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The increasing number of heart transplant recipients receiving immunosuppression with mammalian target of rapamycin inhibitors prompted the implementation of a South American Transplant Physicians Group to register these patients in a database. Everolimus (EVL) is a signal proliferation inhibition that reduces graft vascular disease when used de novo. Recently, its administration has expanded to subjects with resistant rejection or with side effects due to other immunosuppressive drugs (calcineurin inhibitors and/or steroids), allowing for better regulation of the immunosuppressive regimen. Herein we have shown the data collected from patients receiving EVL in ten South American Heart Transplant Centers. We have concluded that the administration of EVL is a useful adjunctive therapy that allows the reduction or suspension of other immunosuppressive drugs that caused unwanted side effects, without a loss of immunosuppressive efficacy, with manageable side effects, and constituting a valuable therapeutic option.

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Despite improvements during the last decades, heart transplantation remains associated with several medical complications, which limit clinical outcomes: acute rejection with hemodynamic compromise, cytomegalovirus (CMV) infections, allograft vasculopathy, chronic renal failure, and neoplasias. Everolimus, a proliferation signal inhibitor, represents a new option for adjunctive immunosuppressive therapy. Everolimus displays better efficacy in de novo heart transplant patients than azathioprine for prophylaxis of biopsy-proven acute rejection episodes of at least ISHLT grade 3A (P < .001), of allograft vasculopathy (P < .01), and of CMV infections (P < .01). These findings suggest that everolimus potentially play an important role as part of immunosuppressive therapy in heart transplant recipients. Heart transplant investigators from Latin America produced recommendations for everolimus use in daily practice based on available data and their own experience.

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INTRODUCTION: A consensus has not yet been reached regarding the indications for orthotopic heart transplantation (OHT) in elderly patients or the age limit contraindicating the procedure. The objective of this study was to assess OHT outcomes to determine whether elderly patients benefit from the procedure. METHODS: From February 1993 to February 2003, 178 OHTs were performed on recipients of mean age 47.4 +/- 15 years (range, 4 to 74) including 80.3% men. The population was divided into two groups: group A included patients >/= 60 years, and group B those younger than that age. Survival was analyzed for the overall population and for both age groups during a 10-year follow-up period. RESULTS: Group A included 36 patients (20.8%) and group B 142 patients (79.2%). Mean age was 63.7 +/- 2.9 years (60 to 74) in A, and 43 +/- 13.9 years (4 to 59) in B. In-hospital mortality was significantly higher among group A (n = 11, 31.4%) compared to B (n = 17, 12.1%, P =.008). Survival at 1, 5, and 10 years was 61.5% +/- 8%, 58.1% +/- 8.3%, and 49.8% +/- 10.5% group A; and 84.2% +/- 3%, 73.7% +/- 4.1%, and 69.9% +/- 4.7 for group B. Elderly patients showed a lower survival rate (49.8%) compared with the younger group (69.9%) at 10-year follow-up (P =.007). Conditional survival at 9 years failed to show significant differences (A 72.2% vs B 79.6%, P =.4). CONCLUSION: In our population, elderly recipients showed a higher in-hospital mortality. However, when the first post-OHT year was excluded, we found similar survival rates for both age groups.

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Heart transplantation is contraindicated as an effective treatment for end-stage Chagas' heart disease because of post-operative recurrence of Trypanosoma cruzi infection and reactivation of disease after immunosupression. In a follow-up study of a heart transplanted patient with Chagas' disease, we prospectively evaluated the usefulness of the polymerase chain reaction (PCR) for early diagnosis of reactivation. We monitored post-operative recurrence of Trypanosoma cruzi infection with microscopic observation of the parasite in peripheral blood (Strout's method), endomyocardial biopsies (EMBs), skin lesions, and 2 PCR assays, based on the amplification of specific T cruzi kinetoplastid and nuclear DNA sequences. During follow-up, parasite DNA was amplified in blood samples and EMB sections 41 days before we observed patent parasitemia and cutaneous manifestations of reactivation, proving that PCR is much more sensitive than direct microscopic observation for early diagnosis of disease reactivation in heart-transplanted Chagas' disease patients.

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Two cases of primary pulmonary artery sarcoma resembling chronic thromboembolic disease features are presented. Tumour identification was achieved after pulmonarv thromboendarterectomy, which was indicated by documentation of a prothrombotic state in both patients. A doubtful history of pulmonary emboli or deep venous thrombosis should alert medical personnel to the possible presence of a primary pulmonary artery sarcoma. Advanced imaging methods such as gadolinium-enhanced magnetic resonance imaging could be useful in considering pulmonary thromboendarterectomy. If a tumour is detected, its surgical resection should be considered with caution, taking into account the poor survival results. Invasion of the adventitia or the right ventricle, as documented in the present cases, is unusual. As far as the present authors know, this is the first report of this kind of tumour and its coexistence with an activated protein C resistance state and type II heparin-induced thrombocytopenia.

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In forty-five patients who underwent orthotopic heart transplantation, the titer of anti-human skeletal muscle glycolipid antibodies (AGA) present in the sera at the moment of transplantation was correlated with the number of histologically diagnosed cellular grade 3A and humoral acute rejection episodes during the first 120 days after transplantation. Determination of a cutoff value of 0.800 for the AGA level was determined by a receiver operating characteristic curve. Thirteen of 19 patients (68.4%) with an AGA titer above 0.800 developed 24 severe rejection episodes, and of the 26 patients with an AGA titer below 0.800, only 4 (15.3%) presented 6 severe rejection episodes during that time. This was especially evident for the humoral rejection episodes, which were diagnosed in only 1 of the 26 patients with AGA below 0.800 and in 7 of the 19 with AGA above 0.800. Comparison by univariate analysis of other well-known risk factors for a greater number of rejection episodes during the early posttransplant period with the AGA level at the moment of transplantation revealed that the latter distinguished a greater number of patients at risk than the other factors, such as a female donor, the lymphocyte direct cross-match, or the status of the patients at transplantation; the odds ratios were 6.33 for the AGA level, 3.17 for the direct cross-match, and 2.76 for the status at transplantation. By multiple logistic regression analysis, the only relevant risk factors in our group of patients were the AGA level (P=0.0009) and the status at transplantation (P=0.0285). These results indicate that determination of the AGA level at the moment of transplantation could represent a useful method for distinguishing which patients are at risk for a greater number of rejection episodes during the early posttransplant period, with a greater sensitivity than other risk factors.

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OBJECTIVES: The impact of amiodarone on mortality in patients with severe congestive heart failure (CHF) (New York Heart Association functional classes II [advanced], III and IV; left ventricular ejection fraction < 35%) In the Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina (GESICA) trial was analyzed in relation to initial mean baseline heart rate (BHR) and its change after 6 months of follow-up. BACKGROUND: Trials of amiodarone therapy in CHF have produced discordant results, suggesting that the effect is not uniform in all patient subgroups with regard to survival. METHODS: The present analysis was carried out in 516 patients randomized to receive amiodarone, 300 mg/day (n = 260), or nonantiarrhythmic therapy (n = 256, control group) and followed up for 2 years. Survival was evaluated for patients with a BHR > or = 90 beats/min (control: n = 132; amiodarone: n = 122) and < 90 beats/min (control: n = 124; amiodarone: n = 138). Survival was also analyzed according to heart rate reduction at 6 months for 367 patients. RESULTS: For patients with a BHR > or = 90 beats/min, amiodarone therapy reduced mortality to 38.4% compared with 62.4% in control patients (relative risk [RR] 0.55, 95% confidence interval [CI] 0.35 to 0.95, p < 0.002). Both sudden death (RR 0.46, 95% CI 0.24 to 0.90, p < 0.02) and progressive heart failure death (RR 0.60, 95% CI 0.30 to 1.03, p < 0.06) were reduced, and functional capacity was improved. In patients with a BHR < 90 beats/min, amiodarone did not alter survival. Among 367 patients who completed 6 months of follow-up, amiodarone reduced 2-year mortality only in those with a BHR > or = 90 beats/min, which was reduced at 6 months. CONCLUSIONS: Elevated rest heart rates in severe CHF identify a subgroup of patients who benefit from treatment with amiodarone. Amiodarone-induced heart rate slowing may be an important benefit for patients.

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OBJECTIVES: This study sought to determine whether the response to amrinone in patients with severe baseline left ventricular dysfunction can predict improvement in left ventricular ejection fraction after coronary artery bypass graft surgery. BACKGROUND: Previous studies have suggested that the inotropic response to dobutamine can identify viable myocardium in the setting of chronic coronary disease and left ventricular dysfunction. However, increased oxygen demand stimulated by dobutamine can lead to superimposition of ischemia on the hibernating state, potentially confounding interpretation of results. Amrinone is an inotropic agent that does not critically augment myocardial oxygen demand and may be useful for identification of hibernating myocardium in the chronically ischemic state. METHODS: Forty-four consecutive patients with coronary artery disease and left ventricular ejection fraction < 40% referred for coronary artery bypass graft surgery underwent amrinone stimulation (1 mg/kg body weight). Left ventricular ejection fraction was determined before amrinone stimulation, 20 min after infusion and 21 days after bypass surgery. RESULTS: Baseline ejection fraction was 28 +/- 7% (mean +/- SD). Ejection fraction increased to 35 +/- 5% after amrinone stimulation (p < 0.0001) and to 33 +/- 6% after bypass surgery (p < 0.0001). Postbypass ejection fraction was significantly correlated with postamrinone ejection fraction (r = 0.65, p < 0.0001). Furthermore, the change in ejection fraction from baseline to after bypass surgery was highly correlated with the change in ejection fraction after amrinone stimulation (r = 0.75, p < 0.0001). Of 13 patients with an increase in ejection fraction > or = 10% after amrinone, all 13 had an increase of at least 8% and 11 (85%) of 13 had an increase > or = 10% after bypass surgery. In contrast, of 31 patients with an increase in ejection fraction < 10% after amrinone, only 2 (6%) had an increase > or = 10% (p < 0.0001) and 28 (90%) of 31 had an increase < 5% after bypass surgery. CONCLUSIONS: Augmentation of myocardial contraction by amrinone in patients with chronic coronary artery disease and severe baseline left ventricular dysfunction predicts improvement in left ventricular ejection fraction after coronary artery bypass graft surgery.

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BACKGROUND AND METHODS: In sixty-three endomyocardial biopsy samples collected from six heart transplant recipients for the diagnosis of acute rejection episodes, the presence of apoptosis in individual cells was investigated in tissue sections by in situ labeling of nuclear DNA breaks by nick end labeling with biotinylated poly deoxyuridin triphosphate introduced by terminal deoxynucleotidyl transferase and alkaline phosphatase-conjugated streptavidin. In the samples collected at the moment of transplantation, no apoptotic cells were observed. Apoptotic nuclei were found in the myocytes and capillary endothelial and connective tissue cells of endomyocardial biopsy samples obtained from day 7 to day 146 after transplantation with a different prevalence according to the rejection grade (International Society for Heart and Lung Transplantation classification). RESULTS: In all the rejection grade 3A (eight of eight), in half of the rejection grade 2 (four of eight), and in some rejection grade 1B (three of eight) cases, apoptotic myocytes were found within or in the neighborhood of the inflammatory areas. In the rejection grades 0 and 1A and in the "Quilty" effect zones, no apoptotic myocytes could be observed. Apoptotic endothelial and interstitial cells were observed in all the rejection grades but with a higher prevalence in rejection grades 2 and 3A. CONCLUSIONS: During rejection episodes, apoptosis of myocytes is one of the mechanisms of immune-mediated death, and its investigation in tissue sections may represent a valuable tool for the diagnosis of myocyte damage.

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BACKGROUND: Vascular endothelium reacts to various pathophysiologic stimuli by releasing several autocoids and cytokines that can be used along with the coagulation and fibrinolytic markers for the diagnosis of hemostatic alterations. Several newer markers for vascular distress, such as tissue plasminogen activator (TPA), tissue plasminogen activator inhibitor-1 (PAI-1), TPA/PAI-1 complex, and the newly reported inhibitor of the coagulation process, namely, tissue factor pathway inhibitor (TFPI), have been implicated in the pathogenesis of pulmonary hypertension. METHODS: To investigate the behavior of endothelial cells at basal and time-dependent venous stasis-induced changes, various markers were measured in patients with primary and secondary pulmonary hypertension and compared with healthy human volunteers (controls) without any family history of thromboembolism or history of hypertensive disorders. The right atrial pressure (RAP) and pulmonary arterial pressure were measured and the hemostatic parameters were correlated to determine the relevance of these parameters with the alterations in the present indices. RESULTS: A fibrinolytic deficit exists in patients with pulmonary hypertension, indicated by the prolongation of the euglobulin clot lysis time at basal conditions and after the venous occlusion test. This defect was mainly due to increased production of PAI-1 by endothelium (patients 59.8 +/- 22.3 AU/ml; controls 30.3 +/- 14.5 AU/ml; p = 0.005). We also report for the first time that a decrease in tissue factor pathway inhibitor antigen was also observed in these patients when RAP was > 9 mmHg [controls 95.6 +/- 61.6 ng/ml; patients with RAP > 9 mmHg 47.2 +/- 19.2 ng/ml (p = 0.044); patients with RAP > 9 mmHg 96.6 +/- 32.4 ng/ml (p = 0.002 compared with patients with RAP > 9 mmHg)], indicating endothelial cell and hemostatic disturbances. CONCLUSIONS: We conclude that the euglobulin clot lysis time was prolonged in patients with pulmonary hypertension compared with controls. The impairment of the fibrinolytic system was due to an elevated concentration of PAI-1. In RAP > 9 mmHg, an additional prothrombotic factor is the decrease in plasma tissue factor pathway inhibitor antigen. It appears from this study that antithrombotic treatment is indicated in these patients.

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In seventeen patients the result of the histological study of 153 endomyocardial biopsies (EMB) was compared with the ELISA titer of anti-human skeletal muscle glycolipid antibodies (AGA) present in serum samples collected simultaneously with the EMB procedure during the first four months following cardiac transplantation. The glycolipids were extracted from the quadriceps femoralis of blood group O patients. In the serum samples corresponding to the histological rejection grades with myocyte necrosis (greater than or equal to 2, International Society for Heart and Lung Transplantation grading) the AGA titer was significantly higher (P<0.005) than in the less severe rejection grades. The follow-up in each patient showed that the AGA titer raised in the serum samples collected immediately after, before, or coincidentally with a histological diagnosis of rejection grade 2 or 3A. In only one rejection grade 3A case was a false-negative result observed. Determination of the cut-off of the AGA level versus rejection grades 2 and 3A was determined by a relative-operating characteristic curve. An optical density (OD) of 0.040 showed maximum efficiency with sensitivity 53% and specificity 79%. Four patients who had AGA with an OD above 0.040 at the time of transplant had a significantly higher number of rejection grade 2 and 3A episodes than eleven patients with low pre-transplant AGA titers (P<0.05). These results indicate that search of anti-skeletal muscle glycolipid antibodies may represent a useful noninvasive method for monitoring heart rejection, and suggest that its investigation prior transplant may be a predictor of the number of grades 2 and 3A rejection episodes.

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In severe heart failure many deaths are sudden and are presumed to be due to ventricular arrhythmias. The GESICA trial evaluated the effect of low-dose amiodarone on two-year mortality in patients with severe heart failure. Our prospective multicentre trial included 516 patients on optimal standard treatment for heart failure. Patients were randomised to 300 mg/day amiodarone (260) or to standard treatment (256). Intention-to-treat analysis showed 87 deaths in the amiodarone group (33.5%) compared with 106 in the control group (41.4%) (risk reduction 28%; 95% CI 4%-45%; log rank test p = 0.024). There were reductions in both sudden death (risk reduction 27%; p = 0.16) and death due to progressive heart failure (risk reduction 23%; p = 0.16). Fewer patients in the amiodarone group died or were admitted to hospital due to worsening heart failure (119 versus 149 in the control group; risk reduction 31%; 95% CI 13-46%; p = 0.0024). The decrease in mortality and hospital admission was present in all subgroups examined and independent of the presence of non-sustained ventricular tachycardia. Side-effects were reported in 17 patients (6.1%); amiodarone was withdrawn in 12. Low-dose amiodarone proved to be an effective and reliable treatment, reducing mortality and hospital admission in patients with severe heart failure independently of the presence of complex ventricular arrhythmias.

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To our knowledge these are the first three cases of laparoscopic cholecystectomy in heart transplant recipients. In one case the procedure was performed in the early posttransplant period. All three patients had uneventful postoperative outcomes and early hospital discharge. Laparoscopic cholecystectomy may be a safe alternative for elective cholecystectomy in heart transplant recipients.

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Successful pregnancy and delivery in women with serious cardiovascular diseases have been reported. We describe here a patient with a transplanted heart, treated with cyclosporine and prednisone, who underwent pregnancy and vaginal delivery with good outcomes for mother and infant.

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