The association between cardiac troponin, inflammation and target organ damage : the SABPA study

MSc (Physiology), North-West University, Potchefstroom Campus, 2016Motivation - Inflammation has been shown to be involved in the pathogenesis and progression of heart failure, and multiple cytokines seem to play a role in the inflammatory response by regulating haematopoiesis, immune- and vascular reactions. Binding of the pro-inflammatory cytokine, tumour necrosis factor-alpha (TNF-α), to its TNFR1 receptor may induce apoptosis in many cell types, including cardiac myocytes. The death of cardiac myocytes has been shown to be one of the changes that occur during cardiac remodelling, along with myocyte hypertrophy and modifications of the extra cellular matrix. Cardiac remodeling is a compensatory mechanism that occurs when the left ventricle fails to maintain an adequate stroke volume in order to provide adequate blood perfusion to the vital organs. Multiple factors that increase in response to left ventricular dysfunction may stimulate cardiac remodeling including inflammation, an increased hemodynamic load, neuro-hormonal activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system as well as the increased production of reactive oxygen species resulting in oxidative stress. As mentioned, the death of myocytes may be involved in cardiac remodelling. Necrosis is a passive process that occurs following cardiac injury and may result in the production of Troponin T (Trop T). Trop T plays a significant role in the excitation-contraction coupling of skeletal and cardiac muscle, but the exact role Trop T plays in the development of end-organ damage has not been thoroughly established in African populations. Left ventricular hypertrophy (LVH) has been shown to be a manifestation of end-organ damage. In urban-dwelling African populations it has been shown that left ventricular structural changes are associated with inflammation and silent ischemia. The increased hemodynamic load accompanied by the structural changes of the left ventricle may therefore lead to an increase in the cardiac wall stress that can result in the production of the N-terminal portion of pro-brain natriuretic peptide (NT-proBNP). NT-proBNP has been shown to be increased in African men as opposed to Caucasian men in whom positive associations were demonstrated between NT-proBNP, pulse pressure (PP) and C-reactive protein. However, socio-economic status was not considered and the relation between NT-proBNP, Trop T and systemic inflammatory markers (IL-6 and TNF-α), still needs to be determined in a bi-ethnic sex population with similar socio-economic status. Objectives - The aim of this study was to determine whether associations exist between inflammation, cardiac troponin and re-modelling in a bi-ethnic sex cohort of South Africa. We aimed at assessing whether relations exist between three known markers of inflammation (CRP, IL-6 and TNF-α), Trop T and markers of cardiac re-modelling (NT-proBNP and LVH). Methods - This study formed part of the Sympathetic activity and Ambulatory Blood Pressure in Africans (SABPA) study which was conducted in 2008 and 2009. Teachers, aged 20-65 years, resided in the Dr Kenneth Kaunda Education District of the North West Province of South Africa. This selection was made to ensure that the participants were from a similar socio-economic status. The exclusion criteria for the SABPA study was: pregnancy, lactation, users of α- and β-blockers or psychotropic substances, blood donors or vaccinations 3 months prior to clinical assessment and a tympanum temperature exceeding 37.5°C. Additional exclusions were made to avoid bias pertaining to cardio-metabolic and inflammatory risk and participants with an HIV positive status (N=19), clinically diagnosed diabetes mellitus (N=10), anti-inflammatory medication usage (N=24), anti-coagulant medication usage (N=2), aspirin usage (N=11) and history of myocardial infarction or stroke (N=4) were excluded. After these exclusions, 165 male (76 African and 89 Caucasian) and 174 female (80 African and 94 Caucasian) participants remained. Informed consent was obtained from all the participants prior to the commencement of the study, and the study complies with the requirements of the Helsinki Convention. It received ethical approval from the Research Ethics Committee of the North-West University prior to commencement. Clinical assessments were obtained over a 48-h period. The Cardiotens CE120® (Meditech, Budapest, Hungary) and accelerometers were applied to record 24-hour ambulatory blood pressure (ABPM), 2-lead ECG as well as 24-h physical activity. The participants’ daily physical activity was monitored over 24-hours with the Actical® activity monitor. Anthropometric measurements were taken by registered level II anthropometrists according to standardized procedures. The Mosteller formula of [weight (kg) x height (cm) ÷ 3600]½ was used to calculate the body surface area. Registered nurses obtained fasting blood samples from the ante-brachial vein with a sterile winged infusion set to measure gamma-glutamyl transferase (γGT), cotinine, ultra-high-sensitivity CRP, IL-6, high sensitive TNF-α, high sensitive Trop T as well as NT-proBNP. The ABPM was measured at 30-minute intervals from 08:00 to 22:00 and at 60-minute intervals from 22:00 to 06:00. Silent ischemia (ambulatory ischemic events profile) was assessed with two-channel ECG recordings. A resting 12-lead ECG was recorded with the Norav NHH-1200® ECG which also determined ECG left ventricular hypertrophy (Cornell product, [RaVL+SV3]. x QRS duration). Values exceeding 244 mV.ms indicated LVH. Statistical analyses were performed with Statistica version 12. Independent t-tests were used to compare baseline characteristics of the two ethnic groups. Chi-square tests (X2) were used to determine prevalence as well as proportions. The a priori covariates used in all the statistical analyses were age, body surface area, log cotinine, log γ-GT and log physical activity. Single two-way interactions between main effects (ethnicity x gender) were performed for all markers (24-h BP, cardiac remodelling, inflammation, cardiac troponin, silent ischemia (ST events), independent of a priori covariates. One-way analysis of covariance (ANCOVA) was performed to compare the ethnic groups by gender adjusting for a priori covariates. Univariate and multivariate regression analyses were computed. Forward stepwise regression analyses were computed in three separate inflammatory models to avoid collinearity (TNF alpha, IL-6 and CRP). Associations were determined between dependent markers: BP, cardiac re-modelling (NT-proBNP, LVH) and independent variables (inflammation, cardiac troponin and silent ischemia, independent of a priori covariates. Pulse pressure was added as covariate when NT-proBNP and LVH were the dependent variables. Results - Africans showed higher unadjusted mean 24-h hypertension, low-grade inflammation (CRP > 3g/l), cardiac troponin and LVH values than Caucasians. Considering confounders, a similar trend emerged in African men and women in most cases, except no differences for NT-proBNP, Trop T and TNF alpha were observed between ethnic-gender groups. In forward stepwise regression analyses, no significant associations were evident in any of the 3 inflammatory models for cardiac remodeling in the women. In the men though, 24-h BP was associated (p<0.05) with Trop T in both Africans and Caucasians. In the TNF alpha and CRP models, SBP was associated with both Trop T and silent ischemia in the African men. Most significantly was the profile emerging in the systemic inflammation model (TNF alpha model) in these men. Positive associations were demonstrated between cardiac re-modelling (NT-proBNP) and a combined profile [adj R2=0.45; TNF alpha (β=0.31; 95% CI 0.14 to 0.48; p<0.001), Trop T (β=0.48; 95% CI 0.28 to 0.67; p