Gevokizumab, an IL1-beta modulating antibody exerts promising cardioprotective effects against ischemia-reperfusion injury in diabetic rats

Aims: Enhanced myocardial interleukin-1 beta (IL1-β) production is involved in ischemia/reperfusion (I/R) induced left ventricular (LV) dysfunction. We tested neutralization of IL-1β as a potential therapeutic target for the treatment of I/R induced LV dysfunction.

Methods: We assessed in diabetic (Goto Kakizaki, GK) rats the preventive effects of gevokizumab, a potent modulator of IL-1β, administered once a week, started 4 weeks prior to a 20 min of transient ischemia induced by left coronary artery occlusion and continued 90 days after I/R, on LV remodeling/function (echocardiography) 7 and 90 days after I/R. LV hemodynamics (LV catheterization), LV tissue perfusion (MRI) and LV collagen density (image analysis) were assessed 90 days after I/R.

Results: I/R induced early LV expansion followed by late LV dilatation, associated with LV dysfunction as well as after 90 days, reduced LV tissue perfusion and LV collagen accumulation (Table). Gevokizumab limited both early LV expansion as well as late LV dilatation, associated with an improved LV function. Ninety days after I/R, gevokizumab improved both LV systolic and LV diastolic functions, illustrated by the increase in LV end-systolic pressure volume relation, and the reductions in LV end-diastolic pressure and LV end-diastolic pressure volume relation. Moreover, long-term gevokizumab moderately increased LV tissue perfusion and significantly reduced LV collagen density (Table 1).

Table 1. LV Remodelling and Function

Groupe	LVDD (7 days post I/R)	LVDD (90 days post IR)	LVFS (7 days post I/R)	LVFS (90 days post I/R)	LVESPVR	LVEDP	LVEDPVR	LV Perfusion	LV Collagen
	(mm)	(mm)	(%)	(%)	(mmHg/RVU)	(mm Hg)	(mmHg/RVU)	(ml/g tissu)	(%)
GK	6.3±0.3	6.5±0.3	47±3	42±1	18.1±0.4	2.8±0.3	1.58±0.14	10.5±0.1	1.6±0.2
GK I/R	8.0±0.3*	8.9±0.4*	29±2*	18±2*	15.5±0.8*	4.3±0.8*	2.79±0.4*	9.7±0.1*	2.8±0.3*
GK I/R+S78	7.2±03	7.4±0.3†	34±3	31±2†	19.8±0.7†	2.8±0.5†	1.41±0.1†	9.9±0.1	1.7±0.2†

LVDD, left ventricular diastolic diameters; LVFS, LV fractional shortening; LVESPVR and LVEDPVR, LV end-diastolic and end-systolic pressure volume relations. *p<0.05 vs GK; ^†p<0.05 vs GK I/R.

Conclusions: Our results, obtained using a clinically relevant model of I/R, suggest a therapeutic benefit of the IL-1β modulating antibody, gevokizumab, in myocardial I/R injury.