1. Type D Personality and Chronic Kidney Disease as Predictors of Pro- and Anti- Inflammatory Cytokine Levels in Heart Failure Interleukin-6 (IL-6), tumor necrosis factor- (TNF-) and soluble TNF- receptors 1 (sTNFR1) and 2 (sTNFR2) are powerful predictors of mortality in chronic heart failure (CHF). However, little is known about (i) the origins of pro- inflammatory cytokine production and (ii) the determinants of substantial interpatient variability in immune activation. We prospectively examined Type D personality (tendency to experience and inhibit emotional distress) and chronic kidney disease (CKD) as predictors of cytokine production in patients with CHF. BACKGROUNDBACKGROUND Dr. Nina Kupper, h.m.kupper@uvt.nl CONTACT INFORMATION Type D personality At 1yr FU, Type D patients had significantly elevated levels of sTNFR1 (p =0.009) and sTNFR2 (p =0.001), and decreased levels of IL-10 (p =0.006) as compared to patients without Type D or CKD. CKD Patients with CKD also had elevated levels of sTNFR1 and sTNFR2 (p <0.0001), but their IL-10 level was not decreased. Predictive qualities In multivariable analyses, Type D personality and CKD independently predicted increased sTNFR1/IL-10 and sTNFR2/IL-10 ratios (all p s≤0.007); Type D also predicted an increased IL-6/IL-10 ratio (p =0.013). Covariates spironolactone and older age were also associated with elevated PIC/AIC ratios. Adjusting for these variables, the odds to have elevated ratios (highest 20%) was still increased in Type D patients and in patients with CKD (see Figures 1a-c & table 1). Type D personality At 1yr FU, Type D patients had significantly elevated levels of sTNFR1 (p =0.009) and sTNFR2 (p =0.001), and decreased levels of IL-10 (p =0.006) as compared to patients without Type D or CKD. CKD Patients with CKD also had elevated levels of sTNFR1 and sTNFR2 (p <0.0001), but their IL-10 level was not decreased. Predictive qualities In multivariable analyses, Type D personality and CKD independently predicted increased sTNFR1/IL-10 and sTNFR2/IL-10 ratios (all p s≤0.007); Type D also predicted an increased IL-6/IL-10 ratio (p =0.013). Covariates spironolactone and older age were also associated with elevated PIC/AIC ratios. Adjusting for these variables, the odds to have elevated ratios (highest 20%) was still increased in Type D patients and in patients with CKD (see Figures 1a-c & table 1). RESULTSRESULTS N= 125 CHF patients (<80 yrs, LVEF ≤40%, pharmacologically stable) Psychological assessment: Type D personality (DS14) and demographics were assessed at baseline Medical: Chronic kidney disease (CKD) was diagnosed according to the K/DOQI guidelines, by calculating the globular filtration rate (GFR) using the MDRD formula. CKD was defined as either kidney damage or having a decreased kidney function, as assessed by a GFR of <60 ml/min per 1.73m2 at baseline. Serum assessments: At 1 yr FU, pro-inflammatory (PIC) factors IL-6, TNF-a, sTNFR1, sTNFR2, and anti-inflammatory (AIC) factors IL-10 and IL-1ra were assessed. Medical records: Clinical variables (incl. LVEF, NYHA class, etiology, co morbid diseases), biomedical risk factors and medication use. N= 125 CHF patients (<80 yrs, LVEF ≤40%, pharmacologically stable) Psychological assessment: Type D personality (DS14) and demographics were assessed at baseline Medical: Chronic kidney disease (CKD) was diagnosed according to the K/DOQI guidelines, by calculating the globular filtration rate (GFR) using the MDRD formula. CKD was defined as either kidney damage or having a decreased kidney function, as assessed by a GFR of <60 ml/min per 1.73m2 at baseline. Serum assessments: At 1 yr FU, pro-inflammatory (PIC) factors IL-6, TNF-a, sTNFR1, sTNFR2, and anti-inflammatory (AIC) factors IL-10 and IL-1ra were assessed. Medical records: Clinical variables (incl. LVEF, NYHA class, etiology, co morbid diseases), biomedical risk factors and medication use. METHODSMETHODS Nina Kupper PhD, Angélique A. Schiffer Msc, Martijn Kwaijtaal PhD, Herbert Hooijkaas PhD, Eric H. Hendriks RN, Jos W. Widdershoven MD PhD, Johan Denollet PhD Co RPS, Medical Psychology, Tilburg University & TweeSteden Hospital, Tilburg, The Netherlands Both Type D personality and CKD independently predict unfavorable cytokine profiles in CHF patients. Such alterations in immune processes may be one mechanism explaining the adverse relationship between these risk factors and prognosis in heart failure. Whether these Type D and CKD related alterations in immune balance actually explain adverse prognosis and mortality in CHF patients is subject for further study. Limitations As only 25% of the sample was female, this might have precluded finding sex differences. Only a limited amount of patients had both CKD and Type D. Potential additive effects would be able to specify those high at risk even further Both Type D personality and CKD independently predict unfavorable cytokine profiles in CHF patients. Such alterations in immune processes may be one mechanism explaining the adverse relationship between these risk factors and prognosis in heart failure. Whether these Type D and CKD related alterations in immune balance actually explain adverse prognosis and mortality in CHF patients is subject for further study. Limitations As only 25% of the sample was female, this might have precluded finding sex differences. Only a limited amount of patients had both CKD and Type D. Potential additive effects would be able to specify those high at risk even further CONCLUSIONSCONCLUSIONS Elevated RatioType D PersonalityOdds Ratio [95% CI]p-value sTNFR1/IL-10Type D3.92 [1.11-13.87].034 Age 70 yrs 0.65 [0.17-2.54].54 Spironolactone5.68 [1.45-22.34].013 Beta blocker0.37 [0.10-1.36].13 sTNFR2/IL-10Type D18.88 [3.61-98.85].001 Age 70 yrs 7.94 [1.79-35.27].006 Spironolactone2.77 [0.53-14.42].23 Beta blocker0.19 [0.04-0.89].036 IL-6/IL-10Type D3.12 [1.03-9.39].044 Age 70 y 2.22 [0.73-6.78].16 Spironolactone1.44 [0.37-5.59].59 Beta blocker1.13 [0.34-3.81].84 Chronic Kidney Disease sTNFR1/IL-10CKD4.23 [1.44-12.45].009 Age 70 yrs 0.70 [0.26-1.94].49 Spironolactone2.24 [0.76-6.58].14 Beta blocker0.48 [0.17-1.31].15 sTNFR2/IL-10CKD7.75 [2.05-29.30].003 Age 70 yrs 4.04 [1.39-11.78].01 Spironolactone0.94 [0.27-3.32].93 Beta blocker0.73 [0.24-2.26].60 Figure 1a-c. Percentage of patients with elevated ratios of PIC vs. AIC in Type D personality and CKD patients compared with a non Type D, non CKD reference group Table 1. Type D personality and chronic kidney disease as predictors of a pro vs. anti inflammatory cytokine imbalance.01.04 Reference CKD Type D Reference CKD Type D.002.001 Reference CKD Type D.16.05