Transforming growth factor beta and myocardial dysfunction following heart transplantation.

OBJECTIVE

We analyzed the role of transforming growth factor-beta (TGF-beta), a fibrogenic cytokine, in the development of left ventricular diastolic dysfunction following heart transplantation.

METHODS

We studied 152 heart transplant recipients who had survived for at least 24 months. We compared histopathological findings (staining of endomyocardial biopsy specimens using Hematoxylin Eosin and polyclonal antibodies), left ventricular function (Doppler echocardiography) and clinical course (NYHA status). Patients are classified into group A (n=56 recipients) with immunohistochemical TGF-beta staining score >7 and group B (n=96 recipients) with a staining score <7.

RESULTS

Doppler echocardiographic evaluation demonstrated greater impairment of left ventricular diastolic function in recipients with higher TGF-beta staining score. The average mitral deceleration time was 129+/-6 ms for recipients group A compared to 167+/-15 ms in group B. While the mean isovolumic relaxation time was 65+/-8 ms for patients in group A compared with 82+/-6 ms for recipients in group B (P=0.0004 and 0.005, respectively). Immunohistochemical scoring correlated inversely with both mitral deceleration and isovolumic relaxation times (r=-0.74, P=0.0004 and r=-0.66, P=0.004, respectively). Mean NYHA status was 2.7+/-1.3 for group A compared to 1.17+/-0.4 in group B was (P=0.002). Five years follow-up revealed persistent left ventricular diastolic impairment for recipients with higher immunohistochemical staining score. Mitral deceleration time and isovolumic relaxation time were 118+/-11 and 62+/-7 ms for group A compared to 156+/-12 and 80+/-5 ms for group B, P=0.006 and P=0.01, respectively. The actuarial development of subsequent coronary artery disease (> 50% stenosis) was 17 and 29% for recipients in group A compared to 4 and 6% for recipients in group B at 3 and 5 years follow-up, respectively (P=0.01 and P=0.005, respectively).

CONCLUSIONS

TGF-beta expression in cardiac allografts is associated with impaired graft function and limited survival. The pathogenesis of diastolic dysfunction may be an aberrant repair process following rejection due to increased TGF-beta expression in transplant recipients.