Inflammation inhibition effects in diabetes induced heart failure

Abstract

Background:Inflammation is appreciated as a leading factor regarding car-diovascular disorders triggering and exacerbation. Nevertheless a promisingantinflammatory treatment concerning cardiac mismatch improvement is not yetconsolidated.Aim:The in vitro evaluation of cardiac effects of the TNF-alpha antagonist adminis-tration during diabetes-induced heart failure (DHF).Material and methods:DHF was classically reproduced in rats by i/p adminis-tration of streprozotocin (50 mg/kg, 5 days) – series 1 (of reference). TNF-alphaantagonist, TNF-McAb (TNF monoclonal antibody, analog of infliximab) has beenadministered i/p during DHF modeling and 5 days after – series 2. After 10 daysanimals of both series have been euthanized, and isolated heart was perfused inisovolumic regimen (Langendorff model) or exterior working (Neely-Rovetto model).Cardiac reactivity was assayed in: (1) hemodynamic effort due to pre- and afterload increase; (2) neuroendocrine activation modulated by action in diverse concentra-tions of norepinephrine, angiotensin II and endothelin-1 (ET-1); (3) in ischemia (30min) followed by reperfusion (45 min) syndrome.Results:TNF-alpha inhibition led to significant increase of cardiac output (CO) ineffort with volume and resistance respectively by 23,7 and 26,2% comparativelyto reference indices. Systolic pressure of left ventricle (LV) was in series 1 higher inall induced hemodynamic stress levels, but on aortic pressure of 100 and 120 cmH20 the increment was significant and averagely represented 18-19%. DHF wascharacterized by LV lusitropic function impairment, whose principal parameters,telediastolic pressure (LVTDP) and index of diastolic myocardial rigidity significantlydecreased during TNF-alpha inhibition by 26-28%. The norepinephrine action ledin DHF to inotrop-chronotropic effect dissociation, but endothelin-1 (ET-1) induceda negative inotropic effect, associated by CO reducing by 10,3%. TNF-alpha inhibi-tion led to appearance of positive inotropic effect to ET-1 action and cardiac outputincrease by 11%. Myocardial ischemic contracture assayed after 30 min of ischemiathereby of LVTDP is doubly more in DHF vs control pattern (56,3±3,6 vs 28,4±1,9mm Hg) and remains above on 45th min of reperfusion (39,2±2,5 vs 18,8±1,2mm Hg). TNF-McAb notably attenuated consequences of ischemia-reperfusionsyndrome, leading to LVTDP drop by 29,3% at finish of ischemia and by 26,8% atfinish of reperfusion.Conclusions:1. TNF-alpha inhibition during diabetes-induced heart failureimproved cardiac functionality, confirming the pathogenical role of inflamma-tion and, on the other hand, the therapeutic relevance of TNF-McAb regardingoutworn heart functioning in hemodynamic and neuroendocrine efforts.2. Most conspicuous TNF-McAb benefit has referred to appearance of positiveinotropic effect to ET-1 action and significant decrease of LV telediastolic pressureby around 29% in ischemia-reperfusion syndrome.