In: Heart Failure16 Dec 2013
The findings of this investigation allow us to make two important clinical observations. First, as in other reports, our results allude to the higher elucidation of TNFa in patients with chronic heart failure, even in the absence of cachexia. Second, and more importantly, we were unable to demonstrate a significant improvement in elaboration of TNFa following clinical resolution of acute decompensation. Thus, in die short-term recovery period (1 to 2 weeks), no significant reduction of TNFa toward normal levels was noted, suggesting that clinical and hemodynamic improvements occurred despite continued elucidation of this cytokine. TNFa has been shown to be increased in a distinct subset of patients with stable heart failure in the setting of cachexia. Following these initial observations, a growing body of experimental evidence has demonstrated that TNFa decreases myocardial contractility, lowers BP, and alters muscle membrane potential and therefore may play a pivotal role in determining the stability of patients with advanced heart failure.
More recently, Torre-Amione et al have examined a cross-sectional cohort of heart failure patients in the SOLVD registry and have successfully demonstrated that circulating levels of proinflamma-tory cytokines tend to increase with functional class. To our knowledge, however, the clinical pattern of TNFa elaboration in the transition from a state of acute decompensation to clinical recovery in advanced heart failure has not been evaluated previously. Our findings suggest that although circulating levels of TNFa are increased in advanced heart failure states with acute decompensation when compared to healthy volunteers, no significant short-term modulation occurs in parallel with resolution of symptoms and restoration of clinical stability.
A more intriguing question concerns the effects of certain inotropic agents on the activity of TNFa. Germane to this is the observation by our laboratory (S.E.) and by others demonstrating that TNFa production can be substantially suppressed ex vivo by the inotrope amrinone, a phosphodiesterase inhibitor, and ves-narinone, a quinolinone derivative. Because inotropic agents bring about a favorable clinical response in decompensated heart failure, an effect that can last long after treatment with the agent is discontinued, investigators have questioned whether part of the long-term clinical benefit derived from these agents is due to a reduction in TNFa synthesis. The results of our clinical study in patients with heart failure who received inotropic therapy with dobutamine and milrinone (an amrinone analogue) do not support an important therapeutic effect of these agents on circulating TNFa levels. Indeed, despite the lack of evidence of significant alterations in serial TNFa levels, clinical and symptomatic recovery was evident following the use of these inotropic agents, suggesting that mechanisms other than TNFa modulation may be responsible for their beneficial therapeutic effects. Other supportive observations have also alluded to a dissociation between circulating cytokines and neurohormonal activation in systolic heart failure.
Certain limitations of this study deserve mention. First, although we examined circulating TNFa levels, this may not reflect actions of TNFa at the tissue level, where its influence remains speculative. Second, we did not measure TNFa receptor shedding, which has been suggested to represent a homeostatic mechanism for regulating TNFa activity. However, spiking experiments evaluating our ultrasensitive ELISA yielded a recovery for TNFa of 97% when a tenfold excess of soluble TNF-receptor 1 over TNFa was applied (personal communication; Biosource; Camarillo, Calif; 1995).
This investigation demonstrates that although non-cachectic patients with chronic heart failure who suffer acute decompensation elaborate significantly higher circulating levels of TNFa compared with healthy control subjects, no significant reduction or alteration in circulating TNFa is noted in the short-term follow-up despite clinical improvement.
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