Primary nitric oxide resistance and oxidative stress in patients with chronic heart failure

Platelet activation has been described in chronic heart failure (CHF) but the mechanism is unknown. Primary platelet nitrate (NO) resistance has been recently been described in ischaemic heart disease (IHD) and may be caused by increased oxidative stress. We therefore studied platelet responsiveness to NO using sodium nitroprusside (SNP) and nitroglycerine (NTG) and oxidative stress in patients with CHF and investigated the effect of underlying aetiology, on these parameters. Methods 52 subjects with CHF [26 due to dilated cardiomyopathy (DCM), 26 ischaemic cardiomyopathy (ICM)] were studied and compared with 15 healthy controls. We assessed the inhibitory effects of SNP and NTG on ADP-induced platelet aggregation (impedance aggregometry). NO resistance was defined as more than 2 SD below the normal inhibition of platelet aggregation by SNP (10-5 M) and/or NTG (10-4 M). Oxidative stress was assessed by lipid-derived free radicals, ex vivo by electron paramagnetic resonance spectroscopy and by markers of lipid peroxidation (TBARS). Results (Mean±SD) Platelet responsiveness to SNP and NTG on ADP-induced aggregation was 73.1 ± 22% and 50 ± 31% respectively in healthy controls compared to 58.4 ± 34% and 40.5 ± 31% in DCM and 55.7 ± 34% and 36.5 ± 32% in ICM. 28% of ICM and 23% of DCM patients exhibited primary platelet NO resistance. Patients with heart failure had greater levels of lipid derived free radicals, (3784 ± 2479 (DCM) and 3378 ± 1781 (ICM) vs 880 ± 372 (C) and TBARS [5.24 ± 2 (DCM), 6.5 ± 3.7 (ICM) vs 3 ± 1.3 (C)] both p<0.05, but there was no correlation with platelet NO resistance. Conclusions Platelet NO responses in CHF are bimodal, with 'resistance' occurring in a quarter of CHF patients, increased oxidative stress is increased in CHF per se but its presence was not directly related to this phenomenon. This data highlights a subset (a quarter) of CHF patients who might particularly benefit from antithrombotic therapy.