BACKGROUND: Tumor necrosis factor alpha (TNFalpha) has been shown to be a prognostic marker in heart failure, but recent clinical trials using TNFalpha antagonists in patients with severe heart failure have been disappointing. Hypertension is one of most common causes to chronic heart failure in humans. HYPOTHESIS: Suppression of a single cytokine in CHF is not an effective treatment strategy because it leads to the upregulation of other proinflammatory cytokines. OBJECTIVES: The aim of the present study was to investigate the effect of chronic treatment with a TNFalpha antagonist in a rat model of the early stage of heart failure due to hypertension. METHODS: Spontaneously hypertensive rats (SHR, n=30) and healthy Wistar Kyoto rats (WKY, n=30) were treated with either the TNFalpha antagonist etanercept or placebo for 12 weeks. At the end of the study, the rats were 26 weeks old and indices of cardiac structure, function and cytokines were analyzed. RESULTS: SHR displayed early stage of heart failure as shown by increased heart weight/body weight ratio and relative wall thickness by echocardiography, downregulated myocardial beta(1)-adrenoceptor, and upregulated myocardial brain natriuretic peptide and interleukin-6 (IL6). Chronic treatment with etanercept in SHR resulted in decreased relative wall thickness but also increased cardiac reserve and higher blood pressure. In addition, IL6 was further upregulated compared with placebo treatment. CONCLUSION: Chronic treatment with etanercept in SHR resulted in favorable cardiac remodeling, but also had a positive inotropic effect and was associated with an upregulation of IL6. These findings indicate that chronic treatment with TNFalpha antagonists is not an effective treatment strategy and may aggravate heart failure in the long term.
BACKGROUND:Tumor necrosis factor alpha (TNFalpha) has been shown to be a prognostic marker in heart failure, but recent clinical trials using TNFalpha antagonists in patients with severe heart failure have been disappointing. Hypertension is one of most common causes to chronic heart failure in humans. HYPOTHESIS: Suppression of a single cytokine in CHF is not an effective treatment strategy because it leads to the upregulation of other proinflammatory cytokines. OBJECTIVES: The aim of the present study was to investigate the effect of chronic treatment with a TNFalpha antagonist in a rat model of the early stage of heart failure due to hypertension. METHODS: Spontaneously hypertensiverats (SHR, n=30) and healthy Wistar Kyoto rats (WKY, n=30) were treated with either the TNFalpha antagonist etanercept or placebo for 12 weeks. At the end of the study, the rats were 26 weeks old and indices of cardiac structure, function and cytokines were analyzed. RESULTS: SHR displayed early stage of heart failure as shown by increased heart weight/body weight ratio and relative wall thickness by echocardiography, downregulated myocardial beta(1)-adrenoceptor, and upregulated myocardial brain natriuretic peptide and interleukin-6 (IL6). Chronic treatment with etanercept in SHR resulted in decreased relative wall thickness but also increased cardiac reserve and higher blood pressure. In addition, IL6 was further upregulated compared with placebo treatment. CONCLUSION: Chronic treatment with etanercept in SHR resulted in favorable cardiac remodeling, but also had a positive inotropic effect and was associated with an upregulation of IL6. These findings indicate that chronic treatment with TNFalpha antagonists is not an effective treatment strategy and may aggravate heart failure in the long term.
Authors: Barry L Burnette; Shaun Selness; Raj Devraj; Gail Jungbluth; Ravi Kurumbail; Loreen Stillwell; Gary Anderson; Stephen Mnich; Jeffrey Hirsch; Robert Compton; Pamela De Ciechi; Heidi Hope; Michael Hepperle; Robert H Keith; Win Naing; Huey Shieh; Joseph Portanova; Yan Zhang; Jian Zhang; Richard M Leimgruber; Joseph Monahan Journal: Pharmacology Date: 2009-07-04 Impact factor: 2.547