Plasma Cystine and Nitrite Levels are Synergistic Determinants of Arterial Stiffness and Mortality in Heart Failure

BackgroundEndothelial dysfunction plays a key role in heart failure with reduced ejection fraction (HFrEF) pathogenesis, and is determined via the balance between oxidative stress (OS) and nitric oxide (NO) bioavailability. Higher cystine levels indicate increased OS. Nitrite is a major oxidative metabolite of NO. We sought to examine the relationship between OS, NO metabolism and vascular function, and their association with clinical outcomes in HFrEF patients.MethodsCystine, nitrite and vascular function were measured in 130 HFrEF patients (mean age: 54.6 ± 12.7 yrs, 59.2% black, 48.5% female). Plasma cystine was quantified by high performance liquid chromatography. Plasma nitrite was determined by ion chromatography (ENO20 Analyzer, Eicom). Arterial stiffness was assessed as Augmentation index (Aix) using pulse wave analysis (SphygmoCor, AtCor Medical). Patients were categorized by median cystine (97.39 μM) and nitrite (0.26 μM) values. Linear regression was used to determine the association between cystine, nitrite and Aix, adjusting for age, gender, race, height, weight and mean arterial pressure. Cox regression was used to estimate the association of cystine, nitrite and Aix, with all-cause mortality, adjusting for age, gender, race, BNP and history of MI.Results: Cystine, nitrite and AixPatients with higher levels of both cystine and nitrite (>median, n=31) had higher Aix (adjusted β =5.7, p=0.006, mean Aix= 27.6 ± 10.3) than those that had either elevated cystine (n=33) (p=0.1, mean Aix= 21.4 ± 7.9) or nitrite (n=33) (p=0.5, mean Aix= 18.9 ± 10.3), or neither (n=33) (P=0.9, mean Aix=22.1 ± 1.0).Cystine, nitrite and mortalityThere were 14 deaths during a median follow up of 375 (IQR 188.5, 696) days. Patients with higher levels of both cystine and nitrite (>median) had a higher mortality (adjusted HR=15.2, 95% CI: 1.8-129.7, p=0.01) than those with elevation of either cystine or nitrite, or neither (Figure 1). Cystine did not correlate with BNP (p=0.2), while nitrite had a weak positive correlation with BNP (r=0.21, p=0.04).Aix and mortalityHigher Aix tended to be associated with mortality (adjusted HR: 1.2, 95% CI: 1.0-1.3, p=0.06), but was not a significant predictor when cystine and nitrite were added to the model (adjusted HR: 1.1, 95% CI: 0.9-1.2, p=0.5).ConclusionsHigher levels of OS and NO metabolites are synergistic determinants of arterial stiffness, and are independent determinants of mortality in HFrEF even after adjusting for BNP. Endothelial dysfunction plays a key role in heart failure with reduced ejection fraction (HFrEF) pathogenesis, and is determined via the balance between oxidative stress (OS) and nitric oxide (NO) bioavailability. Higher cystine levels indicate increased OS. Nitrite is a major oxidative metabolite of NO. We sought to examine the relationship between OS, NO metabolism and vascular function, and their association with clinical outcomes in HFrEF patients. Cystine, nitrite and vascular function were measured in 130 HFrEF patients (mean age: 54.6 ± 12.7 yrs, 59.2% black, 48.5% female). Plasma cystine was quantified by high performance liquid chromatography. Plasma nitrite was determined by ion chromatography (ENO20 Analyzer, Eicom). Arterial stiffness was assessed as Augmentation index (Aix) using pulse wave analysis (SphygmoCor, AtCor Medical). Patients were categorized by median cystine (97.39 μM) and nitrite (0.26 μM) values. Linear regression was used to determine the association between cystine, nitrite and Aix, adjusting for age, gender, race, height, weight and mean arterial pressure. Cox regression was used to estimate the association of cystine, nitrite and Aix, with all-cause mortality, adjusting for age, gender, race, BNP and history of MI. Patients with higher levels of both cystine and nitrite (>median, n=31) had higher Aix (adjusted β =5.7, p=0.006, mean Aix= 27.6 ± 10.3) than those that had either elevated cystine (n=33) (p=0.1, mean Aix= 21.4 ± 7.9) or nitrite (n=33) (p=0.5, mean Aix= 18.9 ± 10.3), or neither (n=33) (P=0.9, mean Aix=22.1 ± 1.0). There were 14 deaths during a median follow up of 375 (IQR 188.5, 696) days. Patients with higher levels of both cystine and nitrite (>median) had a higher mortality (adjusted HR=15.2, 95% CI: 1.8-129.7, p=0.01) than those with elevation of either cystine or nitrite, or neither (Figure 1). Cystine did not correlate with BNP (p=0.2), while nitrite had a weak positive correlation with BNP (r=0.21, p=0.04). Higher Aix tended to be associated with mortality (adjusted HR: 1.2, 95% CI: 1.0-1.3, p=0.06), but was not a significant predictor when cystine and nitrite were added to the model (adjusted HR: 1.1, 95% CI: 0.9-1.2, p=0.5). Higher levels of OS and NO metabolites are synergistic determinants of arterial stiffness, and are independent determinants of mortality in HFrEF even after adjusting for BNP.