Effects of resistin on cardiovascular structure and function
Date
2019
Authors
Norman, Glenda
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Abstract
Beyond conventional risk factors, obesity is a well-recognised predictor of several major cardiovascular events. However, the exact mechanisms responsible for this effect are uncertain. A contemporary hypothesis explaining the adverse effects of obesity on the cardiovascular system is that through the production of several adipocytokines, obesity represents a state of low-grade inflammation. Although studies exploring relationships between most adipocytokines and events are inconsistent, more consistent relationships between circulating concentrations of resistin and several major events or their severity have been noted. However, the exact mechanisms responsible for the cardiovascular effects of resistin are uncertain. In the present thesis in a large community-based study of African ancestry, I explored relationships between resistin concentrations and several cardiovascular intermediate phenotypes known to cause events. In 739 randomly selected participants of African ancestry from a community sample (43.6% obese), I assessed relations between circulating resistin concentrations and left ventricular mass index (LVMI), LVM beyond that predicted by stroke work (inappropriate LVMI [LVMinappr]) and systolic and diastolic LV function (echocardiography). Although resistin concentrations were not independently associated with blood pressure (BP), they were associated with LVMI (p<0.0005), LVMinappr (p<0.0001) and LV hypertrophy (p<0.001) independent of BP, body mass index (BMI), the homeostasis model of insulin resistance (HOMA-IR) and additional confounders including C-reactive protein (CRP). Resistin concentration (p<0.002 in all and p<0.0005 in untreated) was the only factor independently associated with LV midwall fractional shortening and these relations were enhanced at incremental concentrations of CRP, Thus, resistin in-part explains variations in LVM, hypertrophy and myocardial systolic dysfunction, and these effects are independent of insulin resistance and general inflammatory changes. In 683 randomly selected participants of African ancestry from SOWETO, South Africa whom had never received antihypertensive therapy I determined independent relations between circulating resistin concentrations and aortic pulse wave velocity (PWV) and wave reflection. Resistin concentrations were not independently associated with office or 24-hour (n=492) BP. In a stepwise regression model with BMI included in the model, age (p<0.0001), mean arterial pressure (p<0.0001), plasma resistin concentrations (p<0.005), female gender (p=0.01) and creatinine concentrations (p<0.01) contributed independently to variations in PWV. Independent relations between resistin concentrations and PWV persisted with further adjustments for CRP (p<0.005), and HOMA-IR (p<0.02). Thus, resistin is independently associated with aortic stiffness and these effects occur beyond BP, insulin resistance and general inflammation.
In a cross-sectional community-based study in 1010 randomly selected participants of African ancestry I determined the extent to which obesity-associated metabolic and inflammatory changes are associated with renal damage and chronic kidney disease (CKD) as compared to modifiable conventional risk factors. In multivariate regression models with adjustments for conventional risk factors (including HbA1c, office BP or any adiposity index) and additional confounders, HOMA-IR (standardized β-coefficient [β-coeff]=-0.13±0.02, <0.0001) and plasma resistin concentrations (β-coeff=-0.13±0.02, <0.0001) were second only to age and equivalent to systolic BP (β-coeff=-0.09±0.03, <0.005) in the impact on eGFR, whilst alternative conventional risk factors, including BMI contributed little to eGFR. Similar results were obtained in relations with CKD. CRP was not independently associated with eGFR. Neither 24-hour BP, aortic BP, nor PWV, modified the relative contribution of HOMA-IR and resistin concentrations versus alternative parameters to eGFR. Thus, at a community level the combined impact of obesity-associated metabolic and inflammatory changes on glomerular filtration rate and CKD is greater than that of modifiable conventional risk factors. Targeting conventional risk factors alone is therefore likely to result in a marked residual impact on the development of CKD in communities with a high prevalence obesity. In 739 randomly selected participants of African ancestry from a community sample I assessed the extent to which relationships between circulating resistin concentrations and LVM are explained by the adverse effects of resistin on aortic stiffness (ventriculo-vascular coupling) and renal function (cardio-renal syndrome). Independent of confounders, LVMI, LVMinappr and LVH were independently associated with PWV and eGFR. However, adjustments for either PWV or eGFR failed to modify relations between resistin concentrations and LVMI, LVMinappr or LVH. Moreover, in product of coefficient mediation analysis, neither eGFR nor PWV explained a significant proportion of the relationship between resistin and LV structural alterations. Thus, relationships between circulating concentrations of resistin and LVM are not explained by the impact of resistin on ventricular-vascular coupling or the cardio-renal syndrome. Resistin’s effect on LVMI are therefore likely to be through direct actions on the myocardium. In conclusion, in the present thesis I show that elevated circulating concentrations of the adipocytokine resistin, but not CRP are associated with LV hypertrophy and systolic dysfunction, aortic stiffness and glomerular dysfunction beyond conventional risk factors including adiposity indices and BP (office, aortic and ambulatory). Importantly, these effects were similarly independent of insulin resistance as indexed by the homeostasis model and relationships between resistin concentrations and eGFR could not be explained by increases in aortic stiffness and between resistin concentrations and LV hypertrophy could not be explained by the cardio-renal syndrome or ventriculo-vascular coupling. Thus, the present thesis suggests that resistin, possibly through direct effects on several organ systems, may contribute to
cardiovascular events through an impact on LV hypertrophy and dysfunction, increases in aortic stiffness and reductions in glomerular filtration
Description
A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, for the degree of Doctor of Philosophy
Johannesburg, South Africa
2019