Age-Dependent Myocardial Reinduction of Apoptosis Inhibitors under VAD in Heart Failure[∗]

Hemodynamic unloading using the ventricular assist device [VAD] results in partial functional recovery of failing hearts that show increased susceptibility to cardiomyocyte apoptosis. The caspase cascade is the central element of the apoptotic process in cells. We therefore tested expression shifts of left ventricular mRNA of caspases and their endogenous inhibitors from 15 patients with VAD support and successful bridging to transplantation using semiquantitative RT-PCR. Cardiac unloading was shown by the reduction in ventricular Pro-ANP mRNA under VAD. No alteration of mRNA expression under VAD could be observed for initiator caspases, for their selective inhibitors or for apoptotic signal molecules from the mitochondrial intermembrane space. Only two unselective cardiac IAPs (inhibitor of apoptosis protein) were increased under VAD with better recovery in younger patients. In conclusion, our findings indicate that successful hemodynamic unloading by VAD support causes only minor, age-dependent recovery in the expression of IAPs, while presumed alterations in antiapoptotic modulator systems upstream of the caspase cascade still remain to be identified.

Key words:

Apoptosis - Heart failure - Ventricular assist device - Gene expression - Age dependence

1 Presented at the 30^th annual meeting of the German Society for Thoracic and Cardiovascular Surgery in Leipzig, February 18 - 21, 2001

References

• 1 Bing O H. Hypothesis: apoptosis may be a mechanism for the transition to heart failure with chronic pressure overload.  J Mol Cell Cardiol.. 1994;  26 943-948
• 2 Frazier O H, Rose E A, McCarthy P. et al . Improved mortality and rehabilitation of transplant candidates treated with a long-term implantable left ventricular assist system.  Ann Surg.. 1995;  222 327-336; discussion 336 - 338
• 3 Bartling B, Milting H, Schumann H. et al . Myocardial gene expression of regulators of myocyte apoptosis and myocyte calcium homeostasis during hemodynamic unloading by ventricular assist devices in patients with end-stage heart failure.  Circulation.. 1999;  100 II216-223
• 4 Torre-Amione G, Stetson S J, Youker K A. et al . Decreased expression of tumor necrosis factor-alpha in failing human myocardium after mechanical circulatory support: A potential mechanism for cardiac recovery.  Circulation.. 1999;  100 1189-1193
• 5 Nakatani S, McCarthy P M, Kottke-Marchant K. et al . Left ventricular echocardiographic and histologic changes: impact of chronic unloading by an implantable ventricular assist device.  J Am Coll Cardiol.. 1996;  27 894-901
• 6 Budihardjo I, Oliver H, Lutter M, Luo X, Wang X. Biochemical pathways of caspase activation during apoptosis.  Annu Rev Cell Dev Biol.. 1999;  15 269-290
• 7 Seol D W, Billiar T R. A caspase-9 variant missing the catalytic site is an endogenous inhibitor of apoptosis.  J Biol Chem.. 1999;  274 2072-2076
• 8 Irmler M, Thome M, Hahne M. et al . Inhibition of death receptor signals by cellular FLIP.  Nature.. 1997;  388 190-195
• 9 Deveraux Q L, Reed J C. IAP family proteins-suppressors of apoptosis.  Genes Dev.. 1999;  13 239-252
• 10 Desagher S, Martinou J C. Mitochondria as the central control point of apoptosis.  Trends Cell Biol.. 2000;  10 369-377
• 11 Chirgwin J M, Przybyla A E, MacDonald R J, Rutter W J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease.  Biochemistry.. 1979;  18 5294-5299
• 12 Knowlton K U. Atrial natriuretic factor: a molecular marker for cardiac specific, embryonic, and inducible gene expression.  Heart Failure.. 1992;  8 121-128
• 13 James K B, McCarthy P M, Thomas J D. et al . Effect of the implantable left ventricular assist device on neuroendocrine activation in heart failure.  Circulation.. 1995;  92 II191-195
• 14 Margulies K B. Ventricular unloading and myocyte recovery: insight gained into the pathophysiology of congestive heart failure.  Curr Cardiol Rep.. 2000;  2 181-188
• 15 Muller J, Wallukat G, Weng Y G. et al . Weaning from mechanical cardiac support in patients with idiopathic dilated cardiomyopathy.  Circulation.. 1997;  96 542-549
• 16 Testa M, Yeh M, Lee P. et al . Circulating levels of cytokines and their endogenous modulators in patients with mild to severe congestive heart failure due to coronary artery disease or hypertension.  J Am Coll Cardiol.. 1996;  28 964-971
• 17 Torre-Amione G, Kapadia S, Lee J. et al . Tumor necrosis factor-alpha and tumor necrosis factor receptors in the failing human heart.  Circulation.. 1996;  93 704-711
• 18 Deng M C, Erren M, Tjan T D. et al . Left ventricular assist system support is associated with persistent inflammation and temporary immunosuppression.  Thorac Cardiovasc Surg.. 1999;  47 (Suppl 2) 326-331
• 19 Annoni G, Luvara G, Arosio B. et al . Age-dependent expression of fibrosis-related genes and collagen deposition in the rat myocardium.  Mech Ageing Dev.. 1998;  101 57-72
• 20 Miyamoto A, Kawana S, Kimura H, Ohshika H. Impaired expression of Gs alpha protein mRNA in rat ventricular myocardium with aging.  Eur J Pharmacol.. 1994;  266 147-154
• 21 Lee S H, Doliba N, Osbakken M, Oz M, Mancini D. Improvement of myocardial mitochondrial function after hemodynamic support with left ventricular assist devices in patients with heart failure.  J Thorac Cardiovasc Surg.. 1998;  116 344-349

1 Presented at the 30^th annual meeting of the German Society for Thoracic and Cardiovascular Surgery in Leipzig, February 18 - 21, 2001