Exploring leptin from endothelial activation to subclinical organ damage in young black and white adults: the African-PREDICT study
Motivation: Cardiovascular diseases (CVDs) are the most predominant non-communicable diseases worldwide. The most prominent risk factor that is accountable for the development of CVD, namely hypertension, is drastically increasing particularly in sub-Saharan Africa. Recently, obesity emerged as the single most essential risk factor for the development of hypertension and other related metabolic disorders. The mechanisms by which obesity may lead to hypertension development is not yet fully established. Epidemiological studies suggest leptin as a crucial factor underpinning obesity-associated hypertension and cardiovascular disorders primarily in older, obese and diseased individuals. To increase our understanding of the earlier phases of hypertension and CVD development, we, therefore, investigated what role leptin is already playing in healthy young adults who are at risk of hypertension development. Aim The central aim of this study was to determine the relationships that exist between measures of autonomic activity, endothelial activation, blood pressure, large arterial structure and function, as well as the retinal microvasculature with leptin in young black and white adults. Method This present cross-sectional study is a part of the African Prospective study on the Early Detection and Identification of Cardiovascular disease and Hypertension (African-PREDICT study). All the available baseline data of the first 820 participants in the African-PREDICT study were used in this present Ph.D. study. The study participants comprised of both white (n= 389) and black (n= 431) young healthy men and women between the age bracket 20-30 years. Participation in the study was voluntary, and the participants signed consent forms before conducting any measurements. Standard procedures and methods were used to capture all data and included questionnaire data (standard general health and demographic questionnaire), body composition and accelerometry assessments (anthropometric, bioelectrical impedance and accelerometry assessments) and cardiovascular measurements (measures of autonomic function, blood pressure, micro- and macro vascular functions), as well as biochemical analyses of all relevant biomarkers used in the study. For statistical analyses, variables that were not normally distributed were log transformed, means and proportions were compared using either independent t-tests, Chi-square tests or analysis of variance or covariance. Single, partial and multiple regression analyses were used to investigate associations between main variables of interest (independent variable: serum leptin and dependent variables: measures of autonomic function, endothelial cell activation and function, blood pressure, large artery structure and function as well as retinal microvasculature). In either the partial or multiple regression analysis, confounders were adjusted for. In all cases, p≤0.05 was used to indicate statistical significance. Results and conclusion of each manuscript Article 1: We investigated the associations between measures of autonomic function (24-hour heart rates and heart rate variability measures), endothelial cell activation (intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1)) and blood pressure (24-hour blood pressure measures) with leptin, in a young black and white population. Our results showed an independent and a consistent association between markers of autonomic activity (such as 24-hour heart rate, day and night-time heart rate as well as heart rate variability total power) and leptin in both white (all p≤0.001) and black men (all p≤0.040). These particular associations were either not found or less prominent in women, despite their almost ten-fold higher leptin levels than men. An independent association was observed between 24-hour diastolic blood pressure with leptin (Std β = 0.37; p=0.006) only in white men. No independent association was observed between leptin and indicators of endothelial cell activation, irrespective of ethnicity or sex. This study, therefore, suggests the potential role that leptin might play in future blood pressure elevation especially in men. Article 2: We explored the relationships that existed between leptin and large artery structure and function and a marker of endothelial dysfunction, namely von Willebrand (vWF) factor in young healthy men and women of the African-PREDICT study. The results from this cross-sectional association showed that in healthy young men, leptin was independently and negatively associated with carotid intima-media thickening (CIMT) (R2=0.05; β=-0.20; p=0.036) and cross-sectional wall area (CSWA) (R2=0.05; β=-0.20; p=0.035) in a multivariable-adjusted regression analysis. The association was confirmed in only the overweight healthy men after dividing the participants into the various body mass index categories (CIMT: R2=0.15; β=-0.41; p=0.007; CSWA: R2=0.21;β =-0.47; p=0.002). No association was observed in women or between pulse wave velocity and vWF with leptin in any group. This study suggests the potential vascular protective role of leptin in the macrovasculature especially in healthy young men without any overt CVD. Article 3: This article examined whether measurements of the retinal microvasculature are associated with leptin in healthy young black and white men and women. Black men had lower body weight and lower leptin than white men, whereas black women had increased adiposity and leptin compared to white women (all p<0.001). Black individuals had narrower artery, and greater maximum arteriolar and venular dilations in response to light flicker than the white groups (p<0.001). In all groups except black women, arterio-venous ratio was inversely associated with leptin (all p≤0.044), but the association was lost upon adjustment for body mass index and other covariates. We also observed a negative relation between maximal venular dilation and leptin only in black men in single and multiple regression analyses (Std β=-0.22; R2= 0.05; p=0.035). Lastly, no associations were found between other retinal measures with leptin in the other groups. The study suggests the potential detrimental role of leptin in microvasculature of black men who also have been reported to be at a greater risk of CVD development. General conclusion: Despite the higher leptin levels in women than in men, leptin showed an independent association with more measures of cardiovascular function in men than women by showing a consistent association with more markers of autonomic activity in all men, and blood pressure only in white men. Leptin also showed an independent and negative association with measures of subclinical atherosclerosis in all men. However, in the young black men, leptin associated negatively with retinal venular dilation in response to external stimulus. This study, therefore, highlights the potentially beneficial and detrimental associations of leptin with cardiovascular estimates in healthy young adults, particularly men. Our findings suggest that leptin-induced cardiovascular action in young adults are influenced by sex, ethnicity and the different vascular bed.
- Health Sciences