduce local ventricular contractile responses to direct activation of sympathetic or parasympathetic efferent neurons by electrical or chemical means, nor did it affect cardiomyocyte augmentor responses elicited by exogenous beta-adrenergic receptor challenge. CONCLUSIONS: As transmyocardial laser revascularization does not affect afferent or efferent axonal function in the affected ventricle, the efficacy of this form of therapy cannot be ascribed to local denervation.