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The reduction in the frequency of rejection episodes several months after heart transplantation (HTX) correlates with the development of donor-specific nonresponsiveness. This is reflected in a reduced frequency of donor-specific cytotoxic T cells (CTL) in the peripheral blood. We investigated whether the reduced CTL frequency and the incidence of rejection episodes coincided with a change in the frequency of either IL-2- or IL-4-producing helper T lymphocytes (HTL). We measured the frequency of HTL before and at several time points after HTX in the blood of ten recipients, using limiting dilution analysis for IL-2 and IL-4. In most patients, HTL frequencies dropped immediately after transplantation, but returned to pre-HTX values later after transplantation. No consistent decrease or increase in frequencies was observed long after HTX. In contrast to IL-2, the HTL frequencies for IL-4 before transplantation were significantly higher in patients without post-HTX rejection episodes requiring treatment than in patients with such episodes. This phenomenon was observed for the in vitro responses towards both donor and third-party cells. In conclusion, relatively high frequencies of IL-4-producing T cells may have a beneficial effect on the outcome of human heart transplantation, because they are associated with a reduced incidence of rejection episodes after transplantation.

A reliable, sensitive, non-invasive alternative for transvenous endomyocardial biopsy in detecting cardiac allograft rejection is desirable for optimal management of heart transplant patients. To establish whether (31)P magnetic resonance spectroscopy can become a non-invasive tool for detecting cardiac allograft rejection, the cardiac high-energy phosphate metabolism of human heart transplants was serially examined in 13 patients by means of (31)P MRS from post-operative day 13 to day 294, and compared with histologic evaluation of endomyocardial biopsies. Biopsy scores of 2 or higher, according to the Working Formulation criteria of Billingham et al., were considered to indicate rejection. Logistic regression, which was corrected for differences between the individual patients and the time after transplantation, showed no significant correlation between the occurrence of histologically detected rejection and the PCr:ATP ratio. However, using an analysis of variance, the PCr:ATP ratios of non-rejecting cases obtained within 50 days after transplantation (mean: 27 +/- 11 days) appeared to be significantly different from those obtained after post-operative day 50 [0.95 +/- 0.17 (n = 25) vs 1.17 +/- 0.17 (n = 32), mean +/- SD; p < 0.01]. No significant difference was observed between the PCr:ATP ratios obtained 100 days after transplantation (mean: 162 +/- 52 days) and the PCr:ATP ratios in the hearts of healthy volunteers [1.18 +/- 0. 18 (n = 19) and 1.23 +/- 0.17 (n = 6), mean +/- SD, respectively; p = 0.55]. The PCr:ATP ratio in transplanted human hearts is not a sensitive indicator for the detection of early acute human cardiac allograft rejection. This may be due to a temporarily altered high-energy phosphate metabolism early after transplantation irrespective of rejection., (Copyright 1999 John Wiley & Sons, Ltd.)

Background: Use of a permanent left ventricular assist device (LVAD) has been proposed as an alternate treatment of patients with end-stage heart failure. The purpose of this study was to compare the functional capacity of patients following implantation of a LVAD vs heart transplant (HTx)., Methods: Eighteen patients from 6 centers who received an intracorporeal LVAD as a bridge to HTx underwent treadmill testing 1 to 3 months post-LVAD and again post-HTx. Baseline and peak measurements, including oxygen consumption, blood pressures, and respiratory rate were made during each treadmill test., Results: Peak oxygen consumption was 14.5+/-3.9 ml/kg/minute post-LVAD and 17.5+/-5.0 ml/kg/minute post-HTx (p < .005). The percentage of the predicted peak oxygen consumption based on gender, weight, and age was 39.5%+/-5.5% post-LVAD and 47.7%+/-10.9% post-HTx (p < .005). Exercise duration was lower post-LVAD than post-HTx (10.3+/-4.2 minute vs 12.5+/-5.4 minute, p < .05). After LVAD implantation, peak total oxygen consumption correlated with peak LVAD rate and output. Eight patients reached an LVAD rate of 120 beats per minute (bpm) before the conclusion of exercise, the maximum rate for the outpatient electric device. The peak respiratory exchange ratio post-LVAD was 1.15+/-0.22 and post-HTx was 1.15+/-0.18, consistent with a good effort in both groups., Conclusions: Patients demonstrated a lower functional capacity post-LVAD than post-HTx. For some patients functional capacity post-LVAD may be improved by a higher maximum LVAD rate and output.

A 32-year-old woman underwent heart transplantation after having suffered two myocardial infarctions, the first when parturition was pharmacologically induced, the second during diagnostic catheterization. Three years after the heart transplantation she became pregnant three times. In the first two pregnancies therapeutic abortion was performed because of trisomy-21. The third pregnancy was uneventful until week 36. At that time labour was induced because of signs of pre-ecclampsia. A healthy boy was born with normal physical and psychological development after four years. In pregnancy after heart transplantation teratogenic effects of the medication have not been described. The main problems are hypertension and pre-eclampsia in the mother and prematurity and low birth weight in the newborn. A major problem is the limited life expectancy after heart transplantation due to which a patient will only rarely see his or her child grow up into adulthood.

Objective: To describe hemodynamic alterations during coronary artery bypass grafting (CABG) without extracorporeal circulation using the Octopus Tissue Stabilizer, and to describe the two anesthetic management protocols based on either general anesthesia with opioids (34 patients) or general anesthesia with high thoracic epidural anesthesia (TEA; 66 patients)., Design: A prospective observational report., Setting: An academic university heart center., Participants: First 100 patients undergoing CABG using the Octopus Tissue Stabilizer., Interventions: None., Main Results: Current management provided satisfactory results in preventing hypoperfusion of the heart and inadequate systemic circulation without the use of major pharmacologic interventions. Movement of the heart to reach the target site of anastomosis caused hemodynamic alterations. These could easily be corrected by anesthetic interventions, such as fluid load and low doses of inotropes. High TEA allows earlier extubation compared with the opioid anesthesia technique (0.9 v 4.5 hours). Perioperative management and the incidence of postoperative complications did not differ between anesthetic techniques. Major complications, such as death, intraoperative myocardial infarction, and stroke, did not occur., Conclusion: Both anesthetic protocols are safe and effective in handling these patients. Off-pump CABG surgery requires anesthetic interventions because hemodynamic alterations are caused by the presentation of the heart to the surgeon. The complication rate is low but needs to be evaluated, compared with conventional CABG, in a prospective randomized study. High thoracic epidural anesthesia allows early recovery, but improved outcome could not be proved in this patient group.

Off-pump coronary artery bypass grafting requires immobilization of the coronary artery. A suction device (Octopus Tissue Stabilizer), attached to the epicardium and connected rigidly to the operating table rail, was used through limited and full surgical access for single-vessel and multivessel arterial revascularization, respectively. An outline for its application, as used by us to construct 122 anastomoses in 70 patients, including posterior wall grafting (in 9 patients) and sequential grafting on the anterior wall (in 17 patients), is presented.

Objective: Cardiopulmonary bypass and global cardiac arrest enable safe coronary artery bypass grafting but have adverse effects. In off-pump coronary bypass grafting, invasiveness is reduced, but anastomosis suturing is jeopardized by cardiac motion. Therefore the key to successful off-pump coronary bypass grafting is effective local cardiac wall stabilization., Methods: We prospectively assessed the safety and efficacy of the Octopus tissue stabilizer (Medtronic, Inc., Minneapolis, Minn.) in the first 100 patients selected for off-pump coronary bypass via full or limited surgical access. To immobilize and expose the coronary artery, two suction paddles (-400 mm Hg), fixed to the operating table-rail by an articulating arm, stabilized the anastomosis site., Results: One hundred forty-one grafts (96% arterial) were used to create 172 anastomoses (17% side-to-side), up to 4 per patient, on average 23 in the full access group (46 patients) and 1.2 in the limited access group (54 patients). Complications included conversion to cardiopulmonary bypass (2%), conversion from limited to full access (3%), myocardial infarction (4%), predischarge coronary reintervention (2%), and late coronary reintervention (1%). Median postoperative length of hospital stay was 4 days (limited access) or 5 days (full access). Rapid recovery allowed 96% of patients to resume social activities within 1 month. At the 6-month angiographic follow-up, 95% of anastomoses was patent. At the 2- to 22-month follow-up (mean, 13 months), 98 patients were in Canadian Cardiovascular Society class I and 2 patients were in class II., Conclusion: These results suggest that off-pump coronary artery bypass grafting with the Octopus tissue stabilizer is safe. Early clinical outcome and patency rates warrant a randomized study comparing this methods with conventional coronary bypass grafting.

Objective: Target site immobilization is essential to enable meticulous anastomosis suturing during coronary artery bypass grafting on the beating heart. A novel device ('Octopus') was developed for local heart muscle immobilization by suction. The purpose of this study was to investigate the efficacy of the method through a limited access., Methods: The suction device, placed on either side of the recipient coronary artery and fixed to the operating table-rail through an arm construction, restrains anastomosis site motion to 1 x 1 mm. A total of 27 patients underwent off-pump arterial bypass grafting using this method. Preoperatively, all patients had angina class III (NYHA) and were failed or unsuitable candidates for balloon angioplasty. Surgical access was via a 10-cm anterior thoracotomy (n = 26) or 10-cm subxiphoid incision (n = 1)., Results: Harvesting of the graft required 48 +/- 12 min (mean +/- S.D.). Immobilization with the 'Octopus' was effective and facilitated precise anastomosis suturing of 20 single and 7 sequential grafts. Immobilization did not change cardiac index and mean arterial blood pressure. During coronary surgery, however, inotropic drug support was used in 5 of 27 (18%) of patients. There was no myocardial infarction. Only minor transient complications were met. There were electro-cardiographical signs of pericarditis in 6 patients. The postoperative hospital stay ranged from 2 to 6 days, mean 4.0 +/- 1.2 days. The mean follow-up is 6.5 +/- 4 months (range, 1-12 months). All patients except one were in functional class I without angina. Social activities were resumed within 4 weeks. At 6 months angiography was performed in 15 out of 27 patients. The patency rate of 19 out of 20 anastomoses was 95%. All distal grafts were patent. One side to side anastomosis was occluded., Conclusions: The 'Octopus' immobilization method is safe and effective. It facilitates less invasive CABG in selected patients and gives way to fast recovery by reducing invasiveness.

Background: After heart transplantation, expression of various cytokines can be detected in endomyocardial biopsy specimens both in the presence and in the absence of rejection. In this study we have analyzed the contribution of donor-specific CD8+ cytotoxic T cells to intragraft cytokine expression., Methods: T cells were propagated from endomyocardial biopsy specimens in medium containing interleukin-2 and interleukin-4. From the T-cell lines obtained, T-cell clones were generated by limiting dilution. A number of 15 CD8+ donor-specific cytotoxic T-cell clones were generated from a single T-cell line and were analyzed for their cytokine messenger RNA expression. The cytokine profile of the clones was studied on the mRNA level by reverse transcriptase polymerase chain reaction., Results: Almost all clones expressed mRNA for interleukin-1 beta, interleukin-4, and interleukin-10, and 75% of the clones expressed mRNA for interleukin-1 alpha, interleukin-9, and tumor necrosis factor-beta. In about half of the clones expression of interleukin-2, interleukin-6, interleukin-8, and interferon-gamma was detected. Tumor necrosis factor-alpha was only detected in one of the clones. The cytokine profiles exhibited a considerable heterogeneity. The 15 clones had previously been analyzed for their T-cell receptor V beta-gene family expression and T-cell receptor V-D-J region sequence. Homology in the V-D-J regions of the clones indicated that the 15 clones were derived from a limited number of progenitor cells. Interestingly, clones derived from one progenitor expressed a different mRNA cytokine profile., Conclusions: This study shows that donor-specific cytotoxic T cells can contribute to the spectrum of locally produced cytokines. The cytokine expression of these cytotoxic T cells seems not to be limited to a distinct profile.

Background: Although strict selection criteria are being used for the acceptance of human donor hearts for transplantation, problems with respect to functional recovery on reperfusion sometimes still occur. Therefore, evaluation of the viability of a human donor heart before implantation during heart transplantation may be of great value., Methods and Results: In the present study, the energy metabolism of 25 excised human donor hearts arrested with St Thomas' Hospital No. 2 cardioplegic solution was evaluated noninvasively by use of 31P magnetic resonance spectroscopy (MRS) before implantation and was correlated with myocardial function measured with thermodilution in heart transplant patients. No significant correlation was observed between the cardiac index of heart transplant patients during the first hours after transplantation and the phosphocreatine/ATP (r = .13, P = .54), inorganic phosphate/ATP (r = .26, P = .21), phosphomonoesters/ATP (r = .02, P = .92), or phosphocreatine/inorganic phosphate (r = .16, P = .44) ratio or the intracellular pH (r = .06, P = .78) at the time of reperfusion. However, 1 week after transplantation, a significant correlation was observed between the cardiac index and the phosphocreatine/ATP (r = .49, P = .01), phosphomonoesters/ATP (r = .45, P = .02), and phosphocreatine/inorganic phosphate (r = .40, P = .05) ratios at the time of reperfusion. In contrast, the inorganic phosphate/ATP (r = .10, P = .63) ratio and pH (r = .31, P = .13) at the time of reperfusion showed a poor correlation with the cardiac index 1 week after transplantation., Conclusions: Functional recovery after human heart transplantation is related to the metabolic condition of the hypothermic donor heart.

Objectives: We sought to investigate the origin of the fractionated electrogram and its relations to abnormal conduction in cardiomyopathic myocardium., Background: Patients with dilated cardiomyopathy have a high incidence of ventricular tachycardias. Electrograms recorded in these patients are often fractionated., Methods: High resolution mapping (200-microM interelectrode distance) of the electrical activity was carried out in 11 superfused papillary muscles and 6 trabeculae from 7 patients who underwent heart transplantation because of dilated cardiomyopathy. Similar measurements were taken in four papillary muscles from dog hearts in which electrical barriers had been artificially made. Ten human preparations were studied histologically., Results: All preparations revealed sites with fractionated electrograms. In three human preparations, activation patterns showed a discernible line of activation block running parallel to the fiber direction. Fractionated electrograms were recorded at sites contiguous to the line of block. In five preparations, fractionated electrograms were recorded at sites where lines of block were not identified. In these preparations, electrical barriers consisted of short stretches of fibrous tissue. In the remaining nine preparations, fractionated electrograms were recorded, both from sites contiguous to distinct obstacles and sites without evidence of a barrier., Conclusions: Our observations showed that fractionated electrograms recorded in myocardium damaged by cardiomyopathy were due to both distinct, long strands and short stretches of fibrous tissue. Delayed conduction was caused by curvation of activation around the distinct lines of block and by the wavy course of activation between the short barriers. The latter reflects extreme nonuniform anisotropy.

To determine the possibility of myocardial protection against reperfusion injury by allopurinol, 22 aortocoronary bypass patients were studied. Eight patients received allopurinol (200 mg during induction of anesthesia and 100 mg after starting extracorporeal circulation) during surgery (group B), and 14 patients served as a control (group A). Blood samples and myocardial biopsies were taken before and 10 min after aortic cross-clamping. No statistically significant difference between the two groups was observed considering gender, age, prior myocardial infarction, left ventricular end diastolic pressure (LVEDP), and aortic cross-clamp time. Preservation of cardiac tissue was assessed by the measurement of quantitative birefringence (QBR) changes upon the addition of adenosine 5'-triphosphate (ATP) plus calcium in biopsies and the need for postoperative inotropes. The synthesis of peroxides was estimated by the measurement of leukotriene B4 and C4 (LTB4, LTC4). LTB4 was below the level of detection (< 1.5 ng/l) before and after cross-clamping in both groups, while the LTC4 level for group A increased from < 1.5 to 27 +/- 17 ng/l compared to an increase of < 1.5 to 11 +/- 8 ng/l for group B after 10 min of reperfusion (p = .036). The decrease in QBR value in group A was 1.26 +/- 0.28 and 0.35 +/- 0.23 for group B (p < .003). Postoperatively, 11 out of 14 patients in group A needed inotropic support (dopamine or dobutamine), whereas two patients out of eight did so in group B.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: Ventricular tachycardias occurring in the chronic phase of myocardial infarction are caused by reentry. Areas of slow conduction, facilitating reentry, are often found in the infarcted zone. The purpose of this study was to elucidate the mechanism of slow conduction in the chronic infarcted human heart., Methods and Results: Spread of activation was studied in infarcted papillary muscles from hearts of patients who underwent heart transplantation because of infarction. Recordings were carried out on 10 papillary muscles that were superfused in a tissue bath. High-resolution mapping was performed in areas revealing slow conduction. Activation delay between sites perpendicular to the fiber direction and 1.4 mm apart could be as long as 45 milliseconds. Analysis of activation times revealed that activation spread in tracts parallel to the fiber direction. Conduction velocity in the tracts was between 0.6 and 1 m/s. Although tracts were separated from each other over distances up to 8 mm, they often connected with each other at one or more sites, forming a complex network of connected tracts. In this network, wave fronts could travel perpendicular to the fiber direction. Separation of tracts was due to collagenous septa. At sites where tracts were interconnected, the collagenous barriers were interrupted., Conclusions: Slow conduction perpendicular to the fiber direction in infarcted myocardial tissue is caused by a "zigzag" course of activation at high speed. Activation proceeds along pathways lengthened by branching and merging bundles of surviving myocytes ensheathed by collagenous septa.

The case of a 46-year-old patient who underwent orthotopic heart transplantation for treatment of end-stage heart failure as a result of ischemic heart disease is reported. Four months after transplantation a grade II rejection episode was complicated by ventricular fibrillation. Lidocaine and procainamide intravenously did not effectively prevent recurrence. An increase of antirejection therapy in combination with flecainide acetate effectively prevented further episodes of ventricular fibrillation. This case demonstrates that recurrent ventricular fibrillation can be a complication of acute rejection.