Serial evaluation of lipid profiles and risk factors for development of hyperlipidemia after cardiac transplantation.

To determine the prevalence, time course and factors responsible for hyperlipidemia after heart transplantation, 83 consecutive 1-year survivors were studied. By 1 year, 83% of patients had serum total cholesterol levels greater than 5.2 mmol/liter (200 mg/dl) and 28% of the patients had serum total cholesterol higher than the age- and sex-matched ninety-fifth percentile. At the end of 1-year follow-up, serum total cholesterol correlated with the recipient age (p less than 0.0001), the preoperative cholesterol level (p less than 0.001), the actual dose of maintenance prednisone at 1 year (p less than 0.02) and the cumulative 1-year steroid dose (p less than 0.03). Similarly, the serum triglyceride level at 1 year correlated with the pretransplant level of serum triglycerides (p less than 0.0001), recipient age (p less than 0.03) and cumulative 1-year steroid dose (p less than 0.03). Patients with a pretransplant diagnosis of coronary artery disease had a significantly higher level of serum total cholesterol and triglyceride levels at 1 year (p less than 0.02 and p less than 0.03, respectively). Heart transplant recipients with body mass index greater than or equal to 25 kg/m2 also presented with significantly elevated serum total cholesterol and triglyceride levels at 1 year compared with nonobese patients (p less than 0.01 and p less than 0.002, respectively). Hyperlipidemia occurs frequently and is detected within the first month after heart transplantation. Optimal management of this problem requires further study.

Evolution of heart rate responsiveness after orthotopic cardiac transplantation.

Although anatomic reinnervation of the donor heart is unlikely after transplantation, individual subjects have been noted to show near physiologic heart rate (HR) responses to exercise. To assess development of this phenomenon, we studied HR changes in response to orthostasis and treadmill exercise in 52 orthotopic cardiac transplant recipients grouped according to time after transplantation. In group 1 (2.0 +/- 0.9 months), no significant increase in HR was seen up to 100 cardiac cycles after standing. A maximal acceleration of 4.0 +/- 3.8 beats was seen within 100 cardiac cycles after standing in group 2 (15.8 +/- 5.6 months). Patients in group 3 (42.4 +/- 12.4 months) showed significant cardioacceleration by 5 cardiac cycles after standing to a maximum of 10.7 +/- 5.8 beats/min within the first 100 cardiac cycles. During exercise, HR increased more rapidly during the first minute in group 3 compared with group 1 (p less than 0.01). After exercise, HR continued to increase in group 1 but decreased rapidly in the other groups, most notably group 3 (-26.5 +/- 16.5 by 2 minutes, p less than 0.0001 vs groups 1 and 2). These data indicate development of functional reinnervation after orthotopic heart transplantation. The phenomenon of early acceleration of the HR after orthostasis and rapid deceleration after exercise in transplant recipients implies a local cardiac mechanism rather than response to circulating catecholamines.

Frequency of angiographic detection and quantitative assessment of coronary arterial disease one and three years after cardiac transplantation.

The reported high incidence of coronary atherosclerosis in many transplant series led us to critically review our experience in 83 patients who have had selective coronary angiography at greater than or equal to 1 years after transplantation. Angiograms were reviewed for evidence of coronary vascular disease, and quantitative analysis of multiple coronary artery segments was performed in serial films. Qualitative analysis revealed only 3 of 83 patients with any angiographic abnormality at follow-up, 1 with minimal luminal irregularities in the right coronary artery at 1 year, a second with a 50% diameter stenosis of the proximal left anterior descending artery and minimal irregularity of the proximal circumflex artery at 1 year and a third patient who developed a new 30% diameter eccentric proximal right coronary artery stenosis at 3-year follow-up. The cumulative incidence of graft vascular disease assessed angiographically was therefore 2% at 1 year and 4% at 3 years. Quantitative analysis, however, showed a significant decrease in coronary artery luminal diameter over time. The mean left main coronary artery diameter decreased from 5.4 +/- 0.9 mm at 1 year to 4.7 +/- 0.8 mm at 3 years (p = 0.0007).(ABSTRACT TRUNCATED AT 250 WORDS)

Normalization of upright exercise hemodynamics and improved exercise capacity one year after orthotopic cardiac transplantation.

The mechanisms of improved functional capacity over the first year after cardiac transplantation are not well studied. To assess the contribution of cardiac changes to this improvement, the serial evolution of upright rest and exercise hemodynamics during graded upright bicycle exercise was studied in 17 patients at 3 and 12 months after heart transplantation. Heart rate responsiveness, reflected by rapid heart rate acceleration on sitting and rapid deceleration after exercise, developed in the first year. Pulmonary capillary wedge pressure was lower at 1 year, both at rest and at peak exercise (10 +/- 3 vs 13 +/- 5 mm Hg at rest supine and 14 +/- 6 vs 18 +/- 8 mm Hg at peak exercise, p less than 0.05). Similarly, right atrial pressures were also significantly lower at 1 year (4 +/- 2 vs 6 +/- 3 mm Hg at rest supine and 6 +/- 5 vs 11 +/- 5 mm Hg at peak exercise, p less than 0.05). Cardiac index at peak exercise was greater at 12 months (6.4 +/- 1.3 vs 5.8 +/- 0.8 liters/min/m2, p less than 0.05), mediated primarily by higher exercise heart rate (135 +/- 16 vs 125 +/- 12 beats/min, p less than 0.05). In the first year after heart transplantation, improved rest and exercise hemodynamics and heart rate responsiveness contribute significantly to the improved functional capacity observed in these patients.

Reduction in bleeding after heart-lung transplantation. The importance of posterior mediastinal hemostasis.

To reduce perioperative hemorrhage following heart-lung transplantation, several technical modifications were introduced in June 1988 to secure better posterior mediastinal hemostasis. The intraoperative and postoperative use of blood and blood products, as well as the chest tube drainage in the first 24 hours postoperatively, were compared in the seven patients operated on since June 1988 with the nine patients operated on before that date. Significant (p less than 0.05) reductions were demonstrated in the intraoperative and postoperative transfusion of packed cells, in the postoperative administration of fresh frozen plasma, and in the chest tube drainage within the first 24 hours postoperatively. The one-month and total hospital mortality rates were 6 percent and 12.5 percent, respectively. It is concluded that newer techniques to obtain optimal posterior mediastinal hemostasis have significantly reduced blood loss following heart-lung transplantation in our experience and have contributed to our excellent early postoperative results.

Aprotinin significantly decreases bleeding and transfusion requirements in patients receiving aspirin and undergoing cardiac operations.

BACKGROUND: Patients with heart disease are frequently maintained on a regimen of aspirin because of its ability to decrease thrombotic complications and reduce the prevalence of unstable angina and myocardial infarction. Aspirin-induced platelet acetylation also increases bleeding caused by impairment of platelet function during cardiac surgery. METHODS: Between October 1990 and November 1991 this double-blind, randomized, placebo-controlled, parallel group interventional study examined the efficacy of high-dose aprotinin administration (up to 7 million KIU) to decrease blood loss and transfusion requirements in patients receiving aspirin within 48 hours of undergoing coronary bypass or valvular heart operations. Primary outcome measures in this study were total volume of blood loss (intraoperative blood loss plus postoperative chest tube drainage) and volume of transfusion during hospitalization. RESULTS: Patients treated with aprotinin (n = 29) had significantly lower total blood loss (1409 +/- 232 ml versus 2765 +/- 248 ml; p = 0.0002), intraoperative blood loss (503 +/- 53 ml versus 1055 +/- 199 ml; p = 0.0001), postoperative blood loss (906 +/- 204 ml versus 1710 +/- 202 ml; p = 0.0074), and prevalence of transfusion (59% versus 88% of patients; p = 0.016) than the placebo group (n = 25). The prevalence of complications including myocardial infarction was similar in the two groups. CONCLUSIONS: High-dose aprotinin significantly reduces blood loss and red blood cell transfusions in patients receiving aspirin who undergo cardiac operations.

The importance of acquired diffuse bronchomalacia in heart-lung transplant recipients with obliterative bronchiolitis.

The results of heart-lung transplantation are improving with increasing experience in postoperative management, but obliterative bronchiolitis may still develop late postoperatively. We have performed 19 heart-lung transplants, with 1-month, 1-year, and 2-year actuarial survival rates of 95% +/- 5%, 84% +/- 8%, and 69% +/- 16%, respectively. Three early recipients died of bronchiolitis, and four patients who were operated on more than 2 years ago are currently being followed up with bronchiolitis. Since August 1988, 13 surviving recipients have undergone serial postoperative bronchoscopies and transbronchial biopsies with topical analgesia. Diffuse bronchomalacia, involving the main bronchi down to the fifth-order bronchi bilaterally, has developed in four patients with bronchiolitis 9 +/- 2 months after the diagnosis of bronchiolitis was confirmed. Pulmonary function tests have revealed a lower ratio of forced expiratory volume in 1 second to forced vital capacity, lower specific airway conductance, and higher airway resistance in heart-lung recipients with bronchomalacia than in patients with bronchiolitis alone. We conclude that diffuse bronchomalacia occurs frequently in heart-lung transplant recipients who have obliterative bronchiolitis. Bronchomalacia worsens the functional airflow obstruction caused by bronchiolitis and may play an important role clinically in the declining respiratory status of heart-lung transplant recipients.

Pulmonary retransplantation for obliterative bronchiolitis. Intermediate-term results of a North American-European series.

An international series of pulmonary retransplantation was updated to identify the predictors of survival in the intermediate-term after reoperation for obliterative bronchiolitis. The study cohort included 32 patients with end-stage obliterative bronchiolitis who underwent retransplantation in 15 North American and European centers between 1988 and 1992. Five types of retransplantation procedures were done, including repeat ipsilateral single lung transplantation (7 patients), repeat contralateral single lung transplantation (8 patients), repeat double lung transplantation (3 patients), double lung transplantation after a previous single lung transplantation (3 patients), and single lung transplantation after a previous double lung or heart-lung transplantation (11 patients). The mean interval between transplants was 564 +/- 51 days (range 187 to 1589 days). Postoperative follow-up was 100% complete and the average follow-up in surviving patients was 678 +/- 63 days. Actuarial survival was 72%, 53%, 50%, 41%, and 33% at 1, 3, 6, 12, and 24 months, respectively. Survival did not differ according to the age, preoperative diagnosis, ambulatory or ventilator status, or cytomegalovirus serologic status of the recipient before reoperation. Life-table and Cox proportional hazards analysis identified the type of retransplantation procedure and the year of reoperation as significant (p < 0.05) predictors of postoperative survival. Actuarial survival was significantly better in patients without an old, retained contralateral graft after retransplantation and in patients who underwent reoperation between 1990 and 1992, as opposed to between 1988 and 1989. Infection was the most common cause of death at all time intervals after retransplantation, although all deaths beyond 2 years resulted from obliterative bronchiolitis of the second graft. Most surviving patients are in a satisfactory clinical condition, with a mean forced expired volume in 1 second of 59% +/- 13% of predicted (repeat double lung transplant recipients) or 41% +/- 6% of predicted (repeat single lung transplant recipients). We conclude that pulmonary retransplantation for obliterative bronchiolitis is associated with significantly worse survival than after primary lung transplantation. The absence of an old contralateral graft after retransplantation and reoperation after 1989 are important predictors of survival. Additional data and follow-up are required to determine the merit of pulmonary retransplantation for obliterative bronchiolitis.

Heart transplantation after cardioverter-defibrillator implantation. A case control study.

A case control study was performed to determine whether previous implantable cardioverter-defibrillator (ICD) insertion adversely affects outcome after heart transplantation. Six male heart transplant recipients who had undergone ICD insertion 12 +/- 5 months before heart transplantation were compared to a cohort of six heart transplant recipients who were matched according to age, preoperative status and hemodynamics, date of transplantation, graft ischemic time, history of a previous cardiac operation, and duration of follow-up. There were no significant differences in operating room time, chest tube drainage, time to extubation, and the duration of intensive care unit or hospital stay between the two groups. Furthermore, there were no significant differences in the number of units of packed cells, fresh frozen plasma, platelets and cryoprecipitate transfused. The number of treated rejection episodes and the number of patients requiring intravenous antibiotics for infection in the first 90 days was identical between groups. It was concluded that heart transplantation after ICD implantation did not appear to carry more risk than heart transplantation after a previous cardiac operation. Our limited experience supports the potential use of the ICD in patients with life-threatening ventricular dysrhythmias who are awaiting transplantation.

New trends in lung preservation: a collective review.

Since the last review on lung preservation in 1985, enormous progress has been made in experimental and clinical lung transplantation. This comprehensive review examines recent advances in the experimental laboratory in optimizing conditions during organ procurement, lung storage, and reperfusion to minimize ischemia-reperfusion injury in lung allografts.

Redo lung transplantation: a North American-European experience.

An international survey of redo lung transplantation was performed to identify the morbidity and mortality rates and factors correlating with increased or decreased survival after this procedure. Twenty institutions in North America and Europe participated, and the study cohort included 61 patients who underwent 63 redo lung transplantation operations. Patients undergoing a redo heart-lung transplantation were excluded. The indications for reoperation included obliterative bronchiolitis (32 patients), graft failure (14 patients), intractable airway problems (8 patients), severe acute lung rejection (5 patients), and miscellaneous complications (4 patients). Five types of retransplantation procedures were performed, including redo ipsilateral single lung transplantation (24 patients), redo contralateral single lung transplantation (11 patients), single lung transplantation after double lung or heart-lung transplantation (13 patients), redo double lung transplantation (8 patients), and double lung transplantation after a previous single lung transplantation (7 patients). Actuarial survival was 65%, 49%, 42%, 35%, and 32% at 1, 3, 6, 12, and 24 months, respectively; survival was significantly (p < 0.05) worse than that of first-time lung transplant recipients recorded in the International Society for Heart and Lung Transplantation Registry. Actuarial survival did not differ according to the original diagnosis of the recipients, the indication for reoperation, or the type of retransplantation procedure performed. Similarly, recipient cytomegalovirus status and ventilator status before reoperation did not affect postoperative survival. Trends toward an improved outcome were noted in patients who were ambulatory before reoperation and in those receiving an ABO identical, as opposed to ABO compatible, graft at reoperation. Life table and step-wise logistic regression analysis identified donor cytomegalovirus status at reoperation to be an important determinant of outcome, with significantly (p < 0.05) improved survival in the donor cytomegalovirus-negative group. Polymicrobial infection was the most common cause of death at all time intervals after reoperation. The presence of disseminated infection and established multiorgan failure was almost uniformly associated with a fatal outcome. We conclude that redo lung transplantation may be indicated only in well-selected patients with obliterative bronchiolitis, severe airway complications, or graft failure. Donor cytomegalovirus status at reoperation is an important predictor of survival. The presence of disseminated infection and established multiorgan failure should be contraindications to lung retransplantation.

Extending cardiac allograft ischemic time and donor age: effect on survival and long-term cardiac function.

Of 219 heart transplant patients with follow up for at least 3 months after transplantation, cardiac allograft ischemic time was more than 4 hours in 28% and more than 5 hours in 10%. In 1988 and 1989 grafts with ischemic times longer than 4 hours were used in 44% and 45% of cases, respectively. Overall, donor age has been 35 or more years in 22% and 45 or more in 9%. In 1989 donor age was 35 or more years in 39% of cases and 45 or more in 18%. Fifteen of 20 grafts from donors 45 years or older were used for patients aged 50 or older. There was no relationship between donor age or ischemic time and 90-day graft loss. At 3 and 12 months, cardiac function, assessed by treadmill exercise duration, radionuclide angiography, and rest and peak supine exercise hemodynamics, was also unrelated to donor age or ischemic time. Therefore by careful selection of appropriate donors, extending both graft ischemic time and donor age has increased the potential donor pool and has not to date been associated with increased graft loss or adverse effects on cardiac function 3 months and 1 year after heart transplantation.

Successful use of the "unacceptable" heart donor.

Chronic shortage of donor organs has heightened interest in new strategies for increasing donor availability. Unacceptable hearts for transplant have previously been characterized by donor age greater than 40 years, more than 20% donor/recipient weight mismatch, ischemic time more than 4 hours, and the presence of coronary artery disease. A series of 185 consecutive orthotopic heart transplants were retrospectively examined. A significant number of donor hearts used were unacceptable by one or more of the above criteria. Our current approach is to match donors to recipients using a wide range of criteria. Donors are now accepted from any location in North America. We have accepted donors more than 55 years of age and donors weighing less than 50% of the recipient's body weight. Because of the chronic shortage of donor organs, donor criteria have been effectively liberalized, thereby increasing the donor pool without compromising the overall results of heart transplantation.

Basis for aerobic impairment in patients after heart transplantation.

BACKGROUND AND METHODS: To evaluate the physiologic basis for the suboptimal peak oxygen uptake observed after heart transplantation, we calculated the functional aerobic impairment ([(peak predicted oxygen uptake-peak observed oxygen uptake)/peak predicted oxygen uptake] x 100) and related it to donor/recipient, operative, and maximal exercise variables. Fifty-seven heart transplant recipients (mean age 50 +/- 10 years, 1 to 9 years after transplantation) underwent maximal upright cycle exercise testing. Concomitant exercise central hemodynamic measurements were obtained in 36 patients (63%). RESULTS: The mean peak oxygen uptake was 21.7 +/- 6.5 ml/kg/min and functional aerobic impairment was 34% +/- 17%. Functional aerobic impairment correlated positively (p < 0.01) with peak systemic vascular resistance (r = 0.55) and negatively with peak cardiac index (r = -0.62) and peak systemic arteriovenous oxygen difference (r = -0.66). A weak correlation was found between functional aerobic impairment and the duration of cardiac disease (r = 0.35, p < 0.01) but not the origin of heart failure. No correlation was seen between functional aerobic impairment and donor age, total ischemic time, time since transplantation, recipient age, and resting and exercise right and left ventricular filling pressures. CONCLUSIONS: These results suggest that the decreased exercise capacity observed in heart transplant recipients is in part due to increased peripheral vascular resistance and decreased oxygen extraction possibly due to skeletal muscle atrophy. These factors may be the result of irreversible changes from long-standing heart disease, deconditioning, or the effect of cyclosporine and prednisone.

The role of donor age and ischemic time on survival following orthotopic heart transplantation.

BACKGROUND: The advances in immunotherapy, along with a liberalization of eligibility criteria have contributed significantly to the ever increasing demand for donor organs. In an attempt to expand the donor pool, transplant programs are now accepting older donors as well as donors from more remote areas. The purpose of this study is to determine the effect of donor age and organ ischemic time on survival following orthotopic heart transplantation (OHT). METHODS: From April 1981 to December 1996 372 adult patients underwent OHT at the University of Western Ontario. Cox proportional hazards models were used to identify predictors of outcome. Variables affecting survival were then entered into a stepwise logistic regression model to develop probability models for 30-day- and 1-year-mortality. RESULTS: The mean age of the recipient population was 45.6 +/- 12.3 years (range 18-64 years: 54 < or = 30; 237 were 31-55; 91 > 56 years). The majority (329 patients, 86.1%) were male and the most common indications for OHT were ischemic (n = 180) and idiopathic (n = 171) cardiomyopathy. Total ischemic time (TIT) was 202.4 +/- 84.5 minutes (range 47-457 minutes). In 86 donors TIT was under 2 hours while it was between 2 and 4 hours in 168, and more than 4 hours in 128 donors. Actuarial survival was 80%, 73%, and 55% at 1, 5, and 10 years respectively. By Cox proportional hazards models, recipient status (Status I-II vs III-IV; risk ratio 1.75; p = 0.003) and donor age, examined as either a continuous or categorical variable ([age < 35 vs > or = 35; risk ratio 1.98; p < 0.001], [age < 50 vs > or = 50; risk ratio 2.20; p < 0.001], [age < 35 vs 35-49 versus > or = 50; risk ratio 1.83; p < 0.001]), were the only predictors of operative mortality. In this analysis, total graft ischemic time had no effect on survival. However, using the Kaplan-Meier method followed by Mantel-Cox logrank analysis, ischemic time did have a significant effect on survival if donor age was > 50 years (p = 0.009). By stepwise logistic regression analysis, a probability model for survival was then developed based on donor age, the interaction between donor age and ischemic time, and patient status. CONCLUSIONS: Improvements in myocardial preservation and peri-operative management may allow for the safe utilization of donor organs with prolonged ischemic times. Older donors are associated with decreased peri-operative and long-term survival following. OHT, particularly if graft ischemic time exceeds 240 minutes and if these donor hearts are transplanted into urgent (Status III-IV) recipients.

Reduced incidence of severe infection after heart transplantation with low-intensity immunosuppression.

Despite advances in immunosuppressive therapy and prolonged graft and patient survival, infection after heart transplantation remains problematic. From January 1987 through June 1989, 104 heart transplantations were performed in 100 patients. Immunosuppression induction was by antilymphocyte globulin for 7 days, with oral cyclosporine introduced on stabilization of kidney function (day 3). Steroid therapy was rapidly tapered, and azathioprine was added only in cases of positive donor crossmatch or steroid-resistant rejection. No reverse isolation was used. Twenty-two deaths occurred, one from sepsis. Actuarial survival at 6 months, at 1 year, and at 2 years was 85% +/- 4%, 81% +/- 3%, and 75% +/- 4%, respectively. Fifty-four patients had 81 infections, of which 21 were bacterial; 83% of these episodes were treated. Sixty infections were opportunistic (85% viral), and only 23% necessitated treatment. Actuarial infection-free rates (all types necessitating treatment) at 1 month, at 6 months, and at 2 years were 83% +/- 4%, 75% +/- 5%, and 75% +/- 5%, respectively. Of the 100 transplant recipients, 66% were treated with azathioprine; 47 patients (69%) had an infection, whereas only seven (19%) of the patients not receiving azathioprine became infected (p less than 0.00001). Rejection was noted in 66% of patients, with a median time to the first episode of 4 weeks. A low-intensity immunosuppressive regimen has resulted in fewer serious infections, with acceptable graft loss from rejection. Increased infection surveillance is required for the first 30 days postoperatively and after treatment of rejection episodes.

A prospective randomized controlled trial of initial immunosuppression with ALG versus OKT3 in recipients of cardiac allografts.

Thirty-nine heart transplant recipients were randomized prospectively to receive OKT3 or antilymphoblast globulin (ALG) for 7 days, having otherwise identical protocols (group 1: OKT3, n = 20 patients; group 2: ALG, n = 19 patients). No preoperative immunosuppression was given. The protocol consisted of methylprednisolone, 500 mg intraoperatively, followed by 1 mg/kg/day, intravenously or orally, tapering to 0.2 mg/kg/day at 1 month; oral cyclosporine starting 3 to 5 days after transplantation; selective use of azathioprine, 1 to 4 mg/kg/day; and either OKT3, 5 mg/day for 7 days, or ALG, 15 mg/kg/day for 7 days. Of the 39 patients in the study, 34 are alive 6 months to 2 years after transplantation. The actuarial survival at 2 years for the OKT3 and ALG groups was 92% (+/- 0.07%) and 83% (+/- 0.09%), respectively (not significant [NS]). The time to first rejection for group 1 was 5.6 weeks and for group 2 was 5.3 weeks (NS). The mean number of rejections for group 1 and group 2 was 2.1 episodes per patient and 1.4 per patient, respectively (NS). Three patients in each group were free of rejection at 6 months. The total number of infections at 6 months was 1.05 per patient in group 1, 0.74 per patient in group 2 (NS), with 35% of patients receiving OKT3 and 52% of patients receiving ALG actuarially free of infection by 6 months after surgery (NS). During the first 24 hours after surgery, no significant differences were noted in mean blood pressure, central venous pressure, or Po2 between the groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Phase I safety and pharmacokinetic studies of brequinar sodium after single ascending oral doses in stable renal, hepatic, and cardiac allograft recipients.

Brequinar sodium (BQR), a substituted 4-quinoline carboxylic acid, was in clinical development in combination with cyclosporine (CsA) as a potentially effective therapy for the treatment and prophylaxis of rejection in organ transplant patients. This phase I study was performed in stable renal, hepatic, and cardiac transplant patients receiving CsA and prednisone maintenance therapy for immunosuppression. The pharmacokinetic objectives of this study were to characterize the pharmacokinetics of (a) single oral 0.5- to 4-mg/kg doses of BQR when given in combination with CsA and prednisone to stable renal, hepatic, and cardiac transplant patients and (b) steady-state oral doses of CsA, with and without single oral doses of BQR. In all three patient populations, the pharmacokinetics of BQR were characterized by a lower oral clearance (12-19 mL/min) than that seen in previous studies in patients with cancer (approximately 30 mL/min at similar doses) and a long terminal half life (13-18 hrs). This slower oral clearance for BQR could be due either to a drug interaction between BQR and CsA or to altered clearance or metabolic processes in patients with transplants. Steady-state CsA trough levels and the oral clearance of CsA were not affected by BQR coadministration. Among the three transplant populations, the cardiac transplant patients had lower oral clearance values of BQR and of CsA. The cause of this lower clearance is not known. Safety results indicate that BQR was well tolerated by this patient population.

Reversal of pulmonary arteriovenous malformation after diversion of anomalous hepatic drainage.

Pulmonary arteriovenous malformation can occur in up to 25% of patients after a classic Glenn shunt. Although unproven, exclusion of hepatic venous blood from the lungs has been proposed as a possible cause. We present a patient born with anomalous hepatic venous drainage into the left atrium with an intact atrial septum in whom pulmonary arteriovenous malformation developed in childhood. This was reversed after diversion of the hepatic venous drainage to the right atrium, supporting exclusion of hepatic venous flow as the cause of pulmonary arteriovenous malformation. The association with the hepatopulmonary syndrome is discussed.

Longitudinal and radial distensibility of the porcine aortic root.

The aortic root has been shown to be a highly distensible structure. The function of the aortic valve is intimately related to the expansion of the aortic root, and current nonexpansible stent designs may affect its performance. We therefore measured the radial and longitudinal expansion of the porcine aortic root as a function of pressure in both a static pressurization model and in an isolated working heart model. The radial and longitudinal expansion of the aortic root was measured using a custom-built digital sonomicrometer. Multiple ultrasonic crystals were sutured exterior to the commissures and along the length of the aortic root, and their separation was tracked at varying aortic pressures. In static testing, we found that commissural separation at zero pressure was 26% +/- 7% (mean +/- standard deviation) less than at 120 mm Hg, whereas the longitudinal distance between the base of the valve and the commissures decreased by 11% +/- 9%. Approximately one quarter of the total dimensional change occurred over the physiologic range of 80 to 120 mm Hg. In the isolated porcine heart model, we measured a greater distensibility than in the static tests. For example, at aortic pressures of 120/80 mm Hg (systolic/diastolic), the diameter of the aortic root would be 22% +/- 6% less at 80 mm Hg than at 120 mm Hg. The longitudinal dimensions would be 15% +/- 8% less at 80 mm Hg than at 120 mm Hg. We conclude that the aortic root contracts significantly when depressurized, as during valve replacement surgery, and that the in vivo distensibility of the aortic root is much greater that what is generally measured in vitro. These results suggest that dimensional changes in the implanted prosthetic valve and the recipient aortic root must be considered to achieve both optimal valve orifice and, in the case of distensible valves such as allografts, a proper valve cusp geometry.