BACKGROUND: Inflammatory mediators, especially tumor necrosis factor (TNF), have been implicated in heart failure (HF). Thalidomide has anti-inflammatory properties and selectively inhibits TNF. Thus far, thalidomide or thalidomide analogues have not been evaluated in patients with heart failure. METHODS: Thalidomide was assessed in preclinical and clinical studies. First, isolated cardiac myocytes were pretreated with thalidomide or thalidomide analogues, and TNF production was assessed after lipopolysaccharide (LPS) provocation. Second, to determine the safety and potential efficacy of thalidomide, an open-label dose escalation safety study was conducted in seven patients with advanced heart failure. RESULTS: Thalidomide and thalidomide analogues inhibited LPS-induced TNF biosynthesis in cardiac myocytes in a dose-dependent manner. Thalidomide analogues had a greater inhibitory effect on TNF production than did thalidomide. In patients with advanced HF, thalidomide was safe and potentially effective when used at lower doses. However, dose-limiting toxicity was observed in two patients. There was a significant increase in the 6-minute walk distance and a trend toward improvement in left ventricular ejection fraction and quality of life after 12 weeks of maintenance therapy with thalidomide. CONCLUSIONS: Taken together these results suggest that thalidomide or its derivatives may be useful in selected patients with HF. This potential needs to be studied in larger clinical trials.
BACKGROUND: Inflammatory mediators, especially tumor necrosis factor (TNF), have been implicated in heart failure (HF). Thalidomide has anti-inflammatory properties and selectively inhibits TNF. Thus far, thalidomide or thalidomide analogues have not been evaluated in patients with heart failure. METHODS:Thalidomide was assessed in preclinical and clinical studies. First, isolated cardiac myocytes were pretreated with thalidomide or thalidomide analogues, and TNF production was assessed after lipopolysaccharide (LPS) provocation. Second, to determine the safety and potential efficacy of thalidomide, an open-label dose escalation safety study was conducted in seven patients with advanced heart failure. RESULTS:Thalidomide and thalidomide analogues inhibited LPS-induced TNF biosynthesis in cardiac myocytes in a dose-dependent manner. Thalidomide analogues had a greater inhibitory effect on TNF production than did thalidomide. In patients with advanced HF, thalidomide was safe and potentially effective when used at lower doses. However, dose-limiting toxicity was observed in two patients. There was a significant increase in the 6-minute walk distance and a trend toward improvement in left ventricular ejection fraction and quality of life after 12 weeks of maintenance therapy with thalidomide. CONCLUSIONS: Taken together these results suggest that thalidomide or its derivatives may be useful in selected patients with HF. This potential needs to be studied in larger clinical trials.
Authors: R S Ramabadran; Amanda Chancey; Jesus G Vallejo; Philip M Barger; Natarajan Sivasubramanian; Douglas L Mann Journal: Tex Heart Inst J Date: 2008
Authors: Stephan von Haehling; Nicole Ebner; Marcelo R Dos Santos; Jochen Springer; Stefan D Anker Journal: Nat Rev Cardiol Date: 2017-04-24 Impact factor: 32.419
Authors: Elise L Kessler; Martinus I F J Oerlemans; Patricia van den Hoogen; Carmen Yap; Joost P G Sluijter; Saskia C A de Jager Journal: J Cardiovasc Transl Res Date: 2020-05-22 Impact factor: 4.132