Cardiac hypertrophy after transplantation is associated with persistent expression of tumor necrosis factor-alpha.

BACKGROUND: The mechanisms that contribute to cardiac allograft hypertrophy are not known; however, the rapid progression and severity of hypertrophy suggest that nonhemodynamic factors may play a contributory role. Tumor necrosis factor-alpha (TNF-alpha) is a cytokine produced in cardiac allografts and capable of producing hypertrophy and fibrosis; therefore, we suggest that TNF-alpha may play a contributory role. Accordingly, the aims of our study were to define the role of systemic hypertension in the development of hypertrophy, characterize the histological determinants of hypertrophy, and characterize the expression of myocardial TNF-alpha after heart transplantation. METHODS AND RESULTS: To separate the effect of hypertension from immune injury in the development of cardiac allograft hypertrophy, we measured the gain in left ventricular mass by 2D echocardiography in heart transplant recipients and lung transplant recipients who developed similar rates of systemic hypertension. The gain in left ventricular mass was 73% in heart transplant recipients and 7% in lung transplant recipients (P<0.0001). By comparing myocardial samples obtained during the first week after transplant and at 1 year, we found that there was a significant increase in total collagen content (P<0.0001), collagen I (P<0.0001), collagen III (P<0.0001), and myocyte size (P<0.0001). These changes were associated with persistent myocardial TNF-alpha expression. CONCLUSIONS: We suggest that the contribution of hypertension to cardiac allograft hypertrophy is minimal and that persistent intracardiac expression of TNF-alpha may contribute to the development of cardiac allograft hypertrophy.

Decreased expression of tumor necrosis factor-alpha and regression of hypertrophy after nonsurgical septal reduction therapy for patients with hypertrophic obstructive cardiomyopathy.

BACKGROUND: Nonsurgical septal reduction therapy (NSRT) is a novel therapeutic strategy for patients with hypertrophic obstructive cardiomyopathy (HOCM). Although the clinical benefits of this technique appear to be clear, the structural and functional changes that lead to improvements in cardiac function are not completely defined. In these studies, we sought to define the effect of NSRT on myocardial function as well as various markers of hypertrophy including the expression of tumor necrosis factor (TNF)-alpha, a cytokine capable of producing fibrosis, left ventricular hypertrophy (LVH), and cardiomyopathy. METHODS AND RESULTS: We performed endomyocardial biopsies of the RV side of the septum and echocardiograms on 15 HOCM patients at baseline and after successful NSRT. Comparative analysis on paired myocardial samples were performed to determine the effects of NSRT on LVH, end-diastolic volume and chamber stiffness, myocyte size, collagen content, and TNF-alpha levels. At baseline, myocardial TNF-alpha levels were increased in all patients. After NSRT, myocyte size, collagen content, and TNF-alpha were significantly decreased. These changes were accompanied by an increase in left ventricular volumes and a reduction in LVH and chamber stiffness. CONCLUSIONS: We suggest that pressure overload in HOCM patients contributes to the development of hypertrophy. These data provide the initial experimental evidence to suggest that TNF-alpha may play a pathogenetic role in the hypertrophy of pressure overload.

Regression of fibrosis and hypertrophy in failing myocardium following mechanical circulatory support.

BACKGROUND: The cellular and structural changes that occur during long-term ventricular unloading leading to cardiac recovery are poorly understood. However, we have previously demonstrated that left ventricular assist device (LVAD) support leads to a significant decrease in intracardiac tumor necrosis factor-alpha (TNF-alpha), a protein capable of producing hypertrophy and fibrosis. METHODS: To further define the beneficial effects of long-term ventricular unloading on cardiac function, we determined the effect of mechanical circulatory support on fibrosis and hypertrophy in paired myocardial samples of 18 patients with end-stage cardiomyopathy obtained at the time of LVAD implantation and removal. RESULTS: We determined total collagen as well as collagen I and III by a semiquantitative analysis of positive immune-stained areas in pre- and post-LVAD myocardial samples. We found that total collagen content was reduced by 72% (p < 0.001), whereas collagen I content decreased by 66% (p < 0.001) and collagen III content was reduced by 62% (p < 0.001). Next, we determined myocyte size by direct analysis of cellular dimensions utilizing a computerized edge detection system in pre- and post-LVAD myocardial samples. We found that myocyte size decreased in all patients studied for an average reduction of 26% (33.1 +/- 1.32 to 24.4 +/- 1.64 microm, p < 0.001). CONCLUSION: These data demonstrate that long-term mechanical circulatory support significantly reduces collagen content and decreases myocyte size. We suggest that the reduction of fibrosis and hypertrophy observed may in part contribute to the recovery of cardiac function associated with long-term mechanical circulatory support.