In 2007, we initiated a research program to examine the potential use of advanced glycation end-product (AGE) breakers in heart failure. We and others showed that AGEs are end-products formed by oxidative and non-oxidative reactions between sugars and proteins. AGEs form cross-links with long-living tissue proteins, which cause them to accumulate in the body over time. AGEs can bind to the AGE receptor (RAGE) and thereby induce cardiovascular dysfunction. In several papers, we demonstrated that AGEs were related to the severity of heart failure, and were related to clinical outcome in these patients. This resulted in the design and execution of a phase II randomized controlled clinical trial on the effect of the AGE-breaker alagebrium on exercise capacity and clinical outcome in patients with systolic heart failure. We are currently involved in a second phase II randomized controlled clinical trial with another AGE-breaker, TRC4186, specifically aimed at patients with diabetes and heart failure. These studies may lead to larger phase III trials and the potential use of AGE-breakers in heart failure.

 


Key publications

1. Hartog JW, Willemsen S, van Veldhuisen DJ, Posma JL, van Wijk LM, Hummel YM, Hillege HL, Voors AA; BENEFICIAL investigators. Effects of alagebrium, an advanced glycation endproduct breaker, on exercise tolerance and cardiac function in patients with chronic heart failure. Eur J Heart Fail. 2011;13:899-908.
2. Willemsen S, Hartog JW, Heiner-Fokkema MR, van Veldhuisen DJ, Voors AA. Advanced glycation end-products, a pathophysiological pathway in the cardiorenal syndrome. Heart Fail Rev. 2012;17:221-8.
3. Willemsen S, Hartog JW, Hummel YM, van Ruijven MH, van der Horst IC, van Veldhuisen DJ, Voors AA. Tissue advanced glycation end products are associated with diastolic function and aerobic exercise capacity in diabetic heart failure patients. Eur J Heart Fail. 2011;13:76-82.
4. Hartog JW, van de Wal RM, Schalkwijk CG, Miyata T, Jaarsma W, Plokker HW, van Wijk LM, Smit AJ, van Veldhuisen DJ, Voors AA. Advanced glycation end-products, anti-hypertensive treatment and diastolic function in patients with hypertension and diastolic dysfunction. Eur J Heart Fail. 2010;12:397-403.
5. Willemsen S, Hartog JW, Hummel YM, Posma JL, van Wijk LM, van Veldhuisen DJ, Voors AA. Effects of alagebrium, an advanced glycation end-product breaker, in patients with chronic heart failure: study design and baseline characteristics of the BENEFICIAL trial. Eur J Heart Fail. 2010;12:294-300.
6. Hartog JW, Willemsen S, Voors AA. What is the influence of renal function on the prognostic value of advanced glycation end-products and sRAGE in heart failure? J Card Fail. 2008;14:626;
7. Hartog JW, Hummel YM, Voors AA, Schalkwijk CG, Miyata T, Huisman RM, Smit AJ, Van Veldhuisen DJ. Skin-autofluorescence, a measure of tissue advanced glycation end-products (AGEs), is related to diastolic function in dialysis patients. J Card Fail. 2008;14:596-602.
8. Smit AJ, Hartog JW, Voors AA, van Veldhuisen DJ. Advanced glycation endproducts in chronic heart failure. Ann N Y Acad Sci. 2008;1126:225-30. Review.
9. Hartog JW, Voors AA, Bakker SJ, Smit AJ, van Veldhuisen DJ. Advanced glycation end-products (AGEs) and heart failure: pathophysiology and clinical implications. Eur J Heart Fail. 2007;9:1146-55. Review.
10. Hartog JW, Voors AA, Schalkwijk CG, Scheijen J, Smilde TD, Damman K, Bakker SJ, Smit AJ, van Veldhuisen DJ. Clinical and prognostic value of advanced glycation end-products in chronic heart failure. Eur Heart J. 2007;28:2879-85.