M. Yacoub

Tumour necrosis factor and inducible nitric oxide synthase in dilated cardiomyopathy

BACKGROUND Two important features of dilated cardiomyopathy (DCM) are low myocardial contractility and risk of thromboembolism. Nitric oxide (NO) exerts a negative inotropic effect on the myocardium and is produced by NO-synthase, an inducible form of which (iNOS) is stimulated by tumour necrosis factor (TNF-alpha). Accordingly, we hypothesized that locally produced TNF-alpha might contribute to the pathogenesis and complications of DCM by inducing iNOS in the heart. METHODS iNOS and TNF-alpha were quantified by histochemistry and computerised image analysis in explanted heart tissues or myocardial biopsy material from patients with DCM (n = 21) or ischaemic heart disease (HD; n = 10) and from normal donor hearts (n = 9). FINDINGS Immunoreactivity for iNOS was strong in myocytes of DCM hearts, particularly in areas adjacent to the endocardium, and moderately intense in blood vessels of DCM and IHD hearts. The median optical density of the immunostaining for iNOS was greater in cardiac myocytes of patients with DCM (0.86, range 0.21 to 1.29) than in those from patients with IHD (0.20, range 0.095 to 0.26) (p < 0.01) or controls (0.01, range 0.001 to 0.02) (p < 0.001). Staining for TNF-alpha was observed in the vascular endothelium and smooth muscle cells of patients with DCM but not in IHD or control tissues. INTERPRETATION The localisation of iNOS and TNF-alpha within cardiac tissues in DCM suggests that TNF-alpha contributes to both the low contractility and the tendency to thromboembolism in these patients.

Two-stage operation for anatomical correction of transposition of the great arteries with intact interventricular septum.

To allow redevelopment of the posterior ventricle in an infant with transposition of the great arteries and intact interventricular septum, at the age of 4 weeks the pulmonary artery was banded, an aortopulmonary shunt was fashioned proximal to the band, and atrial septectomy was performed. Peak systolic posterior ventricular pressure immediately rose to systemic level (70 mm Hg.) During the next 4 months the pressure drifted back to 55 mm Hg but rose to 72 mm Hg after angiography without a rise in end-diastolic pressure. When the child was six months old anatomical correction of the transposition was successfully performed, the aorta, pulmonary, and coronary arteries being reattached to the appropriate ventricles. Debanding was performed at the same time. For the first 48 hours after operation phenoxybenzamine was given to reduce overload. At 6-month follow-up the child remained symptomless and was not on any cardiac drugs; left-ventricular function was good. This two-stage technique should widen the application of anatomical correction from a small selected group with additional defects to include most patients with transposition of the great arteries.

Lipoprotein(a) and accelerated coronary artery disease in cardiac transplant recipients

High concentrations of serum lipoprotein(a) (Lp(a)) are associated with an increased risk of atherosclerotic vascular disease in the nontransplanted population. However, its relation with accelerated coronary artery disease (CAD) in cardiac transplant recipients has not been reported. We measured serum Lp(a) in 130 cardiac transplant recipients undergoing routine follow-up, which included annual coronary angiography. The median Lp(a) concentration in 33 patients with CAD was 71 mg/dl, which was significantly higher than the corresponding value of 22 mg/dL in the 97 patients without CAD (p = 0.0006). Multivariant analysis showed the serum Lp(a) value to be a higher significant risk factor for CAD irrespective of the other factors included in the regression analysis. Thus a high concentration of serum Lp(a) is an important, independent risk factor for the development of accelerated CAD in transplant recipients.

Determinants of outcome after heterotopic heart transplantation

BACKGROUND Donor availability is currently the major factor limiting the use of heart transplantation as a treatment for severe heart failure. Heterotopic heart transplantation may address this issue by allowing the use of smaller donor organs, which otherwise may not be used. METHODS We analyzed the outcome of 42 consecutive, adult heterotopic transplantations performed between 1993 and 1999 at our center and compared them with the 303 consecutive orthotopic transplants performed in adult patients during the same period. METHODS Univariate analysis showed a relative risk for death of 1.8 at 1 year after transplantation for the heterotopic group compared with the orthotopic transplantation group (p = 0.04). Multiple regression analysis using a proportional hazards model showed that donor-recipient size-mismatch, i.e., donor body surface area < or =75% of recipient body surface area (p = 0.0001), donor age (p = 0.0001), and use of a female donor (p = 0.04) were significant risk factors but heterotopic transplantation per se was not. A Kaplan-Meier survival analysis of heterotopic vs orthotopic transplantation showed that 30-day survival was 76% vs 87%. By 1 year, this was 59% vs 74%. At 3 years, the comparison was 56% vs 69%. Repeating this analysis after sub-dividing the heterotopic group into those size-matched vs size-mismatched, the 1-year survival was 81% vs 45%, respectively (p = 0.02). CONCLUSIONS Heterotopic transplantation using a size-matched graft resulted in similar survival to that seen after orthotopic transplantation during the same period. Heterotopic transplantation with an undersized graft resulted in significantly decreased survival.

Primary cardiac tumours--is there a place for cardiac transplantation?

Between 1979 and 1985, seven patients (five children and two adults) were treated for primary cardiac tumours other than benign atrial myxomas. There were five malignant neoplasms (two non-classifiable sarcomas, one haemangiosarcoma, one histiocytoma and one neurofibrosarcoma) and two benign tumours (fibromas). Echocardiography, cardiac catheterisation, computed tomography and magnetic resonance imaging provided diagnostic confirmation. The two patients with fibroma are alive and well 4 and 5 years after radical resection of the tumours from the interventricular septum. The patient with a neurofibrosarcoma underwent orthotopic cardiac transplantation and is well 5.5 years postoperatively with no evidence of residual disease or recurrence. One patient died awaiting a donor heart for transplantation. Another patient who was a candidate for heart and lung transplantation was found to have an unresectable tumour at the time of operation. One patient with sarcoma who underwent a successful emergency partial resection for relief of cardiac tamponade died 18 months later from widespread metastases. The seventh patient was inoperable due to multiple secondaries. It is concluded that radical resection of large, benign, cardiac tumours can give good results and that early cardiac transplantation probably offers the only hope for patients with malignant tumours of the heart.

Low-dose simvastatin for the treatment of hypercholesterolaemia in recipients of cardiac transplantation

There is increasing evidence that hypercholesterolaemia is an important contributor to the development of accelerated coronary arterial disease in the cardiac allograft. The optimal drug therapy of hypercholesterolaemia in recipients after cardiac transplantation, however, has not been defined. Simvastatin (an inhibitor of hydroxy-methyl glutaryl-coenzyme A reductase), at a dose of 10 mg/day, was administered to 12 recipients with serum total cholesterol greater than or equal to 7.8 mmol/l and serum triglyceride less than or equal to 4.5 mmol/l refractory to dietary measures during a follow-up period of 1-5 years after cardiac transplantation. All patients received maintenance doses of cyclosporin A and, in some instances, azathioprine and prednisolone. After 2 months treatment with simvastatin, serum total cholesterol was significantly reduced from 8.8 +/- 0.3 mmol/l (mean +/- SEM) to 5.5 +/- 0.5 mmol/l, P less than 0.001, low density cholesterol from 6.6 +/- 0.4 to 3.8 +/- 0.3 mmol/l, P less than 0.001 and triglycerides from 2.4 +/- 0.2 mmol/l to 1.8 +/- 0.2 mmol/l, P less than 0.005. These changes were maintained after a period of treatment of 8 months. Serum high density cholesterol, hepatic transaminase levels, serum creatinine, creatine kinase and cyclosporin A blood levels were not altered by treatment with simvastatin. It is concluded that, in this study group, low-dose simvastatin appears to be well tolerated and has favourable lipid modifying properties.

Relationship of immunosuppression and serum lipids to the development of coronary arterial disease in the transplanted heart.

Coronary arterial disease in the cardiac allograft has emerged as the most serious long term complication of cardiac transplantation. The influence of patient-related and other potential risk factors on the development of coronary arterial disease at 1 year subsequent to cardiac transplantation was examined in 207 recipients. The mean age of donors in patients with coronary arterial disease was 28.5 +/- 9.5 years, compared to 22.6 +/- 7.9 years in patients without coronary arterial disease (P less than 0.01). Eight of the 35 patients who received immunosuppression by means of prednisone and azathioprine developed coronary arterial disease compared to 5 of the 172 patients who were treated with cyclosporin and azathioprine without routine oral prednisone (P less than 0.01). The relationship of levels of serum lipids to the subsequent development of coronary arterial disease was investigated in 95 patients with angiographically normal coronary arteries one year after cardiac transplantation. The cumulative probability of coronary arterial disease in those with total cholesterol greater than 5.8 mmol/l was 9.3% at 2 years (n = 40), 24.4% at 4 years (n = 21) and 45% at 4 years (n = 9) compared with 4.3% at 2 years (n = 45), 7.4% at 3 years (n = 32) and 14% at 4 years (n = 14) in those with a total cholesterol less than 5.8 mmol/l (P less than 0.05). Similarly, the incidence of coronary arterial disease was increased in patients with serum triglyceride greater than 1.4 mmol/l (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

HEART TRANSPLANTATION FOR PERIPARTUM CARDIOMYOPATHY

from week 16. After this initial phase she was given weekly exchanges but the antibody levels rose; thereafter she required plasma exchange twice weekly through repeated jugular or femoral puncture to establish and maintain normal antibody levels. At 34 weeks she was successfully delivered by caesarean section of a normal boy weighing 2-05 kg. A serious post-partum haemorrhage complicated delivery, which occurred later in the day after an exchange, and exchanges were phased out and steroids slowly tapered to avoid possible rebound thrombosis. It is impossible to be sure that removal of the antiphospholipid antibody was the prerequisite for the successful pregnancy, but it

Antiheart antibodies following open heart surgery: incidence and correlation with postpericardiotomy syndrome.

One-dimensional sodium dodecyl sulphate polyacrylamide gel electrophoresis of myocardial proteins followed by Western blotting is a sensitive method for the detection of antiheart antibodies after cardiac transplantation. In a previous study we found that the majority of patients made antiheart antibodies after cardiac transplantation. It is possible that these antibodies were formed in response to cardiac damage caused during the surgical procedure rather than being specific to the transplantation situation. In this study we have evaluated the role of open cardiac surgery in the formation of antiheart antibodies for the first 9 months of the postoperative period using the Western blotting technique and correlated that with the development of post-pericardiotomy syndrome. Only 25% (9/36) of patients showed any increase in the pre-existing level of antiheart antibodies or developed antiheart antibodies with new reactivities. None of the patients in the study developed manifestations specific for post-pericardiotomy syndrome during the period of follow-up. The results support the contention that the high incidence of antiheart antibodies formed after cardiac transplantation is due to a humoral immune response to the presence of alloantigens on the grafted heart rather than as a result of the surgical procedure itself.

Early experience with single lung transplantation for emphysema with simultaneous volume reduction of the contralateral lung.

OBJECTIVE Single lung transplantation (SLT) for emphysema has given satisfactory long term results in most patients. The mediastinal shift caused by the native emphysematous lung may require further surgical intervention in selected cases. METHODS We report a technique of simultaneous SLT and volume reduction of the contralateral lung in 4 patients with end stage respiratory failure secondary to emphysema. There were two right and two left SLT, performed in two male and two female patients. Their mean age was 52.2 (S.D. 4) years (range between 41 and 57 years) and the ischaemia time averaged 255.6 (S.D. 16) min (range between 225 and 255 min). The volume of the contralateral lung was reduced using staples. The stapled lines were buttressed by the donors pericardium. RESULTS Their were no operative related complications apart from air leak which settled spontaneously within 5 days postoperatively. Teh pre-operative FEVI showed a mean value of 0.57 (S.D. 0.1) L (17.2% (S.D. 2) of the predicted) which improved to 1.79 (S.D. 0.4) L (58.2% (S.D. 8) of the predicted) at last follow up (P < 0.005). Radiological examinations at 1 year showed central mediastinum with satisfactory respiratory function. CONCLUSION We conclude that this technique can be performed for patients with emphysema without increase in the operative morbidity and with good early respiratory function. Further follow up is required to assess the long term results of this procedure.