Pregnancy in heart transplant recipients.

The aim of this report is to present data from Italian cardiac transplant centers assessing pregnancy after cardiac transplantation. Our retrospective survey included 10 pregnancies occurring in 7 patients during January 1991 to February 2002. Eight pregnancies were completed successfully and 2 abortions were reported (frequency rate 20%). No complications were observed during pregnancy or after delivery. Of 8 infants studied, 6 (75%) were born at term and 2 (25%) pre-term. One baby presented congenital talipes valgus. Pediatric development was uneventful. The data from the literature and our series show that a multidisciplinary approach is mandatory. The course of pregnancy is usually normal and the maternal and fetal outcomes are usually favorable. Although no fetal malformations have been reported, prolonged follow-up of these infants is required.

Heterotopic heart transplantation: a single-centre experience.

INTRODUCTION: Orthotopic heart transplantation (OHTx) represents the therapy of choice for end-stage heart disease not treatable with medical or conservative surgical approach. Heterotopic heart transplantation (HHTx) is a surgical procedure in which the graft is connected to the native heart in a parallel fashion and it was especially employed in precyclosporine era. The aim of this paper is to present our experience with HHTx. METHODS: From November 1985 till May 2003, 713 heart transplanted patients included 12 (1.7%) received HHTx. Eleven were male, mean age was 50.7 +/- 5.8 years. Five patients suffered from dilated cardiomyopathy and seven from ischemic cardiomyopathy. Indication for HHTx was: a body size mismatch in 11 cases and availability of a marginal organ in one case. RESULTS: Mean ischemic time was 149 +/- 48 minutes and mean cross-clamp time was 82.3 +/- 19.1 minutes. In four cases left ventricle aneurysm resection was associated with HHTx. Hospital mortality was 8.3% (one patient due to multiorgan failure). The actuarial survival rates were 92% and 64% at 1 and 5 years, respectively. The causes of death were: liver cancer, liver cirrosis, aortic dissection, cerebrovascular accident, and chronic rejection. CONCLUSIONS: In our experience, HHTx survival rate is comparable to OHTx. Because of the scarcity of donors, use of an undersized or marginal graft is a valid option to increase the number of transplanted patients. The major disadvantages of HHTx are the need for anticoagulant therapy, the more difficult hemodynamic and immunologic follow-up, and the presence of the diseased native heart.

Heart transplantation in patients with amyloidosis: single-center experience.

INTRODUCTION: Amyloidosis is a systemic disease. Heart transplantation in this subset of patients is contraindicated by the majority of authors. In our center, patients with heart failure due to amyloidosis have been evaluated for cardiac transplantation since 1991. The aim of this study was to analyze the outcome of these patients waiting for transplant and the effectiveness of this therapy. MATERIALS AND METHODS: Since 1991, eight patients affected by amyloidosis have been evaluated and enrolled on the waiting list for transplant: five affected by AL lambda type; two by APO A1; and one by TTR. Four were transplanted, three died waiting for a donor (two from cardiac failure, one from sudden death), and one has been recently transplanted after 17 months on waiting list. RESULTS: Since 1985, 713 patients underwent heart transplantation in our center, five of whom were affected by amyloidosis (0.7%). Two are still alive (60 and 41 months) without evidence of cardiac amyloidotic infiltration. One patient recently underwent a combined heart-liver transplantation. Two patients died after the intervention: one sudden death after 23 months with amyloidotic infiltration of transplanted heart, and one multiple organ failure (MOF) due to progression of the systemic disease. CONCLUSIONS: Despite the small size of the group preventing us from drawing definitive conclusion, heart transplantation may prevent therapy to arrest organ damage in patients with isolated cardiac involvement. Cardiac events are the main cause of death. Patients must be followed-up for evolution of systemic disease. The midterm survival is encouraging.

Considerable lack of agreement between S-FPIA and EMIT cyclosporine assay in therapeutic drug monitoring, of heart transplant recipients.

The authors performed a comparative analysis of 60 whole blood samples containing cyclosporine (CsA) from heart transplant (HTx) recipients (n = 60) by the two "specific" monoclonal immunoassays, enzyme-multiplied immunoassay technique (EMIT) and fluorescence polarization immunoassay (S-FPIA), using the Altman-Bland approach based on graphical techniques and simple calculations. The CsA blood concentrations measured by S-FPIA [mean (SD): 268.1 (108.8) ng/mL] showed a statistically significant difference (P < 0.001) from the corresponding concentrations measured by EMIT [219.6 (118.7) ng/mL]. The CsA concentrations were 27% (median) higher when determined by monoclonal S-FPIA than by EMIT. The comparison between EMIT and S-FPIA showed a good correlation (S-FPIA conc. (ng/mL) = EMIT conc. (ng/mL) x 0.88 + 76.1, r = 0.96, P < 0.001). However, a high correlation does not mean that the two methods agree, and their use as interchangeable might be misleading. The authors summarized the degree of agreement by calculating the bias estimated by the mean difference (d) and the standard deviation of the difference (SD). For CsA concentration data, the mean difference (S-FPIA minus EMIT) is +49.9 ng/mL and SD is 31.2 ng/mL. Altman-Bland analysis indicates considerable lack of agreement between EMIT and S-FPIA, with discrepancies of more than 100 ng/mL. The present study's data clearly show that there is a considerable and clinically unacceptable lack of agreement between the S-FPIA and the EMIT techniques in HTx recipients for the whole range of concentrations evaluated (25-500 ng/mL), and this is caused by the variation in the overestimation of the CsA parent compound. Even though a similar CsA reference range was reported during maintenance therapy for both methods (150-250 ng/mL), which might encourage their interchangeability in the clinical setting, this approach should be avoided. Laboratory reports should always state both the concentration of CsA and the analytical method.

Heart transplantation without informed consent: discussion of a case.

OBJECTIVE: To discuss informed consent to heart transplantation in the case of an intensive care unit (ICU) patient: relatives' informed consent was refused by the patient himself whose cognitive ability appeared to be reasonable for the purpose. SETTING: ICU of a university teaching hospital. PATIENT: A 62-year-old man who underwent myocardial revascularization had in the immediate post-operative hemodynamic instability, continuous serious arrhythmias, ventilatory support, fentanyl infusion. Heart transplantation could be the only chance for his survival. INVENTION: Heart transplantation. RESULTS: Despite patient's refusal, we decided to hold the relative's consent as valid, and transplantation was accordingly performed, to the subsequent satisfaction of the patient. CONCLUSIONS: Our decision was based on two beliefs: (1) the severity of the patient's clinical condition may have impaired his cognitive abilities; (2) the very same conditions may mask impairment and certainly make reliable assessment of cognition and judgment impossible. This being so, the preservation of life assumes priority.

FK506 effectiveness in reducing acute rejection after heart transplantation: a prospective randomized study.

BACKGROUND: Tacrolimus (FK506) has recently become available clinically as an alternative to cyclosporine-based immunosuppression. This study reports the middle-term results of a prospective, randomized trial that compared FK506 with cyclosporine-based immunosuppression in heart transplant recipients. METHODS: Twenty-five consecutive patients were randomized at a 2:1 ratio into two groups, one of which received FK506 (15 patients), the other cyclosporine (10 patients). Both groups received similar concomitant immunosuppression. The patients were followed up for 12 months. The following outcome parameters were analyzed: survival, rejection and infection rate, lymphocyte subsets, new-onset diabetes, renal and hepatic function, hypertension, right-sided heart catheterization data, graft coronary artery disease, and neurologic side effects. RESULTS: The mortality rate (two patients) in the FK506 group was 13% versus 0% in the cyclosporine group (p = NS). The two deaths were the consequences of early infections and higher doses of FK506. From the outset, the FK506 group presented a lower prevalence of acute rejection, a lower requirement for rejection treatments and a higher incidence of infections. Accordingly, we reduced overall immunosuppression for the last seven patients in the FK506 group; the decrease in FK506 and prednisone dosage led to a decrease in the early infection rate without an increase in the rejection rate. There was no difference between the two groups in diabetes incidence, renal and hepatic function, right-sided heart catheterization data, or coronary angiograms. Hypertension was less frequent and milder in the FK506 group. CONCLUSIONS: This experience suggests that FK506 can be safely used in heart transplantation. It can decrease the frequency of rejection episodes. Low-dose administration allows a lower infection rate without an increase in rejection. With a protocol of delayed starting and low dosing, side effects such as renal toxicity, hypertension, and neurologic toxicity seem to be unlikely. Further studies are needed to establish the exact dosage and therapeutic levels of the drug.

[Heart transplant over 55 years]. / Il trapianto cardiaco dopo i 55 anni.

BACKGROUND: The age of recipient has been thought for several years to be one of the most important predictors of survival after heart transplantation. Therefore patients older than age 50 years were usually excluded from heart transplantation. The marked improvement in survival after clinical introduction of cyclosporine made a critical revision of selection criteria for heart recipients. In this article we retrospectively analyze the outcome of heart transplantation dividing the patients into two groups: Group A < or = 55 years, Group B > 55 years respectively. METHODS: We analyzed 437 patients who underwent heart transplantation, immunosuppressive protocol for all the patients was cyclosporine, azathioprine and prednisone. Group A included 284 patients, Group B 153 patients. We studied demographic, clinical and haemodynamic data pre- and post-operatory in both groups. RESULTS: In Group A was more frequent dilated cardiomyopathy (p < 0.01) and the patients arrived at heart transplantation in worse haemodynamic conditions requiring more frequently inotropic infusion and/or mechanical support (intraaortic balloon pump, left ventricular assist device). Post-operatory course was more complicated in Group B patients where ischemic cardiomyopathy was more frequent (p < 0.001); intensive care stay, inotropic drugs infusion, mechanical ventilation and hospital mortality were higher in Group B, although non significantly. The donor age was significantly higher in Group B (p < 0.001), anyway the statistical analysis did not show a correlation between donor age and more complicated post-operative course. Follow-up did not show significative differences in the two groups considering haemodynamic data, metabolic disorders, graft coronary disease, infection and rejection rates. On Group B is significantly higher tumor incidence (p < 0.05) and peripheral vascular complications (p < 0.01). Actuarial survival at 5 and 7 years is respectively in Group A 80.3 and 72.9%, in Group B 75.4 and 71% (p = ns). CONCLUSIONS: Heart transplantation in patients older than 55 years with end-stage heart disease is a valid therapeutic option with excellent long-term survival; pre-operative screening must be particularly accurate and older donors should be considered.

Determinants of heart rate variability in heart transplanted subjects during physical exercise.

Respiratory sinus arrhythmia has been described in heart transplanted subjects. In order to investigate the mechanisms involved in the generation of this condition in the transplanted heart and its evolution after surgery, graded exercise was performed (0-75 W in 25 W steps) on a cycle ergometer by 41 subjects (mean age 44 years) who had undergone heart transplantation 28 months (range 3-60) earlier and by six age matched-control subjects. R-R interval, respiratory signal, O2 consumption (VO2) and CO2 production (VCO2) were measured. Respiratory sinus arrhythmia was assessed by the autoregressive power spectrum of the R-R interval and respiration. All subjects reached the anaerobic threshold (heart transplants: 60% at 50 W, 40% at 75 W Controls: 150 W). In control subjects, the respiratory sinus arrhythmia was higher than in heart transplanted subjects (5.80 +/- 0.30 vs 1.45 +/- 0.16 1n ms2) and it decreased significantly (4.66 +/- 0.30 1n ms2, P < 0.05) during exercise, despite the increase in breathing rate and depth. When, the group of heart transplanted subjects was considered as a whole, respiratory sinus arrhythmia was found to be present in all conditions. It significantly increased at 25 W (from 1.45 +/- 0.16 to 2.00 +/- 0.17 1n ms2, P < 0.01), then significantly fell below baseline during recovery (to 0.97 +/- 0.23 1n ms2, P < 0.01). Multiple regression analysis showed that a linear combination of heart rate (inverse correlation) and VO2 (direct correlation) together with months having passed since transplantation surgery, could explain the observed changes in heart rate during exercise (multiple regression: r = 0.658, P < 0.0001). In five long-term transplanted subjects, non respiratory-related low frequency (0.1 Hz) waves were present on the R-R spectrum, but respiratory sinus arrhythmia is also present in the recently transplanted heart and depends on the opposing effects of ventilation and heart rate. In a few cases, sympathetic modulation (re-innervation) could not be excluded.

Successful treatment of aortic dissection after heterotopic heart transplantation.

Heterotopic heart transplantation is a valid option when there is a large donor-recipient size mismatch. However, the presence of the diseased native heart can jeopardize the medium-term and long-term outcome. The problems stemming from this most commonly described in the literature are thromboembolism, angina, and arrhythmias. In this report, we describe the case of a type A aortic dissection in the native aorta that occurred 30 months after heterotopic heart transplantation and the surgical technique successfully applied for its repair. We also discuss some of the alternative techniques.

Different results of cardiac transplantation in patients with ischemic and dilated cardiomyopathy.

We retrospectively analyzed 275 consecutive transplanted patients, dividing them into group A (128 patients) affected by ischemic cardiomyopathy and group B (147 patients) affected by dilated cardiomyopathy. The difference in demographic, clinical and hemodynamic preoperative and postoperative data between the groups was studied; group A patients presented at transplantation with a less compromised hemodynamic picture, requiring inotrope infusion and mechanical assistance less frequently. The influence of etiology on early postoperative complications was also analyzed: group A patients needed postoperative mechanical assistance, inotrope, infusion and prolonged mechanical ventilation more often, therefore requiring a longer stay in the intensive care unit (ICU). Hospital mortality was twice as high in group A. The older age of group A patients per se did not influence these results significantly. The long-term follow-up was then studied with particular attention to parenchymal functions, hemodynamics, coronary artery disease, metabolic and surgical complications, and survival. The complication rate was higher in group A, with more severe hypertension and higher cholesterol levels at 1 year, a higher prevalence of accelerated coronary artery disease (CAD) and a more frequent onset of insulin-dependent diabetes. Surgical and vascular complications were also more frequent. The final result was a better 5-year actuarial survival rate for group B patients. Donor and recipient ages at the time of transplant did not influence this result. We conclude that ischemic patients, even if they are transplanted in better condition and operated more electively, have a more critical early and long-term postoperative course and a worse survival rate. These findings are not explained by advanced age, but could be due to the impact of atherosclerosis and metabolic impairments associated with ischemic disease.

Expression of proliferating cell markers in normal and diseased human hearts.

Proliferating cell nuclear antigen (PCNA) myocyte expression and histopathologic features related to its occurrence were investigated in normal and diseased hearts of adult humans using both immunohistochemical and Western blotting techniques. Ki67 Western blotting was also performed in the same samples used for PCNA blotting. Two hundred seventy-one endomyocardial biopsies, and 15 adult, 1 embryonic and 2 fetal hearts were studied. The biopsies were from normal donor hearts (n = 71), patients with cardiomyopathy and myocarditis (n = 64), and patients with transplantation with (n = 106) and without (n = 30) acute rejection of any grade. The 15 hearts were from 1 heart donor, and from patients with cardiomyopathy (n = 5), valvular heart disease (n = 2), ischemic heart disease (n = 4), amyloidosis (n = 1) and transplantation with acute rejection (n = 2). The PCNA labeling index was plotted against myocyte hypertrophy, inflammatory infiltrates and binucleation index. The PCNA labeling index ranged from 2 to 9% in embryonic and fetal hearts. PCNA was expressed by 1 to 2% of myocyte nuclei in 12% of normal heart biopsies, 1 to 5% of myocyte nuclei in 28% of cardiomyopathy and myocarditis biopsies, and by up to 8% of myocyte nuclei in 53% of biopsies of patients with transplantation, independently of the presence and degree of acute rejection. In the latter biopsies and in myocarditis, some inflammatory cells also showed PCNA expression. PCNA positive myocytes were both mono- and binucleated, and there was no correlation between binucleation and PCNA labeling indexes. Ki67 and PCNA blotting confirmed immunohistochemical results.(ABSTRACT TRUNCATED AT 250 WORDS)

Pneumocystis carinii pneumonia in heart transplant recipients.

Seven cases of Pneumocystis carinii pneumonia (PCP) (two in 1988, three in 1989, one in 1990 and one in 1991) have been observed in a group of 241 heart transplant recipients transplanted in Pavia, Italy, from November 1985 through December 1991. Median time to onset of symptoms was 100 days after transplantation (range 59-333 days). Diagnosis was achieved in all patients by cytological examination of bronchoalveolar lavage (BAL) fluid and/or transbronchial biopsy. Clinical and roentgenographic features were remarkably similar in all PCP-affected heart transplant recipients. A dry, persistent hacking cough associated with dyspnoea was consistently observed. Fever ranged from 37.6 to 39.4 degrees C, median leukocyte count and median arterial oxygen saturation (SaO2) values were 7,300/mm3 (range 3,000-16,000/mm3) and 61% (range 49.3-93%), respectively. Median CD4+ count at the onset of symptoms was 211/mm3 (range 28-739/mm3). The only patient experiencing a recurrence of PCP had a CD4+ cell count of 28/mm3 at the end of treatment with trimethoprim-sulfamethoxazole (TMP-SMX). In all patients human cytomegalovirus was isolated from BAL fluids; however, treatment with TMP-SMX alone (20 mg/kg/day of TMP) was consistently followed by a complete recovery.

Emergency and elective cardiac retransplantation.

Among 265 patients transplanted at our Institution, 7 underwent cardiac retransplantation. There were five emergency retransplantations, the indication being graft failure in one case and acute rejection in four cases. Two patients, retransplanted because of acute rejection, had a positive panel reactivity antibody and a negative donor crossmatch. In the rejection cases immunosuppression was enhanced by perioperative plasmapheresis and a postoperative 1-month course of cyclophosphamide. In two cases emergency retransplantations were successfully performed despite a highly positive prospective crossmatch. Two patients underwent elective retransplantations for chronic rejection 12 and 41 months, respectively, after the primary transplants. The overall early and late survival rates are 71% and 57%, respectively, with a mean follow-up of 48.5 months. The early and late mortality for elective retransplantation is zero. Our experience confirms both the high operative risk for emergency retransplantation and the excellent results for elective retransplantation. The use of plasmapheresis and cyclophosphamide allowed us to undertake retransplantation successfully in 2 cases with positive donor crossmatch. Both hyperimmunized patients in our series were retransplanted because of irreversible acute rejection despite a negative crossmatch with the primary donor. The meaning of negative crossmatch in patients with preformed cytotoxic antibodies is therefore questionable.

Histopathologic and molecular profile of human cytomegalovirus infections in patients with heart transplants.

From November 1985 to December 1990, 2,552 endomyocardial biopsy specimens from 209 heart transplant patients were studied. Forty-four (21%) patients developed 45 episodes of major human cytomegalovirus infection (HCMV). Human cytomegalovirus infection was primary in 13 of 44 patients. Thirty-one patients developed episodes of recurrent major infection. One patient had both primary and recurrent infections. Conventional histopathologic and immunohistochemical study, in situ hybridization, and polymerase chain reaction were used to diagnose HCMV myocardial involvement on corresponding endomyocardial biopsy specimens performed during infection. Conventional morphologic study showed typical viral inclusion bodies in four biopsy specimens. Two cases had myocyte HCMV localization with necrotizing myocarditis, whereas two had endothelial cell involvement without any inflammatory reaction. In these four biopsy specimens, immunohistochemistry showed a higher number of infected cells than that recognized by conventional histopathologic study. In situ hybridization detected infected cells with no evidence of cytopathic effect. Polymerase chain reaction gave HCMV amplification products in two additional biopsy specimens otherwise interpreted as moderate and mild rejection, respectively. Therefore, 6 biopsies showed HCMV myocardial involvement (6 of 45; 13.3%): all were from patients with primary HCMV infection (6 of 13; 46%). None of 32 major recurrent infections showed any myocardial involvement. In conclusion, our study is the first to demonstrate that myocardial HCMV involvement preferentially occurs in primary infection and HCMV endothelial localization can be free from inflammatory reaction, whereas HCMV myocyte localization leads to necrotizing myocarditis. Polymerase chain reaction has a higher diagnostic sensitivity than in situ hybridization. However, polymerase chain reaction findings of HCMV DNA on otherwise negative endomyocardial biopsy specimens remains of questionable significance because polymerase chain reaction-positive biopsy samples do not necessarily indicate tissue infection. It is impossible to determine whether amplified sequences derive from circulating leukocytes or from tissue cells.

Endomyocardial biopsy of normal donor hearts before cardiac transplantation. A morphological and morphometrical study in 97 cases.

Endomyocardial biopsies from 97 normal donor hearts were examined. Morphometric analysis showed: mean myocyte diameter 22.21 +/- 6.93 mu, mean nuclear dimension 7.32 +/- 2.33 mu, mean nuclear/sarcoplasmic ratio 0.33 +/- 0.02. 31 biopsies showed enlarged myocytes (mean diameter 31.65 +/- 3.98 mu) with increased nuclear size (mean 10.45 +/- 1.39 mu), but preserved nuclear/sarcoplasmic ratio (mean 0.33 +/- 0.01). The mean age of these latter subjects was significantly higher. Endocardial thickness mean value was 17.73 +/- 4.58 mu, but in 28 cases the value exceeded the considered upper normal limit of 20 mu. Interstitial mononuclear cells were rare and randomly present. Interstitial fibrosis was observed in 15% and focal fibrosis in 27% of cases. Our results show that histology of biopsies from clinically normal hearts can widely vary, sometime overriding the pathologic boundaries. These apparently "benign" abnormalities should be kept in mind when specific pathologic substrates of cardiac diseases have to be defined.

[Endomyocardial biopsy in the heart transplant patient: the state of the art]. / La biopsia endomiocardica nel paziente cardiotrapiantato: stato dell'arte.

Data regarding 2176 endomyocardial biopsies (EMB) (Nov. '85-Dec. '89) performed in 164 transplanted hearts (4 etherotopic) from 158 patients (6 retransplants) are herein reported. This study was aimed to evaluate: 1) Incidence and characteristics of early ischemic myocardial damage. 2) The influence of different immunosurveillance protocols on incidence, degree and aggressiveness of acute rejection and the inflammatory infiltrate composition. 3) The immunophenotype of infiltrating cells in moderate acute rejection episodes. 4) HLA-DR antigen expression on myocyte sarcolemma. 5) Characterization of cells expressing immune response mediators. 6) Myocardial localization of opportunistic infections. 7) Useful information on chronic rejection. Our results demonstrate that: a) Mild rejection seldom progresses to moderate degree. b) Different immunosuppressive protocols can influence the incidence of acute rejection: in fact, in OKT3 protocol, the incidence of rejection episodes is higher than in other protocols as well as aggressiveness toward myocytes. c) Infiltrating cells maintain T lymphocyte prevalence with minor amounts of B lymphocytes and macrophages in the 3 different protocols. T cell subset characterization showed a slight prevalence of CD8 bearing cells over CD4 positive cells whereas CD57 cells were few and scattered. d) Class II Major Histocompatibility Complex (HLA-DR) expression never occurs on myocyte sarcolemma. e) TNF alpha is expressed in acute cardiac rejection by immunologically activated T lymphocytes and macrophages and the number of immunoreactive cells increases with progression of the rejection. f) Human cytomegalovirus infections can be primary or recurrent. Myocardial involvement has been observed in primary forms. Virus can affect endothelial cells (with no inflammatory reaction) or myocytes (myocarditis) and its diagnosis requires a combination of immunohistochemical and molecular biology techniques. Diagnosis of Toxoplasma gondii infection can be usually accomplished by routine histopathological study. g) Chronic rejection diagnosis is rarely based on biopsy derived information.

Expression of tumor necrosis factor in human acute cardiac rejection. An immunohistochemical and immunoblotting study.

The authors performed an immunohistochemical study on expression of tumor necrosis factor alpha (TNF alpha) in endomyocardial biopsies from human cardiac allografts. TNF alpha immunoreactivity was found in 45% biopsies with mild acute rejection, in 83% biopsies with focal moderate rejection, in 80% biopsies with diffuse moderate rejection. Biopsies with absent rejection did not show immunoreactive cells. In mild rejection, positive cells were few and scanty monocytes and macrophages (MAC-387 and LN5 positive cells) and T lymphocytes (UCHL-1/CD45 RO positive cells) (up to 20% of all infiltrating cells). Expression of major histocompatibility complex (MHC) class II antigens on infiltrating and endothelial cells occurred earlier and independent of TNF alpha reactivity. Number of immunoreactive cells increased in moderate rejection (up to 50%). Immunoreactivity was also present in nonpigmented macrophages in part of the biopsies with resolving rejection (45%). The authors conclude that TNF alpha is expressed in acute cardiac rejection by immunologically activated inflammatory cells. Immunoreactive cells increase in number with increasing severity of the reaction.