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Only few data exist concerning right ventricular function in the chronic stage after cardiac transplantation. Therefore, we investigated hemodynamic and right ventricular volumetric data by a computerized thermodilution Swan-Ganz catheter in 17 patients (median age: 53, range: 18-63 yr) at a median of 24 (4 to 44) months after cardiac transplantation during rest and supine bicycle exercise. Myocardial biopsy showed grade one or less according to the classifications of Billingham. Sixteen patients with coronary artery disease, but without prior myocardial infarction, served for comparison. While angiographic left ventricular ejection fraction was nearly identical in transplant recipients [77 (60-92)%, median (range)] and in patients with coronary artery disease [78 (64-94)%], right ventricular ejection fraction was lower (p < 0.001) in patients after cardiac transplantation [37 (16-58)%] as compared to patients with coronary artery disease [56 (46-62)%]. In transplant recipients right atrial pressure was significantly higher both at rest [10 (2-18) mmHg] and exercise [18 (8-30) mmHg] than in patients with coronary artery disease [5 (1-11) and 8 (3-18) mmHg]. Pulmonary capillary wedge pressure behaved similar in both groups. To further evaluate reasons for right ventricular impairment, a correlation analysis was performed. This showed a negative correlation between right ventricular ejection fraction and the time interval after transplantation (p < 0.0002). However, there was no correlation between right ventricular ejection fraction and acute rejection or a rejection score. In conclusion, right ventricular function may be severely altered in transplant recipients, in contrast to an only slight impairment of left ventricular function.

Dysfunction of the vagal nerve, an early symptom in the development of autonomic neuropathy, can be assessed reliably by the beat-to-beat variation in heart rate. Patients after a cardiac transplantation are a unique model to investigate the beat-to-beat variation of a completely denervated heart. Heart rate and the beat-to-beat variation during normal and deep respiration were investigated in diabetic subjects with an autonomic neuropathy (n = 10), age and sex matched healthy controls (n = 10) and cardiac transplanted patients (n = 10). Further studies during pharmacological blockade of the parasympathetic nervous system with atropine were performed. In the denervated heart the coefficient of variation of the beat-to-beat interval was 0.38 +/- 0.02% during normal respiration, compared to 1.32 +/- 0.13% (P less than 0.0001) and 2.56 +/- 0.13% (P less than 0.0001) in the diabetic and control subjects, respectively. Administration of atropine (2 mg intravenously) decreased the coefficient of variation of the RR-interval to 0.73 +/- 0.09% in the diabetic patients (P less than 0.0005) and to 0.67 +/- 0.07% in the controls (P less than 0.0001), whereas the coefficient of variation remained unaffected in the cardiac denervated patients (0.39 +/- 0.02%). In the three groups an almost parallel increase of the RR-variation was observed during deep respiration at a rate of 6 breaths/min (from 0.38 +/- 0.02% to 1.99 +/- 0.38% in cardiac transplanted patients, P less than 0.0025; from 1.32 +/- 0.13% to 3.10 +/- 0.43% in diabetic patients, P less than 0.0025; from 2.56 +/- 0.13% to 5.42 +/- 0.94% in healthy controls, P less than 0.005). We conclude that a beat-to-beat variation of heart rate is present in the completely denervated heart. This RR-variation can not be influenced by a pharmacological blockade of the parasympathetic nervous system with atropine. The beat-to-beat variation increases during deep respiration not only in healthy controls but also in diabetic patients with autonomic neuropathy (partially denervated hearts) and cardiac transplanted patients (completely denervated hearts). This indicates an intracardiac mechanism in the modulation of heart rate.

The acute cardiotoxicity of cyclosporin A was studied in isolated cardiac myocytes from adult rats. In an initial series of 7 animals, myocytes were incubated with concentrations of cyclosporin A ranging from 1 microgram/ml to 50 micrograms/ml. Shape changes of untreated cells, cells treated with cyclosporin A and cells treated with the solvent of cyclosporin A, Tween 80/ethanol, were evaluated. After 8 hours and 16 hours, respectively, of incubation 92 +/- 4.3% and 72 +/- 8.7% of the non-treated control cells were still rod-shaped. Cyclosporin A, however, in a concentration of 5 micrograms/ml decreased the number of rod-shaped cells (79 +/- 3.2% at 8 hours and 51 +/- 3.5% at 16 hours) in comparison to the solvent (94 +/- 3.5% at 8 hours and 76 +/- 5.8% at 16 hours, P less than 0.02). This effect became more pronounced with higher concentrations of cyclosporin A. On the other hand, Tween 80/ethanol alone in higher concentrations also led to a reduced number of rod-shaped cells. In a second series of 7 animals using Tween 80/ethanol and methanol as drug vehicles, myocytes were incubated for 16 hours with 15 micrograms/ml of cyclosporin A in a calcium containing medium (1 mM) or a calcium free medium (10(-4) M ethylene glycol-bis(beta-aminoethyl ether) N,N,N',N'-tetraacetic acid). The number of remaining rod-shaped cells was higher in the calcium free medium as opposed to the medium containing calcium when the cells were exposed to cyclosporin A. It is concluded that in the applied model cyclosporin A at high concentrations has an acute cardiotoxic effect which in part appears to be calcium related.