In vivo quantification of myocardial muscarinic receptors in heart transplant patients.

BACKGROUND: Decreased myocardial adenylate cyclase activity in response to guanine nucleotide stimulation has been recently demonstrated in denervated myocardium of transplant patients, suggesting that changes in left ventricular muscarinic receptors may occur. METHODS AND RESULTS: The concentration and affinity constants of myocardial muscarinic receptors were determined by positron emission tomography with 11C-labeled methylquinuclidinyl benzilate (MQNB), a specific hydrophilic antagonist, in six transplant patients 4.7 +/- 2.3 months after surgery and in six normal subjects. Patients had no sign of cardiac rejection at endomyocardial biopsy. After intravenous injections of MQNB, time-activity curves were obtained over different regions of interest and were fitted to a nonlinear mathematical model. No difference in the concentration of muscarinic receptors was found in transplant patients compared with control subjects: 24 +/- 4 versus 26 +/- 7 pmol/mL tissue, respectively (P = NS). The association rate constant k+1, the dissociation rate constant k-1, and thus the equilibrium-dissociation constant Kd were the same in transplant patients compared with control subjects. CONCLUSIONS: Despite known decreased GTP-stimulated adenylate cyclase activity in transplant patients, the density and affinity constants of myocardial muscarinic receptors are not altered. This suggests abnormalities of the signal-transduction function, such as a change in the guanine nucleotide binding proteins.

[Cardiac and extracardiac abscesses in bacterial endocarditis]. / Les abcès cardiaques et extracardiaques dans l'endocardite infectieuse.

Cardiac abscesses are observed in 20 to 30% of cases of infective endocarditis and in at least 60% of prosthetic valve endocarditis. The aortic valve ring is more frequently affected than the mitral valve ring. A cavity contiguous with a cardiac chamber forming a pseudo-aneurysm or a closed purulent collection, the abscess may extend to the neighbouring cardiac structures or to the ascending aorta. This extension may cause conduction defects, abnormal communications between the cardiac chambers, pericardial disease and, exceptionally, myocardial ischaemia, complications which are clinical signs of abscess formation in patients with infective endocarditis. The presence of a cardiac abscess is a poor prognostic factor in infective endocarditis. The diagnosis must be made at an early stage when surgical treatment is optimal. The most valuable investigation is transoesophageal echocardiography with a sensitivity of over 80% and a specificity of about 95%. This investigation has become practically routine in all patients with endocarditis in order to diagnose abscesses at an early stage, especially in cases of aortic or prosthetic valve endocarditis. Information about the site, size and extension of the abscess may be obtained and existing or potential complications may be envisaged with a view to surgery. Other imaging diagnostic techniques, such as angiography, CT scanning and nuclear magnetic resonance imaging have a number of disadvantages and are not more sensitive than transoesophageal echocardiography. Surgical techniques depend on the site and extension of the abscess. They are sutured or closed with dacron or pericardial patches after having been cleaned and filled with formulated resorcin glue. The valvular prosthesis is inserted either in anatomical position or in a sub or supracoronary dacron tube necessitated by the perivalvular extension of the infectious lesions. These complex procedures may require associated coronary reimplantation or revascularisation when the coronary ostia are affected. The highest operative mortality is observed in prosthetic valve endocarditis with abscess and extra-annular prosthetic implants. The risk of secondary valvular dehiscence, often recurrent, is much higher when there is an abscess at operation. Extracardiac abscesses in cases of infective endocarditis are mainly observed in the cerebral and/or splenic territories. They may become the main problem, especially cerebral abscesses, but they rarely require surgery.

Coronary artery vasomotion in cardiac transplant patients with normal coronary angiograms.

In 18 consecutive transplant patients with normal coronary angiograms and without calcium blocker therapy, and in 20 controls, we measured the diameters of the left anterior descending artery using quantitative coronary angiography. Measurements were effected on the frames recorded 5 min or more after intravenous administration of 0.4 mg methylergometrine, and 2 min after subsequent 2 mg bolus intracoronary isosorbide dinitrate administration. The arterial vasodilatory capacity was defined as the ratio of the difference of the largest and smallest arterial diameters and the smallest diameter. We observed normal vasoconstriction of the different coronary arterial segments. Coronary arterial diameter decrease from basal state was about 8% and was more pronounced at the distal segments of the left anterior descending artery. There was no difference of vasodilatory capacity between transplant patients and controls for the proximal and middle portion of the left anterior descending artery, while the difference was highly significant for the distal portion. In eight patients, the decrease of the vasodilatory capacity was beyond the lower limit of the normal range of values. The significance of those quantitative angiographic abnormalities is still unproven. They could be due to early vasomotor capacity blunting after transplantation and to late structural alterations of distal coronary vessels in cardiac transplant patients.

Implications of de novo ELAM-1 and VCAM-1 expression in human cardiac allograft rejection.

Both cytokines produced by activated monocytes and T cells and direct cell-to-cell contact with antigen-primed T cells during inflammatory reactions are known to induce the expression of several adhesion proteins on endothelial cells. In this prospective longitudinal study, we analyzed the expression of ELAM-1, VCAM-1, and ICAM-1 on myocardial allograft biopsy specimens taken from 16 cardiac allograft recipients either for routine monitoring or for the investigation of suspected rejection. Infiltrating T cells were identified using anti-CD3 antibodies. Three to six sequential biopsies taken at one-week intervals were analyzed by means of conventional histology and immunohistochemistry. Seven patients did not develop rejection during the study; their biopsies were negative for VCAM-1 and ELAM-1, although faint ICAM-1 staining was present on capillaries, reflecting constitutive expression. Three patients entered the study with clear-cut clinical and histologic signs of acute rejection. Intense VCAM-1 and ICAM-1 expression was detected on capillary and postcapillary venules, together with a heavy CD3+ T cell infiltrate; VCAM-1 was also expressed on arteriolar endothelial cells. ELAM-1 was undetectable in all three cases. Six patients developed acute rejection during the course of the study. In four, ELAM-1 and VCAM-1 were expressed on both capillary and postcapillary venules one or two weeks before the histological diagnosis of rejection (heavy CD3+ cell infiltrate). Importantly, ELAM-1 expression was short-lived and had disappeared by the time CD3+ cellular infiltrate was detected, thus extending in vivo the finding that ELAM-1 expression is usually transient in vitro. Only VCAM-1 expression was observed in the other two patients, one week prior to the histological diagnosis of rejection. These results suggest that ELAM-1 and VCAM-1 might represent early predictive markers of acute cardiac allograft rejection. ELAM-1 expression is, however, usually transient, necessitating frequent testing.

[Acute cardiac graft rejection after orthotopic cardiac transplantation. Elements of diagnosis and monitoring, therapeutic attitude]. / Le rejet aigu de greffon cardiaque après transplantation cardiaque orthotopique. Eléments de diagnostic et de surveillance, attitude thérapeutique.

The diagnosis of acute rejection in heart allograft recipients receiving cyclosporine is still an important challenge. The poor diagnostic value of clinical signs and the ECG means that regular endomyocardial biopsies must be performed. Despite their diagnostic value during the first year after transplantation, endomyocardial biopsies are less sensitive there after and currently suffer from the lack of a universally accepted histological classification. Doppler echocardiography can be used for routine surveillance and has proven reliable for the diagnosis of acute rejection with various clinical presentations when used in conjunction with endomyocardial biopsies. Immunohistological examination of myocardial specimens can further increase the sensitivity of histological diagnosis. Similarly, immunoscintigraphy with indium 111-labelled antimyosin antibodies is of value for the prediction of acute rejection after the first year. Therapeutic approaches have been standardized, but must still be tailored to the individual patient according to the severity of the rejection and the presence of associated infection and/or metabolic disturbances.

[Immediate and long-term results of coronary surgery under age 40]. / Résultats immédiats et à distance de la chirurgie coronaire avant 40 ans.

The results of coronary artery surgery in young adults have not been extensively studied. We analysed the results of 221 patients under 40 years of age operated between 1979 and 1989 at the Pitié-Salpêtrière Hospital. The patients were 200 men and 21 women with an average age of 36.2 years. The most common cardiovascular risk factors were smoking (69.6%) and hyperlipidaemia (52%). One hundred and eighteen patients (53.4%) had previous myocardial infarction (MI). Triple vessel disease was present in 129 cases, double vessel disease in 59 cases and single vessel disease in 33 cases. Twenty three patients had significant left main coronary disease. The number of bypass grafts per patient averaged 2.3. The operative mortality was 2.07% (6 cases), death being due to myocardial infarction in 4 cases. Perioperative myocardial infarction was diagnosed in 12 cases (5.05%). One hundred and ninety nine patients were followed up for an average of 7.4 years. Seven of the 17 late fatalities were of cardiac origin. The actuarial 9 year survival rate was 84%. Five patients were reoperated after an average of 6.4 years. Eighty five per cent of patients were asymptomatic at the last follow-up examination. In conclusion, the symptoms of coronary artery disease in young adults can be effectively treated with a low operative risk by myocardial revascularisation surgery. Long-term follow-up remains essential to define the outcome in these patients. Systematic use of internal mammary artery bypass grafting should improve these results in the future.

[Coronary pathology after heart transplantation]. / Pathologie coronaire après transplantation cardiaque.

Graft coronary disease is a frequent and devastating complication with rapid development after heart transplantation. Until now, non-invasive and invasive methods have proved to be insensitive in the prediction and detection of the early stages of this disease. Conventional arteriography is considered as the only reliable means of diagnosis, but it remains insensitive in the accurate evaluation of the severity of graft coronary lesions (obliterative, diffuse and distal lesions). Precise quantitation of coronary lumen changes may be a sensitive method for the accurate evaluation of graft coronary disease and help in the understanding of the natural course of development of this disease. The pathogenesis of the disease is still unclear. It is possible that graft coronary disease is a consequence of non-treated low-grade cellular rejections. In most cases, retransplantation must be considered as the unique solution.

Heart-lung transplantation in situs inversus. A case report in a patient with Kartagener's syndrome.

After a long history of recurrent chronic pulmonary infections in a 25-year-old woman with Kartagener's syndrome, a heart-lung transplantation was performed. A modified surgical procedure was needed to perform transplantation because of the presence of a situs inversus, which is usually associated with bronchiectasis and sinusitis in this congenital syndrome. A large single atrium was created with both the right and left recipient atria used to facilitate anastomosis with the donor's right atrium. The patient was discharged after resolution of early ventilatory complications and is in good condition 8 months after transplantation.

Heart and heart-lung transplantation in the 1990s.

After 22 years of clinical application in our unit, heart transplantation is now an accepted therapeutic method. Its indications are well established, its surgical technique and post-operative control and treatment well defined, mostly due to better diagnosis of the rejection episodes with the aid of echocardiography and endomyocardial biopsy and the use of cyclosporin. The results are remarkable with a survival rate of 70% at 5 years, and a full rehabilitation into family, social and often professional life for almost all the survivors. Its use has dramatically changed the prognosis of patients with irreversible cardiac failure but underlines the lack of a sufficient number of donors' hearts. The heart-lung transplantation, making use of the progress of heart transplantation, has been used successfully since 1982 and for the first time in Europe by our group. Improvement in the selection of recipients, lung preservation, surgical technique and post-operative management have brought a new and real hope to patients not only irreversible cardiopulmonary lesions but also terminal pulmonary disease.

Chronic liver dysfunction in heart transplant recipients, with special reference to viral B, C, and non-A, non-B, non-C hepatitis. A retrospective study in 80 patients with follow-up of 60 months.

In order to assess the prevalence, causes, and severity of chronic liver dysfunction (LD) in heart transplant patients, 80 transplanted patients followed for 60 months (median; range, 1.5-98 months) were reviewed. Sustained liver dysfunction was found in 50 patients, occurring during the first year after heart transplantation in 42 (84%) of them. Most patients were asymptomatic (80%). Causes for the liver dysfunction included non-A, non-B hepatitis in 16 cases (32%), viral B hepatitis in 13 (26%), delta hepatitis in one (2%), drug-induced hepatitis in six (12%), and cardiac failure in seven (14%). Anti-HCV antibodies were found in 56.2% of patients with non-A, non-B hepatitis and in 22% of patients with HBV hepatitis. It was found neither in patients with drug-induced hepatitis cardiac failure nor in patients with normal liver tests. This study outlines a high prevalence of LD (62.5%) in heart transplant patients, the high frequency of viral-related chronic LD (usually of moderate severity), and high incidence of HCV and HBV hepatitis.

[Heart transplantations: impact on female fertility]. / Transplantations cardiaques: répercussions sur la fécondité féminine.

Improvements in the management of patients with cardiac transplantation make it possible for these patients in the child-bearing age to expect a pregnancy. In fact, since 1987, several cases of pregnancy after cardiac transplantation have been reported. We report here two cases of successful pregnancy two years after cardiac transplantation. First Case. Pregnancy was uneventful until 36 weeks of gestation with no evidence of transplant rejection. At 38 weeks of gestation, a cesarean section was performed for increasing blood pressure, cholestatic pruritus and cephalopelvic disproportion. Cesarean section was performed under regional anesthesia and a healthy baby boy of 2680 gr was delivered. The patient was discharged one week after. Eighteen months after, both the mother and the baby are in good condition. Second case. Pregnancy was complicated by severe maternal anemia and fetal hypotrophia. Because of increasing renal insufficiency and pre eclampsia, a cesarean section was performed under regional anesthesia at 36 weeks of gestation. Delivery of a healthy baby girl of 1700 g. Five other cases have been reported. Cesarean section performed in september 1984 for a patient who underwent cardiac transplantation in 1980. Delivery of a healthy baby of 3280 gr. Death of the mother five months after following heart transplant rejection. Vaginal delivery performed in august 1986 for a patient who underwent cardiac transplantation in 1984. Delivery of a preterm baby at 31 weeks of gestation who survived without any sequelae. Vaginal delivery performed in august 1987 for a patient who underwent cardiac transplantation in april 1985. Delivery of a healthy baby of 2550 gr at 38 weeks of gestation. Vaginal delivery of twins (baby girl of 1200 and 1100 gr) in april 1988 of a patient who underwent cardiac transplantation in 1986. Vaginal delivery at 38 weeks of gestation performed in november 1990 for a patient who underwent cardiac transplantation in 1986. All the cases reported showed that: The foetus is not affected by the immuno-suppressive treatment of the mother. This was already known for pregnant patients with renal transplant. The cardiovascular changes associated with pregnancy are well tolerated by the heart transplant. Preexisting hypertension is increased, particularly during the third trimester of pregnancy and during labour. The incidence of preterm labor is increased in patients with heart transplant. Transplant rejection never occurred during pregnancy.

Lipoproteins in heart transplantation: proton magnetic resonance spectroscopy of plasma.

Despite the major improvement in immunosuppressive therapy, noninvasive detection of heart graft rejection remains a challenge. As lipoproteins are involved in several immunomodulation mechanisms, we studied their proton NMR spectra in plasma from patients after heart transplantation. NMR data were compared to clinical and functional evaluation of rejection process. The total linewidth (TLW) of methyl and methylene peaks, mainly arising from lipoproteins, were significantly lower for patients without a rejection process than for patients before surgery and patients with evidences of a rejection process. When TLW values are referred to TLW on the 8th day for each patient, the sensitivity and the specificity of the test are increased, with resulting positive and negative predictive values of 90 and 91%, respectively. The results obtained on more than 400 samples from 46 patients justify the use of proton NMR spectroscopy as a clinical tool.

Ventricular function during the acute rejection of heterotopic transplanted heart: gated blood-pool studies.

Twenty patients who had undergone a heterotopic heart transplant were studied prospectively to determine the relationship between rejection and ventricular dysfunction assessed from gated blood-pool studies. A fully automated method for detecting ventricular edges was implemented; its success rate for the grafted left and right ventricles was 94% and 77%, respectively. The parameters, peak ejection and filling rates, were calculated pixel per pixel using a two-harmonic Fourier algorithm and then averaged over the ventricular region of interest. Peak filling and ejection rates were closely related with the severity of the rejection, while the left ventricular ejection fraction was not. Peak filling rates of both ventricles were the indices closely related to the presence of moderate rejection. Despite the low number of patients, these data suggested that gated blood-pool-derived indices of ventricular function are associated with ventricular dysfunction resulting from myocarditis rejection. Radionuclide ventriculography provides parametric data which are accurate and reliable for the diagnosis of rejection.

[Intermediate and late changes in human cardiac graft]. / Modifications vasculaires semi-tardives et tardives du greffon cardiaque humain.

Chronic rejection, the most serious complication in long-term survivors of cardiac transplantation, was studied in 5 cardiac grafts obtained at retransplantation and in 15 post-mortem studies of patients who had survived 3 months to 10 years after transplantation. The usual clinical presentation was cardiac failure. Coronary angiography was performed in several cases and showed narrowing and non-opacification of small arteries often accompanied by thrombosis. Histology showed three types of vascular rejection: the most characteristic one, usually observed after the 6th month, was a stenosing fibrous endarteritis; another type of rejection, occurring earlier, was associated with acute myocardial rejection and presented as an inflammatory arteritis; the third type of vascular rejection was accompanied by widespread atheromatous lesions. The significance and pathogenesis of these lesions are discussed with respect to the clinical context with electron microscopic and immuno-histochemical data.

Heart transplantation: La Pitié experience, 1968-1989.

Heart transplantation is now an accepted therapeutic modality for end-stage heart disease. However, better immunosuppressive treatments and new methods to monitor rejection or detect early atherosclerosis must be developed to improve the long-term results after heart transplantation.